Biomarkers of Exposure and Biomarkers of Potential Harm in Adult Smokers Who Completely Switch to E-vapor Products

An Open-Label, Parallel-Group, Controlled Study to Evaluate Changes in Biomarkers of Cigarette Smoke Exposure and Biomarkers of Potential Harm in Adult Smokers Who Completely Switch to Using e-Vapor Products for 24 Weeks

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04800211

Enrollment

450

Registered

2021-03-16

Start date

2017-01-17

Completion date

2018-11-06

Last updated

2025-03-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Tobacco Use

Brief summary

The purpose of this study was to estimate changes in biomarkers of exposure (BoE) and biomarkers of potential harm (BoPH) in adult cigarette smokers (AS) who switched to using an e-vapor product (EVP) relative to adult smokers who continue smoking exclusively.

Detailed description

This study was conducted as a randomized, parallel-group, open-label, 24-week, controlled clinical study split into an initial 12-week study (Study 1), with a follow-up at 24 weeks (Study 2) in a sub-population of switchers. For Study 1 a total of 450 subjects were enrolled. Of those subjects who successfully completed Study 1, 150 were then enrolled into Study 2 with no interruption in study participation. The study compared changes in BoE and BoPH in AS who switched to ad libitum use of one of two test EVPs with those in the Control group who continued to smoke conventional cigarettes. The study enrolled AS who were considered to be in overall good health.

Interventions

OTHERExperimental: Test Product 1

Subjects were instructed to completely replace their cigarettes with the Test Product 1 EVP (Nu Mark LLC, MarkTen® XL Bold CLASSIC)

OTHERExperimental: Test Product 2

Subjects were instructed to completely replace their cigarettes with the Test Product 2 EVP (Nu Mark LLC, MarkTen® XL Bold MENTHOL)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

NONE

Intervention model description

This research study utilized a parallel-group, open-label, controlled design and was conducted at multiple study sites.

Eligibility

Sex/Gender

ALL

Age

30 Years to 65 Years

Healthy volunteers

Yes

Inclusion criteria

Study 1 Subjects must satisfy the following criteria before being enrolled into the study. Subjects must: 1. sign an IRB-approved informed consent form (ICF) for the study; 2. be between the ages of 30 and 65 years, inclusive, at the time of Screening, Visit 1; 3. have \> 500 ng/ml urine cotinine measurement at Screening, Visit 1; 4. have smoked for ≥ 10 years and smoked an average of ≥ 10 manufactured cigarettes per day during the 12 months prior to Screening, Visit 1; a) Brief periods \[i.e., up to 7 consecutive days\] of non smoking during the 12 months prior to Screening, Visit 1 due to illness, trying to quit, or participation in a study where smoking was prohibited are acceptable. 5. indicate that he/she is definitely or probably willing and able to replace their cigarettes for 12 weeks with the assigned test e-Vapor product; 6. have daily access to text messaging capable cellular phone for daily product use reporting; 7. have a negative ethanol breath test and amphetamines, opiates, cannabinoids, and cocaine urine drug screen results at Screening, Visit 1; a) Subjects with a prescription from a licensed physician will not be exempted from this criterion. 8. if female (all females), have a negative serum pregnancy test at Visit 1 and negative urine pregnancy test at Visit 2 through Visit 7, inclusive; 9. if female, heterosexually active, and of childbearing potential (i.e., not surgically sterile or 2 years naturally postmenopausal), must have used a medically accepted method of contraception (listed below in a) and b)) prior to Screening, Visit 1 and must agree to continue to use such method(s) through the End of Study; 1. Surgically sterile includes bilateral tubal ligation, Essure, hysterectomy, or bilateral oophorectomy at least 6 months prior to Screening, Visit 1. Naturally postmenopausal is defined as women having 2 years without menses. 2. Acceptable methods of contraception are: hormonal (i.e., oral, transdermal patch, implant, or injection) consistently for at least 3 months prior to Screening, Visit 1; double barrier (i.e., condom with spermicide or diaphragm with spermicide) consistently for at least 4 weeks prior to Screening, Visit 1; and intrauterine device for at least 3 months prior to Screening, Visit 1; or only have a partner who has been vasectomized for at least 6 months prior to Screening, Visit 1. 10. Be willing and able to comply with the requirements of the study. Study 2 Subjects must satisfy the following criteria before being enrolled into the study. Subject must: 1. have participated in and completed the 12-week ALCS-RA-16-06-EV study and have Baseline biomarker samples collected; 2. demonstrate willingness to participate by signing an Institutional Review Board (IRB)-approved ICF for the study; 3. have demonstrated consistent daily reporting of product use in the 12-week ALCS-RA-16-06-EV (≥ 80% reporting compliance); 4. if randomized to a Test group, have reported an average of no more than 10% of Baseline cigarette smoking per day through Week 11 of the 12-week ALCS-RA-16-06-EV study; 5. if randomized to a Test group, have reported use of at least two Test product cartridges per week in the 12-week ALCS-RA-16-06-EV study; 6. if randomized to a Test group, have exhaled carbon monoxide (eCO) measurements of ≤ 8 ppm at each post-Baseline time point in the 12-week ALCS-RA-16-06-EV study; 7. have daily access to text messaging capable cellular phone for daily product use reporting; 8. if female (all females), have a negative urine pregnancy test at Week 12 (Visit 1) through Week 24 (Visit 5), inclusive; 9. if female, heterosexually active, and of childbearing potential (i.e., not surgically sterile or 2 years naturally postmenopausal), must have used a medically accepted method of contraception (listed below in a) and b)) prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study and must agree to continue to use such method(s) through Week 24 (EOS); 1. Surgically sterile includes bilateral tubal ligation, Essure, hysterectomy, or bilateral oophorectomy at least 6 months prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study. Naturally postmenopausal is defined as women having 2 years without menses. 2. Acceptable methods of contraception are: hormonal (i.e., oral, transdermal patch, implant, or injection) consistently for at least 3 months prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; double barrier (i.e., condom with spermicide or diaphragm with spermicide) consistently for at least 4 weeks prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; and intrauterine device for at least 3 months prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; or only have a partner who has been vasectomized for at least 6 months prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study. 10. Be willing and able to comply with the requirements of the study.

Exclusion criteria

Study 1 Subjects may be excluded from the study if there is evidence of any of the following criteria. Exceptions may be permitted at the discretion of the Investigator and in consultation with the Sponsor or designee provided there would be no additional risk to the subject. Any exceptions will be documented. 1. History or presence of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, urologic, diabetes, existing respiratory diseases, immunologic, psychiatric, or cardiovascular disease, or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or impact the validity of the study results. (Note: chronic medical conditions controlled and on stable medications \[over past 3 months\] may not necessarily be exclusionary per Investigator discretion); 2. Currently taking medication for depression, asthma or diabetes; 3. Allergy to menthol; 4. Systolic blood pressure \> 140 mmHg and / or diastolic blood pressure \> 90 mmHg at Screening Visit 1. 5. Have clinically significant abnormal findings on the physical examination, vital signs, electrocardiogram (ECG), or medical history that would jeopardize the safety of the subject, in the opinion of the Investigator; 6. Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV) at Screening, Visit 1; 7. Current evidence or any history of congestive heart failure; 8. Any acute illness (e.g., upper respiratory infection, viral infection) requiring treatment within 2 weeks before Visit 3 (Day 1); 9. History of drug or alcohol abuse within 24 months of Visit 3 (Day 1) as defined by the Investigator; 10. BMI greater than 40.0 kg/m2 or less than 18.0 kg/m2 at Screening, Visit 1; 11. Post-bronchodilator Forced expiratory volume at one second (FEV1):Forced vital capacity (FVC) ratio \< 0.7 and FEV1 \< 50% of predicted at Screening, Visit 2; 12. Post-bronchodilator FEV1:FVC ratio \< 0.75 and FEV1 increase ≥ 12% and \> 200 mL from pre- to post-bronchodilator at Screening, Visit 2; 13. Estimated creatinine clearance (by Cockcroft-Gault equation) \< 80 mL/min at Screening, Visit 1; 14. Serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \> 1.5 times the upper limit of the reference range at Screening, Visit 1; 15. Female candidates who are pregnant, lactating, or intend to become pregnant from Screening, Visit 1 through End of Study; 16. Use of HDL-C raising medication / supplements (e.g., niacin, gemfibrizole, fenofibrate, etc.) within the past 3 months prior to Screening, Visit 1 or any time during the study; 17. Use of nicotine-containing products other than manufactured cigarettes (e.g., roll-your-own cigarettes, e-cigarette or e-Vapor products, Bidis, snuff, nicotine inhaler, pipe, cigar, smokeless tobacco, nicotine patch, nicotine spray, nicotine lozenge, or nicotine gum) within 14 days prior to Screening, Visit 1 through Visit 3 (Day 1) except as required for the purpose of this study; 18. Donation of blood or blood products, including plasma, history of significant blood loss in the opinion of the investigator, or receipt of whole blood or a blood product transfusion within 60 days prior to Visit 3 (Day 1); 19. Participation in a clinical study of an investigational drug, medical device, biologic, or of a tobacco product, within 30 days before Visit 3 (Day 1); 20. Participation in more than two ALCS studies within 12 months before Visit 3 (Day 1); 21. Already enrolled or failed screening for the current study at a different study site; 22. Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current or former employee of the tobacco industry or a named party or class representative in litigation with any tobacco company. Study 2 Subjects may be excluded from the study if there is evidence of any of the following. Exceptions may be permitted at the discretion of the Investigator and in consultation with the Sponsor or designee provided there would be no additional risk to the subject. Any exceptions will be documented. 1. Have clinically significant abnormal findings on the physical examination, vital signs, or ECG at the EOS visit (Visit 7) of the 12-week ALCS-RA-16-06-EV study that would jeopardize the safety of the subject, in the opinion of the Investigator; 2. Female subjects who are pregnant (as determined at the EOS visit \[Visit 7\] of the 12-week study), lactating, or intend to become pregnant from Visit 1 (Week 12) through Week 24 (EOS); 3. Use of any medication for depression, asthma, or diabetes at any time during the study; 4. Use of HDL-C raising medication / supplements (e.g., niacin, gemfibrozil, fenofibrate, etc.) at any time during the study; 5. Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current or former employee of the tobacco industry or a named party or class representative in litigation with any tobacco company; 6. Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current or former employee of Celerion or any of the clinical study sites.

Design outcomes

Primary

Measure	Time frame	Description
Summary of Whole Blood COHB Absolute Change From Baseline (% Saturation) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization	Summary of whole blood COHB absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3 and 7 and analyzed for the biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3
Summary of Whole Blood WBC Absolute Change From Baseline (10^3 Cells/uL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization	Summary of whole blood WBC absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3 and 7 and analyzed for the biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3
Summary of Serum HDL-C Absolute Change From Baseline (mg/dL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization	Summary of serum HDL-C absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3 and 7 and analyzed for the biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3
Summary of Urine 8-epi-prostaglandin F2alpha Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization	Summary of urine 8-epi-prostaglandin F2alpha absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). The first urine void of the day on Visits 3 and 7 was analyzed for the urine biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3
Summary of Urine 11-dehydrothromboxane B2 Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization	Summary of urine 11-dehydrothromboxane B2 absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). The first urine void of the day on Visits 3 and 7 was analyzed for the urine biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3
Summary of Plasma sICAM-1 Absolute Change From Baseline (ng/mL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization	Summary of plasma sICAM-1 absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3 and 7 and analyzed for the biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3
Summary of Urine Total NNAL Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization	Summary of urine total NNAL absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). The first urine void of the day on Visits 3 and 7 was analyzed for the urine biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3
Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12	Summary of urine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) (ng/g) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3 The first urine void of the day was collected at Visits 3, 5 and 7. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration values as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value
Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]	Summary of Urine Total NNAL (ng/g) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). The first urine void of the day was collected at Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study
Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12	Summary of whole blood carboxyhemoglobin (COHb) (% Saturation) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3, 5, and 7. Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3
Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]	Summary of Whole Blood COHb (% Saturation) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). Blood samples were collected via direct venipuncture on Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study
Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12	Summary of whole blood white blood cell (WBC) count (10\^3 cells/uL) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3, 5, and 7. Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3
Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]	Summary of Whole Blood WBC Count (10\^3 cells/uL) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). Blood samples were collected via direct venipuncture on Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study
Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12	Summary of serum high density lipoprotein cholesterol (HDL-C) (mg/dL) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3, 5, and 7. Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3
Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]	Summary of serum HDL-C (mg/dL) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). Blood samples were collected via direct venipuncture on Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study
Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12	Summary of urine 8-epi-prostaglandin F2alpha (ng/g) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3 The first urine void of the day was collected at Visits 3, 5 and 7. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration values as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value
Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]	Summary of urine 8-epi-prostaglandin F2alpha (ng/g) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). The first urine void of the day was collected at Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study
Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12	Summary of urine 11-dehydrothromboxane B2 (ng/g) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3 The first urine void of the day was collected at Visits 3, 5 and 7. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration values as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value
Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]	Summary of urine 11-dehydrothromboxane B2 (ng/g) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). The first urine void of the day was collected at Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study
Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12	Summary of plasma soluble Intercellular Adhesion Molecule-1 (sICAM-1) (ng/mL) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3, 5, and 7. Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3
Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]	Summary of plasma sICAM-1 (ng/mL) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). Blood samples were collected via direct venipuncture on Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study

Secondary

Measure	Time frame	Description
Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Weeks 12 (Study ALCS-RA-16-06-EV) and Week 24 (Study ALCS-RA-17-11-EV) from randomization	Participant compliance for the abstention of any type of tobacco/nicotine product for the duration of the study was assessed by measuring the participant's exhaled carbon monoxide (eCO, ppm). According to their eCO measurements at Weeks 12 (study ALCS-RA-16-06-EV) and Week 24 (study ALCS-RA-17-11-EV), participants were categorized into 1 of 3 categories: 'eCO ≤ 5', 'eCO \< 5 - ≤ 8', or 'eCO \> 8'. Lower eCO values represent lower smoking exposure and increased compliance, with the 'eCO ≤ 5' category indicating that the participant abstained from smoking, the 'eCO \< 5 - ≤ 8' category indicating low smoking exposure to the participant, and the 'eCO \> 8' category indicating non-compliance with the study criteria that the participant refrain from smoking during the study.
Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Assessments at Screening (Day -28 to Day -5) and Week 12 (Day 84 +/- 3 )	Percentage of predicted forced expiratory volume in the first second (FEV1) and absolute change from Baseline to Week 12 by Study Group is presented (Study ALCS-RA-16-06-EV). Baseline / Screening = Day -28 to Day -5 Visit 7 (Week 12) = Day 84 ± 3 Absolute change from baseline = Post Product Use Value - Baseline Value FEV1 = Forced Expiratory Volume in 1 Second
Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Assessments at Screening (Day -28 to Day -5) and Week 12 (Day 84 +/- 3 )	Percentage of predicted forced vital capacity (FVC) and absolute change from Baseline to Week 12 by Study Group is presented (Study ALCS-RA-16-06-EV). Baseline / Screening = Day -28 to Day -5 Visit 7 (Week 12) = Day 84 ± 3 Absolute change from baseline = Post Product Use Value - Baseline Value FVC = Forced Vital Capacity
Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Assessments at Screening (Day -28 to Day -5) and Week 12 (Day 84 +/- 3 )	Percentage of predicted FEV1/FVC and absolute change from Baseline to Week 12 by Study Group is presented (Study ALCS-RA-16-06-EV). Baseline / Screening = Day -28 to Day -5 Visit 7 (Week 12) = Day 84 ± 3 Absolute change from baseline = Post Product Use Value - Baseline Value FEV1 = Forced Expiratory Volume in 1 Second, FVC = Forced Vital Capacity.

Other

Measure	Time frame	Description
Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]	Summary of urine nicotine equivalents (mg/g Cr) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). The first urine void of the day was collected at Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Nicotine equivalents (μg/mL) = (nicotine \[ng/mL\]/162.23 \[mg/mmol\] + nicotinegluc (ng/mL)/338.36 \[mg/mmol\] + cotinine \[ng/mL\]/176.22 \[mg/mmol\] + cotininegluc \[ng/mL\]/352.34 \[mg/mmol\] + trans-3'-hydroxycotinine \[ng/mL\]/192.22 \[mg/mmol\] + trans-3'-hydroxycotinine-gluc \[ng/mL\]/368.34 \[mg/mmol\]) x 162.23 (mg/mmol) x 1 μg/1000 ng Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Val
Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12	Summary of urine Nicotine Equivalents (mg/g) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). The first urine void of the day was collected at Visits 3, 5 and 7. Nicotine equivalents (μg/mL) = (nicotine \[ng/mL\]/162.23 \[mg/mmol\] + nicotinegluc (ng/mL)/338.36 \[mg/mmol\] + cotinine \[ng/mL\]/176.22 \[mg/mmol\] + cotininegluc \[ng/mL\]/352.34 \[mg/mmol\] + trans-3'-hydroxycotinine \[ng/mL\]/192.22 \[mg/mmol\] + trans-3'-hydroxycotinine-gluc \[ng/mL\]/368.34 \[mg/mmol\]) x 162.23 (mg/mmol) x 1 μg/1000 ng Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3

Countries

United States

Participant flow

Pre-assignment details

After screening, subjects who met all eligibility criteria were randomized to one of the study groups. Eligible subjects who completed ALCS-RA-16-06-EV were entered into the ALCS-RA-17-11-EV 12-week extension study and assigned to the same study groups as the ALCS-RA-16-06-EV study.

Participants by arm

Arm	Count
Test 1 Exclusive ad libitum use of test e-Vapor Product NuMark LLC, MarkTen® XL Bold CLASSIC\* without use of any other type of tobacco/nicotine containing product, for the entire duration of study participation. \*Product no longer sold commercially Experimental: Test Product 1: Subjects were instructed to completely replace their cigarettes with the Test Product 1 EVP (Nu Mark LLC, MarkTen® XL Bold CLASSIC)	151
Test 2 Exclusive ad libitum use of test e-Vapor Product Nu Mark LLC, MarkTen® XL Bold MENTHOL\* without use of any other type of tobacco/nicotine containing product, for the entire duration of study participation. \*Product no longer sold commercially Experimental: Test Product 2: Subjects were instructed to completely replace their cigarettes with the Test Product 2 EVP (Nu Mark LLC, MarkTen® XL Bold MENTHOL)	150
Control Continue smoking under ad libitum use of subjects' own brand of conventional lit-end cigarettes, without use of any other type of tobacco/nicotine containing product, for the entire duration of study participation.	149
Total	450

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
ALCS-RA-16-06-EV (Weeks 1-12)	Adverse Event	4	1	0
ALCS-RA-16-06-EV (Weeks 1-12)	Failure To Meet Ie Post Enrollment	1	0	0
ALCS-RA-16-06-EV (Weeks 1-12)	Lost to Follow-up	8	8	2
ALCS-RA-16-06-EV (Weeks 1-12)	Non-Compliance With Study Procedures	8	7	2
ALCS-RA-16-06-EV (Weeks 1-12)	Other	1	2	2
ALCS-RA-16-06-EV (Weeks 1-12)	Physician Decision	0	0	1
ALCS-RA-16-06-EV (Weeks 1-12)	Pregnancy	0	0	1
ALCS-RA-16-06-EV (Weeks 1-12)	Withdrawal by Subject	8	7	5
ALCS-RA-17-11-EV (Weeks 12-24)	Non-Compliance With Study Procedures	0	0	1
ALCS-RA-17-11-EV (Weeks 12-24)	Other	0	0	2
ALCS-RA-17-11-EV (Weeks 12-24)	Withdrawal by Subject	1	0	0

Baseline characteristics

Characteristic	Test 2	Total	Test 1	Control
Age, Continuous	44.1 years STANDARD_DEVIATION 9.26	44.1 years STANDARD_DEVIATION 9.24	43.9 years STANDARD_DEVIATION 8.45	44.4 years STANDARD_DEVIATION 10.1
Annual Income $100,000 - $149,999	4 Participants	14 Participants	4 Participants	6 Participants
Annual Income $150,000 AND OVER	0 Participants	5 Participants	1 Participants	4 Participants
Annual Income $20,000 - $29,999	25 Participants	89 Participants	39 Participants	25 Participants
Annual Income $30,000 - $39,999	20 Participants	66 Participants	25 Participants	21 Participants
Annual Income $40,000 - $49,999	11 Participants	33 Participants	10 Participants	12 Participants
Annual Income $50,000 - $59,999	8 Participants	27 Participants	7 Participants	12 Participants
Annual Income $60,000 - $74,999	8 Participants	18 Participants	5 Participants	5 Participants
Annual Income $75,000 - $99,000	10 Participants	29 Participants	10 Participants	9 Participants
Annual Income I DO NOT WISH TO ANSWER	17 Participants	40 Participants	13 Participants	10 Participants
Annual Income UNDER $20,000	47 Participants	129 Participants	37 Participants	45 Participants
Body Mass Index	27.915 (kg/m²) STANDARD_DEVIATION 5.1466	27.820 (kg/m²) STANDARD_DEVIATION 5.0753	27.810 (kg/m²) STANDARD_DEVIATION 5.1312	27.733 (kg/m²) STANDARD_DEVIATION 4.9777
Daily Cigarette Use	17.0 Cigarettes per day STANDARD_DEVIATION 5.23	17.5 Cigarettes per day STANDARD_DEVIATION 5.59	18.2 Cigarettes per day STANDARD_DEVIATION 5.71	17.4 Cigarettes per day STANDARD_DEVIATION 5.79
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants	20 Participants	8 Participants	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	142 Participants	430 Participants	143 Participants	145 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Height	171.40 cm STANDARD_DEVIATION 9.682	171.31 cm STANDARD_DEVIATION 9.56	171.51 cm STANDARD_DEVIATION 9.402	171.00 cm STANDARD_DEVIATION 9.651
Highest Degree COLLEGE 1 YEAR TO 3 YEARS (SOME COLLEGE	56 Participants	191 Participants	69 Participants	66 Participants
Highest Degree COLLEGE 4 YEARS OR MORE (COLLEGE GRADUATE	24 Participants	55 Participants	12 Participants	19 Participants
Highest Degree GRADE 12 OR GED (HIGH SCHOOL GRADUATE)	55 Participants	166 Participants	61 Participants	50 Participants
Highest Degree GRADES 1 THROUGH 8 (ELEMENTARY)	1 Participants	2 Participants	1 Participants	0 Participants
Highest Degree GRADES 9 THROUGH 11 (SOME HIGH SCHOOL)	9 Participants	19 Participants	4 Participants	6 Participants
Highest Degree I DO NOT WISH TO ANSWER	1 Participants	2 Participants	0 Participants	1 Participants
Highest Degree OTHER	0 Participants	1 Participants	1 Participants	0 Participants
Highest Degree POSTGRADUATE/MASTERS/DOCTORATE/LAW/MD	4 Participants	14 Participants	3 Participants	7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	2 Participants	2 Participants	0 Participants
Race (NIH/OMB) Asian	2 Participants	6 Participants	0 Participants	4 Participants
Race (NIH/OMB) Black or African American	37 Participants	119 Participants	44 Participants	38 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	3 Participants	2 Participants	1 Participants
Race (NIH/OMB) White	111 Participants	320 Participants	103 Participants	106 Participants
Sex: Female, Male Female	75 Participants	222 Participants	74 Participants	73 Participants
Sex: Female, Male Male	75 Participants	228 Participants	77 Participants	76 Participants
Weight	82.2 kilograms STANDARD_DEVIATION 17.63	81.8 kilograms STANDARD_DEVIATION 16.98	82.0 kilograms STANDARD_DEVIATION 17.43	81.1 kilograms STANDARD_DEVIATION 15.9
Years Smoked	25.0 years STANDARD_DEVIATION 9.48	24.5 years STANDARD_DEVIATION 9.2	24.1 years STANDARD_DEVIATION 8.32	24.5 years STANDARD_DEVIATION 9.78

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk
deaths Total, all-cause mortality	0 / 151	0 / 150	0 / 149	0 / 450	0 / 48	0 / 50	0 / 52	0 / 150
other Total, other adverse events	49 / 151	47 / 150	24 / 149	120 / 450	13 / 48	15 / 50	10 / 52	38 / 150
serious Total, serious adverse events	1 / 151	1 / 150	1 / 149	3 / 450	0 / 48	0 / 50	0 / 52	0 / 150

Outcome results

Primary

Summary of Plasma sICAM-1 Absolute Change From Baseline (ng/mL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of plasma sICAM-1 absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3 and 7 and analyzed for the biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3

Time frame: Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization

Population: Modified ITT Population with Outliers Excluded: All subjects were randomized according to the randomization schedule; who used at least one study products after randomization was recorded and for whom there was a valid (within ±3 days of the planned measurement day) baseline and at least one post-baseline biomarker. Data outliers, defined as any observation with a studentized residual that is greater than +/- 4, were excluded from the analysis.

Arm	Measure	Value (MEAN)	Dispersion
Test 1	Summary of Plasma sICAM-1 Absolute Change From Baseline (ng/mL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-23.71 ng/mL	Standard Deviation 52.739
Test 2	Summary of Plasma sICAM-1 Absolute Change From Baseline (ng/mL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-26.02 ng/mL	Standard Deviation 46.433
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 Absolute Change From Baseline (ng/mL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-7.056 ng/mL	Standard Deviation 37.619

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.000395% CI: [-32.447, -7.573]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-34.837, -10.295]Mixed Models Analysis

Primary

Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of plasma soluble Intercellular Adhesion Molecule-1 (sICAM-1) (ng/mL) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3, 5, and 7. Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3

Time frame: 12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12

Population: Modified ITT: All subjects were randomized according to the randomization schedule; who used at least one study products after randomization was recorded and for whom there was a valid (within ±3 days of the planned measurement day) baseline and at least one post-baseline biomarker.

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	230.4 ng/mL	Standard Deviation 76.704
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-31.96 ng/mL	Standard Deviation 50.532
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	204.1 ng/mL	Standard Deviation 58.502
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-23.71 ng/mL	Standard Deviation 52.739
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	198.5 ng/mL	Standard Deviation 54.783
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-25.34 ng/mL	Standard Deviation 46.825
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	222.8 ng/mL	Standard Deviation 77.888
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	199.8 ng/mL	Standard Deviation 65.911
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	197.7 ng/mL	Standard Deviation 71.517
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-22.43 ng/mL	Standard Deviation 47.51
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	199.2 ng/mL	Standard Deviation 60.529
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-24.56 ng/mL	Standard Deviation 49.652
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	226.6 ng/mL	Standard Deviation 77.25
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-27.16 ng/mL	Standard Deviation 49.166
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	200.8 ng/mL	Standard Deviation 65.523
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	230.6 ng/mL	Standard Deviation 77.084
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	224.3 ng/mL	Standard Deviation 70.515
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-6.613 ng/mL	Standard Deviation 39.668
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-7.056 ng/mL	Standard Deviation 37.619
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	224.6 ng/mL	Standard Deviation 64.515

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-39.375, -26.208]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-33.398, -18.443]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-31.99, -18.979]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-34.135, -19.663]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 + Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 + Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-31.716, -21.103]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Control is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Control is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.02895% CI: [-13.278, -0.763]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Control is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Control is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.097295% CI: [-12.881, 1.077]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-37.189, -14.353]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.000295% CI: [-29.825, -7.101]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.000295% CI: [-33.619, -8.375]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 + Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 + Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-29.061, -11.955]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is equal to Test 2 on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to Test 2 on Visit 7 (Week 12). (mITT Population)p-value: 0.850495% CI: [-9.216, 11.172]Mixed Models Analysis

Primary

Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of plasma sICAM-1 (ng/mL) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). Blood samples were collected via direct venipuncture on Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study

Time frame: 24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	187.9 ng/mL	Standard Deviation 52.027
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-26.73 ng/mL	Standard Deviation 53.383
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	184.4 ng/mL	Standard Deviation 55.223
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	184.0 ng/mL	Standard Deviation 48.515
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-22.54 ng/mL	Standard Deviation 45.013
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	206.6 ng/mL	Standard Deviation 60.303
Test 1	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-25.36 ng/mL	Standard Deviation 56.8
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	205.0 ng/mL	Standard Deviation 57.117
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	176.7 ng/mL	Standard Deviation 41.375
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-23.27 ng/mL	Standard Deviation 57.191
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-21.06 ng/mL	Standard Deviation 67.737
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	182.2 ng/mL	Standard Deviation 50.009
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	184.7 ng/mL	Standard Deviation 62.726
Test 2	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-28.33 ng/mL	Standard Deviation 49.987
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-23.09 ng/mL	Standard Deviation 62.5
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	180.2 ng/mL	Standard Deviation 44.893
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	184.8 ng/mL	Standard Deviation 50.712
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-24.82 ng/mL	Standard Deviation 55.227
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-25.52 ng/mL	Standard Deviation 47.484
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	184.6 ng/mL	Standard Deviation 58.971
Test 1 + Test 2 Group	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	205.8 ng/mL	Standard Deviation 58.381
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	1.702 ng/mL	Standard Deviation 47.092
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	2.091 ng/mL	Standard Deviation 47.116
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	244.3 ng/mL	Standard Deviation 78.272
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-11.80 ng/mL	Standard Deviation 36.195
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	229.5 ng/mL	Standard Deviation 69.888
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	244.9 ng/mL	Standard Deviation 85.893
Control	Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	241.3 ng/mL	Standard Deviation 81.966

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 1 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-41.957, -20.557]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 1 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-44.234, -15.491]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 1 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-46.971, -16.053]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 2 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-47.522, -26.872]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 2 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-44.96, -17.923]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.000295% CI: [-43.34, -13.853]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 1 + Test 2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 + Test 2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-40.943, -19.166]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Control is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Control is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.266795% CI: [-16.37, 4.563]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Control is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Control is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.208595% CI: [-4.95, 22.485]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Control is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Control is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.104195% CI: [-2.595, 27.505]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 1 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.005895% CI: [-45.41, -5.295]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 1 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.00195% CI: [-65.062, -12.197]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 1 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.000595% CI: [-72.443, -15.491]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 2 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.000395% CI: [-51.159, -11.428]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 2 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.000495% CI: [-65.941, -14.477]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.001195% CI: [-68.965, -13.138]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 1 + Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 1 + Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-60.902, -24.116]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Plasma sICAM-1 (ng/mL) in Test 2 is equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Plasma sICAM-1 (ng/mL) in Test 2 is NOT equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.783595% CI: [-23.855, 18.025]Mixed Models Analysis

Primary

Summary of Serum HDL-C Absolute Change From Baseline (mg/dL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of serum HDL-C absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3 and 7 and analyzed for the biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3

Time frame: Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization

Arm	Measure	Value (MEAN)	Dispersion
Test 1	Summary of Serum HDL-C Absolute Change From Baseline (mg/dL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	3.3 mg/dL	Standard Deviation 6.68
Test 2	Summary of Serum HDL-C Absolute Change From Baseline (mg/dL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	2.3 mg/dL	Standard Deviation 6.95
Test 1 + Test 2 Group	Summary of Serum HDL-C Absolute Change From Baseline (mg/dL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	0.4 mg/dL	Standard Deviation 7.54

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population with Outliers Excluded)p-value: 0.036295% CI: [0.11, 4.705]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.214295% CI: [-0.569, 3.953]Mixed Models Analysis

Primary

Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of serum high density lipoprotein cholesterol (HDL-C) (mg/dL) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3, 5, and 7. Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3

Time frame: 12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	47.3 mg/dL	Standard Deviation 14.43
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	44.8 mg/dL	Standard Deviation 14.15
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	2.3 mg/dL	Standard Deviation 6.15
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	47.2 mg/dL	Standard Deviation 15.01
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	3.3 mg/dL	Standard Deviation 6.68
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	48.9 mg/dL	Standard Deviation 14.52
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	48.0 mg/dL	Standard Deviation 12.52
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	1.6 mg/dL	Standard Deviation 7.47
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	46.1 mg/dL	Standard Deviation 12.56
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	3.1 mg/dL	Standard Deviation 9.37
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	3.2 mg/dL	Standard Deviation 8.17
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	45.5 mg/dL	Standard Deviation 13.35
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	47.6 mg/dL	Standard Deviation 13.78
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	48.2 mg/dL	Standard Deviation 14.46
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	2.0 mg/dL	Standard Deviation 6.84
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	0.8 mg/dL	Standard Deviation 8.88
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	0.6 mg/dL	Standard Deviation 10.36
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	47.6 mg/dL	Standard Deviation 18.13
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	46.8 mg/dL	Standard Deviation 16.84
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	47.4 mg/dL	Standard Deviation 18

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.000295% CI: [1.369, 4.273]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [1.85, 5.086]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.002295% CI: [0.812, 3.679]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [1.768, 4.891]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 + Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 + Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [2.252, 4.545]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Control is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Control is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.076195% CI: [-0.132, 2.633]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Control is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Control is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.021195% CI: [0.269, 3.286]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.384195% CI: [-0.951, 4.092]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.393495% CI: [-1.084, 4.464]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.778295% CI: [-1.505, 3.494]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 + Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 + Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.084995% CI: [-0.224, 3.466]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is equal to Test 2 on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to Test 2 on Visit 7 (Week 12). (mITT Population)p-value: 0.901695% CI: [-2.064, 2.341]Mixed Models Analysis

Primary

Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of serum HDL-C (mg/dL) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). Blood samples were collected via direct venipuncture on Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study

Time frame: 24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	46.3 mg/dL	Standard Deviation 13.05
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	1.5 mg/dL	Standard Deviation 5.8
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	4.2 mg/dL	Standard Deviation 6.51
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	50.4 mg/dL	Standard Deviation 14.44
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	4.1 mg/dL	Standard Deviation 9.02
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	48.4 mg/dL	Standard Deviation 13.35
Test 1	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	50.6 mg/dL	Standard Deviation 17.37
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	2.8 mg/dL	Standard Deviation 12.2
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	48.5 mg/dL	Standard Deviation 17.95
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	47.8 mg/dL	Standard Deviation 14.61
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	5.5 mg/dL	Standard Deviation 11.96
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	3.5 mg/dL	Standard Deviation 13.67
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	50.7 mg/dL	Standard Deviation 16.02
Test 2	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	45.2 mg/dL	Standard Deviation 12.29
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	49.5 mg/dL	Standard Deviation 17.61
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	45.7 mg/dL	Standard Deviation 12.61
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	50.5 mg/dL	Standard Deviation 15.19
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	48.1 mg/dL	Standard Deviation 13.98
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	4.8 mg/dL	Standard Deviation 9.68
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	2.2 mg/dL	Standard Deviation 9.83
Test 1 + Test 2 Group	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	3.8 mg/dL	Standard Deviation 11.65
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	44.0 mg/dL	Standard Deviation 22.75
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-1.1 mg/dL	Standard Deviation 6.79
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-0.2 mg/dL	Standard Deviation 12.26
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	44.0 mg/dL	Standard Deviation 21.54
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	44.4 mg/dL	Standard Deviation 16.04
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-0.4 mg/dL	Standard Deviation 10.1
Control	Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	40.8 mg/dL	Standard Deviation 13.01

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 1 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.000495% CI: [2.511, 8.662]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 1 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.114195% CI: [-0.62, 5.732]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 1 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.000795% CI: [2.367, 8.705]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 2 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [3.68, 9.577]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 2 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.007295% CI: [1.118, 7.047]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.002395% CI: [1.691, 7.686]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 1 + Test 2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 + Test 2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [2.874, 7.35]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Control is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Control is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.60395% CI: [-2.165, 3.72]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Control is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Control is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.505395% CI: [-1.96, 3.967]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Control is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Control is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.660795% CI: [-2.347, 3.694]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 1 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.130995% CI: [-0.827, 10.446]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 1 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.977695% CI: [-4.212, 7.318]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 1 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.142295% CI: [-0.939, 10.663]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 2 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.033495% CI: [0.307, 11.396]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 2 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.562295% CI: [-2.501, 8.66]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.284195% CI: [-1.643, 9.672]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 1 + Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 1 + Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.017895% CI: [0.774, 8.103]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Serum HDL-C (mg/dL) in Test 2 is equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Serum HDL-C (mg/dL) in Test 2 is NOT equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.694495% CI: [-3.398, 5.093]Mixed Models Analysis

Primary

Summary of Urine 11-dehydrothromboxane B2 Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of urine 11-dehydrothromboxane B2 absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). The first urine void of the day on Visits 3 and 7 was analyzed for the urine biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3

Time frame: Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization

Arm	Measure	Value (MEAN)	Dispersion
Test 1	Summary of Urine 11-dehydrothromboxane B2 Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-47.736 ng/g	Standard Deviation 488.1213
Test 2	Summary of Urine 11-dehydrothromboxane B2 Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-55.751 ng/g	Standard Deviation 486.6897
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-3.878 ng/g	Standard Deviation 414.5263

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.677895% CI: [-177.281, 68.485]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.749795% CI: [-168.697, 71.908]Mixed Models Analysis

Primary

Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of urine 11-dehydrothromboxane B2 (ng/g) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3 The first urine void of the day was collected at Visits 3, 5 and 7. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration values as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value

Time frame: 12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	824.877 ng/g	Standard Deviation 726.5075
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	680.700 ng/g	Standard Deviation 371.6959
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	703.664 ng/g	Standard Deviation 444.1672
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-47.736 ng/g	Standard Deviation 488.1213
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-148.001 ng/g	Standard Deviation 660.1311
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-55.751 ng/g	Standard Deviation 486.6897
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	614.562 ng/g	Standard Deviation 312.1994
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	714.007 ng/g	Standard Deviation 413.0628
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	761.598 ng/g	Standard Deviation 518.6039
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-141.502 ng/g	Standard Deviation 409.6231
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	792.622 ng/g	Standard Deviation 628.7305
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	647.766 ng/g	Standard Deviation 344.2553
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-144.765 ng/g	Standard Deviation 548.7304
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-51.917 ng/g	Standard Deviation 486.3259
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	709.060 ng/g	Standard Deviation 427.3102
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	5.028 ng/g	Standard Deviation 424.6884
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-2.414 ng/g	Standard Deviation 427.2816
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	776.000 ng/g	Standard Deviation 480.7616
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	777.506 ng/g	Standard Deviation 471.4327
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	785.424 ng/g	Standard Deviation 457.4472

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.000395% CI: [-177.973, -52.539]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.046795% CI: [-148.706, -1.102]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-206.668, -81.402]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.080795% CI: [-133.221, 7.71]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 + Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 + Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.009595% CI: [-120.753, -16.907]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.958695% CI: [-61.873, 58.687]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.940295% CI: [-71.714, 66.443]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.03995% CI: [-223.33, -3.996]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.454395% CI: [-199.091, 54.554]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.005195% CI: [-252.08, -32.805]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.606195% CI: [-184.286, 64.046]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 + Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 + Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.124295% CI: [-150.672, 18.284]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to Test 2 on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to Test 2 on Visit 7 (Week 12). (mITT Population)p-value: 0.811795% CI: [-112.35, 88.052]Mixed Models Analysis

Primary

Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of urine 11-dehydrothromboxane B2 (ng/g) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). The first urine void of the day was collected at Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study

Time frame: 24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	616.618 ng/g	Standard Deviation 317.4293
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	710.827 ng/g	Standard Deviation 429.3286
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-93.029 ng/g	Standard Deviation 372.9436
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-68.815 ng/g	Standard Deviation 363.6867
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	665.371 ng/g	Standard Deviation 399.2899
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	567.102 ng/g	Standard Deviation 375.2503
Test 1	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-165.586 ng/g	Standard Deviation 402.137
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-47.287 ng/g	Standard Deviation 382.6278
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	703.961 ng/g	Standard Deviation 467.6549
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	706.929 ng/g	Standard Deviation 341.1676
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-46.559 ng/g	Standard Deviation 438.032
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	750.519 ng/g	Standard Deviation 463.9992
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	731.003 ng/g	Standard Deviation 403.6885
Test 2	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-14.677 ng/g	Standard Deviation 390.028
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-102.493 ng/g	Standard Deviation 394.1247
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	701.170 ng/g	Standard Deviation 400.7346
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	641.676 ng/g	Standard Deviation 362.2939
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	731.287 ng/g	Standard Deviation 445.6561
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-68.826 ng/g	Standard Deviation 406.6859
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-39.285 ng/g	Standard Deviation 377.1052
Test 1 + Test 2 Group	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	662.109 ng/g	Standard Deviation 403.0592
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	107.568 ng/g	Standard Deviation 617.2994
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	842.642 ng/g	Standard Deviation 493.4473
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	856.055 ng/g	Standard Deviation 517.3135
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	942.559 ng/g	Standard Deviation 644.6484
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	6.436 ng/g	Standard Deviation 462.7865
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	103.927 ng/g	Standard Deviation 469.7284
Control	Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	969.562 ng/g	Standard Deviation 545.1937

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.056795% CI: [-227.151, 3.237]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.210395% CI: [-197.025, 43.569]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.005295% CI: [-288.22, -51.251]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.34995% CI: [-162.721, 57.711]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.84195% CI: [-123.333, 100.507]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.346595% CI: [-165.4, 58.27]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 + Test 2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 + Test 2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.008795% CI: [-194.865, -28.435]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.268895% CI: [-49.678, 177.565]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.009695% CI: [37.114, 265.33]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Control is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.002395% CI: [65.754, 299.509]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.161295% CI: [-390.865, 39.063]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.039695% CI: [-448.725, -7.175]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.000295% CI: [-573.315, -131.418]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.561695% CI: [-327.445, 94.547]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.217695% CI: [-375.57, 50.299]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.024295% CI: [-451.334, -21.059]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 + Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 1 + Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-434.513, -154.05]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 11-dehydrothromboxane B2 (ng/g creatinine) in Test 2 is NOT equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.152495% CI: [-275.521, 43.18]Mixed Models Analysis

Primary

Summary of Urine 8-epi-prostaglandin F2alpha Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of urine 8-epi-prostaglandin F2alpha absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). The first urine void of the day on Visits 3 and 7 was analyzed for the urine biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3

Time frame: Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization

Arm	Measure	Value (MEAN)	Dispersion
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-61.644 ng/g	Standard Deviation 138.3599
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-18.092 ng/g	Standard Deviation 135.9049
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-11.452 ng/g	Standard Deviation 133.6618

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.02595% CI: [-75.396, -3.605]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.999795% CI: [-37.896, 32.016]Mixed Models Analysis

Primary

Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of urine 8-epi-prostaglandin F2alpha (ng/g) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3 The first urine void of the day was collected at Visits 3, 5 and 7. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration values as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value

Time frame: 12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	377.138 ng/g	Standard Deviation 211.0106
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-39.547 ng/g	Standard Deviation 191.4551
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	332.952 ng/g	Standard Deviation 212.6164
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-44.354 ng/g	Standard Deviation 162.5679
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	332.455 ng/g	Standard Deviation 219.2878
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	335.687 ng/g	Standard Deviation 143.1724
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-33.320 ng/g	Standard Deviation 120.3646
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-18.092 ng/g	Standard Deviation 135.9049
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	355.984 ng/g	Standard Deviation 177.9443
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	315.095 ng/g	Standard Deviation 150.5924
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	366.397 ng/g	Standard Deviation 194.8302
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	334.134 ng/g	Standard Deviation 183.3207
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-38.882 ng/g	Standard Deviation 143.0167
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	324.096 ng/g	Standard Deviation 184.324
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-28.401 ng/g	Standard Deviation 164.9314
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	355.639 ng/g	Standard Deviation 233.4254
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	346.856 ng/g	Standard Deviation 195.702
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	368.710 ng/g	Standard Deviation 200.0174
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-7.204 ng/g	Standard Deviation 178.4608
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-15.247 ng/g	Standard Deviation 141.7366

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.003195% CI: [-59.038, -12.075]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.037195% CI: [-60.818, -1.882]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.004395% CI: [-57.877, -10.834]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.209195% CI: [-46.375, 10.183]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 + Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 + Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.019795% CI: [-45.473, -3.973]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.235395% CI: [-36.08, 8.891]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.732995% CI: [-32.159, 22.641]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.54295% CI: [-62.989, 19.065]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.597595% CI: [-61.867, 20.344]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 + Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 + Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.244495% CI: [-53.637, 13.709]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to Test 2 on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to Test 2 on Visit 7 (Week 12). (mITT Population)p-value: 0.516995% CI: [-53.427, 26.919]Mixed Models Analysis

Primary

Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of urine 8-epi-prostaglandin F2alpha (ng/g) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). The first urine void of the day was collected at Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study

Time frame: 24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-87.745 ng/g	Standard Deviation 92.1074
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	295.921 ng/g	Standard Deviation 199.4031
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-35.569 ng/g	Standard Deviation 162.6996
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	331.217 ng/g	Standard Deviation 145.3767
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	305.481 ng/g	Standard Deviation 310.8112
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	251.448 ng/g	Standard Deviation 105.3359
Test 1	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-32.869 ng/g	Standard Deviation 328.5303
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	314.650 ng/g	Standard Deviation 145.3787
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	331.678 ng/g	Standard Deviation 190.5315
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	359.269 ng/g	Standard Deviation 204.436
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	337.996 ng/g	Standard Deviation 138.6722
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-31.868 ng/g	Standard Deviation 179.4879
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-21.273 ng/g	Standard Deviation 159.7813
Test 2	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-48.891 ng/g	Standard Deviation 115.7881
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-32.335 ng/g	Standard Deviation 258.3306
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	345.677 ng/g	Standard Deviation 177.9266
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	317.835 ng/g	Standard Deviation 170.8786
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	285.922 ng/g	Standard Deviation 131.884
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	319.453 ng/g	Standard Deviation 252.6784
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-28.123 ng/g	Standard Deviation 160.495
Test 1 + Test 2 Group	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-66.552 ng/g	Standard Deviation 106.8853
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	413.638 ng/g	Standard Deviation 328.91
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-20.874 ng/g	Standard Deviation 255.5397
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	421.529 ng/g	Standard Deviation 277.7803
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-54.946 ng/g	Standard Deviation 159.6202
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-7.891 ng/g	Standard Deviation 226.9262
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	344.100 ng/g	Standard Deviation 142.3191
Control	Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	403.656 ng/g	Standard Deviation 359.5415

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.135995% CI: [-93.12, 12.772]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.012995% CI: [-127.961, -15.49]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.326295% CI: [-112.293, 37.678]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.434395% CI: [-70.468, 30.444]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.096795% CI: [-97.481, 8.167]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.419895% CI: [-99.915, 41.966]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 + Test 2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 + Test 2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.212195% CI: [-85.475, 19.193]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.544595% CI: [-35.614, 67.212]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.953495% CI: [-51.951, 55.116]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Control is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.836695% CI: [-65.126, 80.295]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.543795% CI: [-154.862, 42.916]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.297495% CI: [-177.224, 30.608]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.902695% CI: [-181.909, 92.126]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.895495% CI: [-132.513, 60.891]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.748595% CI: [-146.766, 54.288]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.957895% CI: [-169.77, 96.653]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 + Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 1 + Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.363595% CI: [-129.208, 47.757]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine 8-epi-prostaglandin F2alpha (ng/g creatinine) in Test 2 is NOT equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.871395% CI: [-110.097, 93.431]Mixed Models Analysis

Primary

Summary of Urine Total NNAL Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of urine total NNAL absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). The first urine void of the day on Visits 3 and 7 was analyzed for the urine biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3

Time frame: Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization

Arm	Measure	Value (MEAN)	Dispersion
Test 1	Summary of Urine Total NNAL Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-191.327 ng/g	Standard Deviation 220.6982
Test 2	Summary of Urine Total NNAL Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-160.201 ng/g	Standard Deviation 192.1456
Test 1 + Test 2 Group	Summary of Urine Total NNAL Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-15.898 ng/g	Standard Deviation 149.1447

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-225.708, -133.022]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-198.93, -107.509]Mixed Models Analysis

Primary

Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of urine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) (ng/g) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3 The first urine void of the day was collected at Visits 3, 5 and 7. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration values as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value

Time frame: 12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12

Population: Modified Intention-to-Treat (mITT): All subjects were randomized according to the randomization schedule; who used at least one study products after randomization was recorded and for whom there was a valid (within ±3 days of the planned measurement day) baseline and at least one post-baseline biomarker.

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-180.390 ng/g	Standard Deviation 206.3278
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	127.254 ng/g	Standard Deviation 191.0786
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-191.327 ng/g	Standard Deviation 220.6982
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	101.544 ng/g	Standard Deviation 146.4668
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	309.098 ng/g	Standard Deviation 253.5221
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	124.000 ng/g	Standard Deviation 163.0721
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-173.299 ng/g	Standard Deviation 186.803
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-160.201 ng/g	Standard Deviation 192.1456
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	120.568 ng/g	Standard Deviation 157.7745
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	294.831 ng/g	Standard Deviation 212.1778
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	113.159 ng/g	Standard Deviation 155.3513
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	301.854 ng/g	Standard Deviation 233.0988
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	123.925 ng/g	Standard Deviation 174.9627
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-176.859 ng/g	Standard Deviation 196.4791
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-175.228 ng/g	Standard Deviation 206.5607
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-8.733 ng/g	Standard Deviation 140.9375
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	308.521 ng/g	Standard Deviation 220.7403
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	311.851 ng/g	Standard Deviation 245.2203
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	300.819 ng/g	Standard Deviation 217.6292
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-15.898 ng/g	Standard Deviation 149.1447

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-204.899, -152.678]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-211.184, -157.598]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 2 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 2 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-200.964, -149.237]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-187.543, -135.609]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 + Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 + Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-192.08, -153.886]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Control is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Control is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.778195% CI: [-28.572, 21.401]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Control is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Control is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.545795% CI: [-32.993, 17.465]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-220.445, -129.961]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-222.672, -130.582]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 2 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 2 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-216.626, -126.404]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-199.27, -108.354]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 + Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 + Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-195.898, -134.541]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is equal to Test 2 on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g) in Test 1 is NOT equal to Test 2 on Visit 7 (Week 12). (mITT Population)p-value: 0.218895% CI: [-59.223, 13.593]Mixed Models Analysis

Primary

Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Urine Total NNAL (ng/g) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). The first urine void of the day was collected at Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study

Time frame: 24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	258.644 ng/g	Standard Deviation 190.1771
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-222.851 ng/g	Standard Deviation 172.2263
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-221.403 ng/g	Standard Deviation 177.5875
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	37.240 ng/g	Standard Deviation 74.0723
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-218.417 ng/g	Standard Deviation 171.7527
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	34.715 ng/g	Standard Deviation 73.2359
Test 1	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	40.991 ng/g	Standard Deviation 80.9328
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-234.967 ng/g	Standard Deviation 198.3954
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	80.808 ng/g	Standard Deviation 174.5894
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	56.986 ng/g	Standard Deviation 110.8673
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-228.678 ng/g	Standard Deviation 187.6797
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-215.432 ng/g	Standard Deviation 213.0743
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	65.631 ng/g	Standard Deviation 105.4324
Test 2	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	294.309 ng/g	Standard Deviation 217.0554
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	62.227 ng/g	Standard Deviation 139.6906
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	277.028 ng/g	Standard Deviation 204.202
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	51.875 ng/g	Standard Deviation 92.2293
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	46.863 ng/g	Standard Deviation 95.7548
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-225.153 ng/g	Standard Deviation 181.9443
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-229.460 ng/g	Standard Deviation 186.0037
Test 1 + Test 2 Group	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-216.825 ng/g	Standard Deviation 193.8228
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	294.906 ng/g	Standard Deviation 194.0554
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-85.075 ng/g	Standard Deviation 134.0116
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-78.423 ng/g	Standard Deviation 149.1454
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	357.472 ng/g	Standard Deviation 261.5709
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	368.502 ng/g	Standard Deviation 255.5299
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-11.030 ng/g	Standard Deviation 130.5603
Control	Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	274.912 ng/g	Standard Deviation 186.7002

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 1 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-286.423, -210.199]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 1 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-280.904, -214.241]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 1 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-284.945, -206.791]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 2 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-271.603, -198.282]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 2 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 2 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-275.269, -212.829]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-258.371, -184.398]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 1 + Test 2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 + Test 2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-261.113, -206.14]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Control is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Control is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.167295% CI: [-11.13, 63.661]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Control is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Control is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.01495% CI: [-71.881, -8.221]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Control is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Control is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.028895% CI: [-80.785, -4.484]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 1 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-345.428, -203.726]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 1 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-269.198, -145.844]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 1 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-275.683, -130.784]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 2 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-330.647, -191.769]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 2 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-263.396, -144.599]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-249.092, -108.408]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 1 + Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 1 + Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-237.134, -144.85]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Total NNAL (ng/g creatinine) in Test 2 is equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Total NNAL (ng/g creatinine) in Test 2 is NOT equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.35995% CI: [-77.096, 28.13]Mixed Models Analysis

Primary

Summary of Whole Blood COHB Absolute Change From Baseline (% Saturation) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of whole blood COHB absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3 and 7 and analyzed for the biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3

Time frame: Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization

Arm	Measure	Value (MEAN)	Dispersion
Test 1	Summary of Whole Blood COHB Absolute Change From Baseline (% Saturation) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-2.57 percent saturation	Standard Deviation 2.363
Test 2	Summary of Whole Blood COHB Absolute Change From Baseline (% Saturation) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-2.44 percent saturation	Standard Deviation 2.187
Test 1 + Test 2 Group	Summary of Whole Blood COHB Absolute Change From Baseline (% Saturation) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	0.07 percent saturation	Standard Deviation 1.92

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-3.084, -2.054]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-3.092, -2.081]Mixed Models Analysis

Primary

Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of whole blood carboxyhemoglobin (COHb) (% Saturation) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3, 5, and 7. Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3

Time frame: 12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-2.34 percent saturation	Standard Deviation 2.278
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	3.26 percent saturation	Standard Deviation 1.79
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-2.49 percent saturation	Standard Deviation 2.498
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	2.99 percent saturation	Standard Deviation 1.55
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	5.63 percent saturation	Standard Deviation 2.073
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	2.92 percent saturation	Standard Deviation 1.141
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-2.30 percent saturation	Standard Deviation 2.355
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-2.44 percent saturation	Standard Deviation 2.187
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	3.10 percent saturation	Standard Deviation 1.449
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	5.39 percent saturation	Standard Deviation 1.868
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	2.95 percent saturation	Standard Deviation 1.351
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	5.51 percent saturation	Standard Deviation 1.971
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	3.18 percent saturation	Standard Deviation 1.626
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-2.32 percent saturation	Standard Deviation 2.313
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-2.46 percent saturation	Standard Deviation 2.337
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	0.40 percent saturation	Standard Deviation 1.813
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	6.05 percent saturation	Standard Deviation 2.029
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	5.61 percent saturation	Standard Deviation 1.957
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	5.68 percent saturation	Standard Deviation 1.986
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	0.07 percent saturation	Standard Deviation 1.92

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-2.582, -1.992]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-2.722, -2.107]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-2.673, -2.09]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-2.782, -2.19]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 + Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 + Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-2.668, -2.233]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Control is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Control is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.001295% CI: [0.185, 0.747]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Control is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Control is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.495795% CI: [-0.187, 0.386]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-3.266, -2.239]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: <0.000195% CI: [-3.359, -2.336]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 + Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 + Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: <0.000195% CI: [-2.901, -2.199]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is equal to Test 2 on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to Test 2 on Visit 7 (Week 12). (mITT Population)p-value: 0.737295% CI: [-0.346, 0.489]Mixed Models Analysis

Primary

Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Whole Blood COHb (% Saturation) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). Blood samples were collected via direct venipuncture on Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study

Time frame: 24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-3.08 percent saturation	Standard Deviation 2.252
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	2.17 percent saturation	Standard Deviation 0.635
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	2.61 percent saturation	Standard Deviation 0.759
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-3.13 percent saturation	Standard Deviation 1.947
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-2.65 percent saturation	Standard Deviation 1.94
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	2.28 percent saturation	Standard Deviation 0.786
Test 1	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	5.36 percent saturation	Standard Deviation 2.096
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-2.33 percent saturation	Standard Deviation 1.994
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	5.27 percent saturation	Standard Deviation 1.572
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	2.52 percent saturation	Standard Deviation 0.796
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	2.92 percent saturation	Standard Deviation 0.944
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	2.34 percent saturation	Standard Deviation 0.94
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-2.75 percent saturation	Standard Deviation 1.863
Test 2	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-2.89 percent saturation	Standard Deviation 1.941
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	2.40 percent saturation	Standard Deviation 0.796
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-2.47 percent saturation	Standard Deviation 1.966
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-3.00 percent saturation	Standard Deviation 1.937
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	5.31 percent saturation	Standard Deviation 1.835
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	2.78 percent saturation	Standard Deviation 0.876
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-2.91 percent saturation	Standard Deviation 2.057
Test 1 + Test 2 Group	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	2.26 percent saturation	Standard Deviation 0.813
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	6.34 percent saturation	Standard Deviation 2.052
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	5.59 percent saturation	Standard Deviation 1.46
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	0.75 percent saturation	Standard Deviation 2.019
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	5.60 percent saturation	Standard Deviation 1.607
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	1.18 percent saturation	Standard Deviation 1.894
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	6.74 percent saturation	Standard Deviation 1.971
Control	Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	0.04 percent saturation	Standard Deviation 1.511

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 1 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-3.502, -2.71]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 1 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-3.235, -2.414]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 1 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-3.553, -2.904]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 2 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-3.221, -2.457]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 2 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-2.828, -2.07]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-3.328, -2.718]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 1 + Test 2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 + Test 2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-3.354, -2.897]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Control is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Control is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [0.518, 1.298]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Control is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Control is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [0.902, 1.679]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Control is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Control is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: 0.277295% CI: [-0.142, 0.49]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 1 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-4.75, -3.278]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 1 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-4.865, -3.365]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 1 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-4.005, -2.801]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 2 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-4.473, -3.02]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 2 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-4.461, -3.018]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-3.784, -2.61]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 1 + Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 1 + Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: <0.000195% CI: [-3.678, -2.921]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood COHb (% Saturation) in Test 2 is equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood COHb (% Saturation) in Test 2 is NOT equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (MiTT Population)p-value: 0.34895% CI: [-0.638, 0.226]Mixed Models Analysis

Primary

Summary of Whole Blood WBC Absolute Change From Baseline (10^3 Cells/uL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of whole blood WBC absolute change from Baseline in Week 12 is presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3 and 7 and analyzed for the biomarker. Data outliers were examined through Proc Mixed model residual diagnosis (+/- 4 studentized residuals). A sensitivity analysis excluding outliers was performed for Visit 7 (Week 12). Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 7 (Week 12) = Day 84 ± 3

Time frame: Week 1 (Baseline) and Week 12 for a total of of 12 weeks from randomization

Arm	Measure	Value (MEAN)	Dispersion
Test 1	Summary of Whole Blood WBC Absolute Change From Baseline (10^3 Cells/uL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-0.564 10^3 cells/uL	Standard Deviation 1.8111
Test 2	Summary of Whole Blood WBC Absolute Change From Baseline (10^3 Cells/uL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	-0.389 10^3 cells/uL	Standard Deviation 1.7261
Test 1 + Test 2 Group	Summary of Whole Blood WBC Absolute Change From Baseline (10^3 Cells/uL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]	0.227 10^3 cells/uL	Standard Deviation 1.6425

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population with Outliers Excluded)p-value: 0.000295% CI: [-1.228, -0.309]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population with Outliers Excluded)p-value: 0.017595% CI: [-0.972, -0.068]Mixed Models Analysis

Primary

Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of whole blood white blood cell (WBC) count (10\^3 cells/uL) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). Blood samples were collected via direct venipuncture at Visits 3, 5, and 7. Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3

Time frame: 12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	6.292 10^3 cells/uL	Standard Deviation 1.6619
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	7.003 10^3 cells/uL	Standard Deviation 2.3185
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-0.564 10^3 cells/uL	Standard Deviation 1.8111
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	6.363 10^3 cells/uL	Standard Deviation 1.6203
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-0.656 10^3 cells/uL	Standard Deviation 1.785
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	6.583 10^3 cells/uL	Standard Deviation 1.8742
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-0.490 10^3 cells/uL	Standard Deviation 1.4902
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-0.325 10^3 cells/uL	Standard Deviation 1.858
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	6.947 10^3 cells/uL	Standard Deviation 1.9468
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	6.490 10^3 cells/uL	Standard Deviation 1.678
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	6.477 10^3 cells/uL	Standard Deviation 1.7565
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	6.974 10^3 cells/uL	Standard Deviation 2.1346
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	6.391 10^3 cells/uL	Standard Deviation 1.6696
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-0.573 10^3 cells/uL	Standard Deviation 1.6424
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-0.440 10^3 cells/uL	Standard Deviation 1.8356
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-0.098 10^3 cells/uL	Standard Deviation 1.4878
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	6.672 10^3 cells/uL	Standard Deviation 1.8449
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	6.788 10^3 cells/uL	Standard Deviation 1.9267
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	6.997 10^3 cells/uL	Standard Deviation 2.0107
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	0.227 10^3 cells/uL	Standard Deviation 1.6425

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to zero on Visit 5. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to zero on Visit 5. (mITT Population)p-value: <0.000195% CI: [-0.951, -0.481]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to zero on Visit 7. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to zero on Visit 7. (mITT Population)p-value: <0.000195% CI: [-0.966, -0.406]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to zero on Visit 5. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to zero on Visit 5. (mITT Population)p-value: <0.000195% CI: [-0.755, -0.288]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to zero on Visit 7. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to zero on Visit 7. (mITT Population)p-value: 0.013195% CI: [-0.612, -0.072]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 + Test 2 is equal to zero on Visit 7. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 + Test 2 is NOT equal to zero on Visit 7. (mITT Population)p-value: <0.000195% CI: [-0.712, -0.316]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Control is equal to zero on Visit 5. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Control is NOT equal to zero on Visit 5. (mITT Population)p-value: 0.043595% CI: [-0.455, -0.007]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Control is equal to zero on Visit 7. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Control is NOT equal to zero on Visit 7. (mITT Population)p-value: 0.401295% CI: [-0.149, 0.371]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to Control on Visit 5. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to Control on Visit 5. (mITT Population)p-value: 0.013395% CI: [-0.895, -0.074]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to Control on Visit 7. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to Control on Visit 7. (mITT Population)p-value: 0.000295% CI: [-1.277, -0.317]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to Control on Visit 5. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to Control on Visit 5. (mITT Population)p-value: 0.264195% CI: [-0.699, 0.119]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to Control on Visit 7. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to Control on Visit 7. (mITT Population)p-value: 0.063995% CI: [-0.924, 0.018]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 + Test 2 is equal to Control on Visit 7. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 + Test 2 is NOT equal to Control on Visit 7. (mITT Population)p-value: 0.000195% CI: [-0.945, -0.305]Mixed Models Analysis

Comparison: Null hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to Test 2 on Visit 7. Alternate hypothesis: Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to Test 2 on Visit 7. (mITT Population)p-value: 0.077695% CI: [-0.725, 0.038]Mixed Models Analysis

Primary

Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Whole Blood WBC Count (10\^3 cells/uL) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). Blood samples were collected via direct venipuncture on Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Value, where Baseline = values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV study Baseline = Day 1 (Week 1), Visit 1 = Week 12 (Day 84 ± 3), Visit 3 = Week 18 (Day 126 ± 3), and Visit 5 = Week 24 (Day 168 ± 3), relative to the start of the 12-week ALCS-RA-16-06-EV study

Time frame: 24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	6.547 10^3 cells/uL	Standard Deviation 1.6295
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-0.521 10^3 cells/uL	Standard Deviation 1.2722
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-0.340 10^3 cells/uL	Standard Deviation 1.3015
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	6.207 10^3 cells/uL	Standard Deviation 1.6
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-0.622 10^3 cells/uL	Standard Deviation 1.5029
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	5.986 10^3 cells/uL	Standard Deviation 1.2707
Test 1	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	5.972 10^3 cells/uL	Standard Deviation 1.275
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-0.224 10^3 cells/uL	Standard Deviation 1.9141
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	6.152 10^3 cells/uL	Standard Deviation 1.4051
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	6.642 10^3 cells/uL	Standard Deviation 1.7254
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-0.402 10^3 cells/uL	Standard Deviation 1.7483
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-0.762 10^3 cells/uL	Standard Deviation 1.5132
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	6.450 10^3 cells/uL	Standard Deviation 1.7554
Test 2	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	6.851 10^3 cells/uL	Standard Deviation 1.8432
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	6.067 10^3 cells/uL	Standard Deviation 1.3408
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	6.704 10^3 cells/uL	Standard Deviation 1.7406
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	6.332 10^3 cells/uL	Standard Deviation 1.6776
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	6.347 10^3 cells/uL	Standard Deviation 1.5643
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-0.372 10^3 cells/uL	Standard Deviation 1.5404
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-0.357 10^3 cells/uL	Standard Deviation 1.6547
Test 1 + Test 2 Group	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-0.696 10^3 cells/uL	Standard Deviation 1.5014
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	7.073 10^3 cells/uL	Standard Deviation 2.0805
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	0.202 10^3 cells/uL	Standard Deviation 1.5842
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	0.035 10^3 cells/uL	Standard Deviation 1.9567
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	7.230 10^3 cells/uL	Standard Deviation 1.9184
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	7.082 10^3 cells/uL	Standard Deviation 1.9593
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	0.174 10^3 cells/uL	Standard Deviation 1.9309
Control	Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	7.401 10^3 cells/uL	Standard Deviation 1.6116

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.005595% CI: [-1.055, -0.186]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.001195% CI: [-1.24, -0.316]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-1.26, -0.54]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.01595% CI: [-0.938, -0.103]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.104895% CI: [-0.771, 0.074]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-1.185, -0.507]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 1 + Test 2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 + Test 2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-1.127, -0.619]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Control is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Control is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.252595% CI: [-0.178, 0.671]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Control is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Control is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.650395% CI: [-0.33, 0.527]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Control is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Control is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.175995% CI: [-0.109, 0.588]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.029395% CI: [-1.674, -0.06]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.036295% CI: [-1.714, -0.038]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 1 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-1.809, -0.469]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.062195% CI: [-1.559, 0.025]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.525995% CI: [-1.246, 0.352]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-1.736, -0.435]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 1 + Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 1 + Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: <0.000195% CI: [-1.532, -0.693]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Whole Blood WBC (x 10\^3/uL) in Test 2 is equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Whole Blood WBC (x 10\^3/uL) in Test 2 is NOT equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.824895% CI: [-0.535, 0.427]Mixed Models Analysis

Secondary

Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)

Participant compliance for the abstention of any type of tobacco/nicotine product for the duration of the study was assessed by measuring the participant's exhaled carbon monoxide (eCO, ppm). According to their eCO measurements at Weeks 12 (study ALCS-RA-16-06-EV) and Week 24 (study ALCS-RA-17-11-EV), participants were categorized into 1 of 3 categories: 'eCO ≤ 5', 'eCO \< 5 - ≤ 8', or 'eCO \> 8'. Lower eCO values represent lower smoking exposure and increased compliance, with the 'eCO ≤ 5' category indicating that the participant abstained from smoking, the 'eCO \< 5 - ≤ 8' category indicating low smoking exposure to the participant, and the 'eCO \> 8' category indicating non-compliance with the study criteria that the participant refrain from smoking during the study.

Time frame: Weeks 12 (Study ALCS-RA-16-06-EV) and Week 24 (Study ALCS-RA-17-11-EV) from randomization

Arm	Measure	Group	Category	Value (COUNT_OF_PARTICIPANTS)
Test 1	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 12	eCO ≤ 5	76 Participants
Test 1	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 12	eCO < 5 - ≤ 8	13 Participants
Test 1	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 12	eCO > 8	23 Participants
Test 1	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 24	eCO ≤ 5	35 Participants
Test 1	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 24	eCO > 8	2 Participants
Test 1	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 24	eCO < 5 - ≤ 8	5 Participants
Test 2	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 24	eCO < 5 - ≤ 8	4 Participants
Test 2	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 12	eCO ≤ 5	77 Participants
Test 2	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 24	eCO ≤ 5	40 Participants
Test 2	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 24	eCO > 8	4 Participants
Test 2	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 12	eCO > 8	23 Participants
Test 2	Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)	Exhaled CO at Week 12	eCO < 5 - ≤ 8	21 Participants

Secondary

Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]

Percentage of predicted forced expiratory volume in the first second (FEV1) and absolute change from Baseline to Week 12 by Study Group is presented (Study ALCS-RA-16-06-EV). Baseline / Screening = Day -28 to Day -5 Visit 7 (Week 12) = Day 84 ± 3 Absolute change from baseline = Post Product Use Value - Baseline Value FEV1 = Forced Expiratory Volume in 1 Second

Time frame: Assessments at Screening (Day -28 to Day -5) and Week 12 (Day 84 +/- 3 )

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	91.059 percentage of predicted FEV1	Standard Deviation 13.9979
Test 1	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-1.070 percentage of predicted FEV1	Standard Deviation 6.5798
Test 1	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	89.989 percentage of predicted FEV1	Standard Deviation 13.714
Test 2	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	91.335 percentage of predicted FEV1	Standard Deviation 12.8396
Test 2	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-0.416 percentage of predicted FEV1	Standard Deviation 5.4848
Test 2	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	90.918 percentage of predicted FEV1	Standard Deviation 13.3174
Test 1 + Test 2 Group	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	90.480 percentage of predicted FEV1	Standard Deviation 13.4818
Test 1 + Test 2 Group	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	91.205 percentage of predicted FEV1	Standard Deviation 13.3671
Test 1 + Test 2 Group	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-0.725 percentage of predicted FEV1	Standard Deviation 6.0205
Control	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	90.139 percentage of predicted FEV1	Standard Deviation 13.4146
Control	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-2.396 percentage of predicted FEV1	Standard Deviation 6.2471
Control	Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	87.743 percentage of predicted FEV1	Standard Deviation 13.4729

Comparison: Null hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FEV1 (%) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FEV1 (%) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.083995% CI: [-0.19, 3.04]ANCOVA

Comparison: Null hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FEV1 (%) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FEV1 (%) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.008995% CI: [0.53, 3.66]ANCOVA

Secondary

Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]

Percentage of predicted FEV1/FVC and absolute change from Baseline to Week 12 by Study Group is presented (Study ALCS-RA-16-06-EV). Baseline / Screening = Day -28 to Day -5 Visit 7 (Week 12) = Day 84 ± 3 Absolute change from baseline = Post Product Use Value - Baseline Value FEV1 = Forced Expiratory Volume in 1 Second, FVC = Forced Vital Capacity.

Time frame: Assessments at Screening (Day -28 to Day -5) and Week 12 (Day 84 +/- 3 )

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	0.017 percentage of predicted FEV1/FVC	Standard Deviation 4.4796
Test 1	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	98.219 percentage of predicted FEV1/FVC	Standard Deviation 7.7279
Test 1	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	98.202 percentage of predicted FEV1/FVC	Standard Deviation 7.5989
Test 2	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	0.600 percentage of predicted FEV1/FVC	Standard Deviation 3.3508
Test 2	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	97.535 percentage of predicted FEV1/FVC	Standard Deviation 7.9699
Test 2	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	98.135 percentage of predicted FEV1/FVC	Standard Deviation 7.3706
Test 1 + Test 2 Group	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	0.325 percentage of predicted FEV1/FVC	Standard Deviation 3.9251
Test 1 + Test 2 Group	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	98.175 percentage of predicted FEV1/FVC	Standard Deviation 7.5234
Test 1 + Test 2 Group	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	97.849 percentage of predicted FEV1/FVC	Standard Deviation 7.7859
Control	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-1.285 percentage of predicted FEV1/FVC	Standard Deviation 5.5994
Control	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	95.959 percentage of predicted FEV1/FVC	Standard Deviation 8.1492
Control	Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	97.243 percentage of predicted FEV1/FVC	Standard Deviation 8.1131

Comparison: Null hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FEV1/FVC (%) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FEV1/FVC (%) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.013695% CI: [0.31, 2.66]ANCOVA

Comparison: Null hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FEV1/FVC (%) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FEV1/FVC (%) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.000995% CI: [0.8, 3.08]ANCOVA

Secondary

Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]

Percentage of predicted forced vital capacity (FVC) and absolute change from Baseline to Week 12 by Study Group is presented (Study ALCS-RA-16-06-EV). Baseline / Screening = Day -28 to Day -5 Visit 7 (Week 12) = Day 84 ± 3 Absolute change from baseline = Post Product Use Value - Baseline Value FVC = Forced Vital Capacity

Time frame: Assessments at Screening (Day -28 to Day -5) and Week 12 (Day 84 +/- 3 )

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	92.709 percentage of predicted FVC	Standard Deviation 12.7747
Test 1	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-0.976 percentage of predicted FVC	Standard Deviation 5.1281
Test 1	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	91.733 percentage of predicted FVC	Standard Deviation 13.3234
Test 2	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-1.059 percentage of predicted FVC	Standard Deviation 5.3244
Test 2	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	93.789 percentage of predicted FVC	Standard Deviation 11.7222
Test 2	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	92.730 percentage of predicted FVC	Standard Deviation 11.9222
Test 1 + Test 2 Group	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-1.020 percentage of predicted FVC	Standard Deviation 5.2205
Test 1 + Test 2 Group	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	93.280 percentage of predicted FVC	Standard Deviation 12.2126
Test 1 + Test 2 Group	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	92.260 percentage of predicted FVC	Standard Deviation 12.5822
Control	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Screening (Baseline)	92.809 percentage of predicted FVC	Standard Deviation 12.2784
Control	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline at Week 12	-1.257 percentage of predicted FVC	Standard Deviation 5.1665
Control	Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]	Week 12	91.552 percentage of predicted FVC	Standard Deviation 12.7403

Comparison: Null hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FVC (%) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FVC (%) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.710195% CI: [-1.13, 1.66]ANCOVA

Comparison: Null hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FVC (%) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Screening) for Percentage of Predicted FVC (%) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.732595% CI: [-1.12, 1.59]ANCOVA

Other Pre-specified

Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of urine Nicotine Equivalents (mg/g) and absolute change from Baseline in Weeks 6 and 12 are presented (Study ALCS-RA-16-06-EV). The first urine void of the day was collected at Visits 3, 5 and 7. Nicotine equivalents (μg/mL) = (nicotine \[ng/mL\]/162.23 \[mg/mmol\] + nicotinegluc (ng/mL)/338.36 \[mg/mmol\] + cotinine \[ng/mL\]/176.22 \[mg/mmol\] + cotininegluc \[ng/mL\]/352.34 \[mg/mmol\] + trans-3'-hydroxycotinine \[ng/mL\]/192.22 \[mg/mmol\] + trans-3'-hydroxycotinine-gluc \[ng/mL\]/368.34 \[mg/mmol\]) x 162.23 (mg/mmol) x 1 μg/1000 ng Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline = Post Product Use Value - Baseline Value Baseline / Visit 3 (Week 1) = Day 1 Visit 5 (Week 6) = Day 42 ± 3 Visit 7 (Week 12) = Day 84 ± 3

Time frame: 12 weeks total with measurement timepoints at Week 1/Baseline, Week 6 and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	10.666 mg/g	Standard Deviation 7.4649
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	0.219 mg/g	Standard Deviation 5.2922
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	10.869 mg/g	Standard Deviation 7.5555
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	10.865 mg/g	Standard Deviation 5.6124
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-0.109 mg/g	Standard Deviation 5.7252
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-0.600 mg/g	Standard Deviation 5.0695
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	0.435 mg/g	Standard Deviation 4.9935
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	11.054 mg/g	Standard Deviation 7.0353
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	10.026 mg/g	Standard Deviation 7.0465
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	10.629 mg/g	Standard Deviation 5.5776
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	10.965 mg/g	Standard Deviation 7.2768
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	10.347 mg/g	Standard Deviation 7.2519
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-0.353 mg/g	Standard Deviation 5.4032
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	0.330 mg/g	Standard Deviation 5.1304
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	10.745 mg/g	Standard Deviation 5.5851
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 12)	-0.943 mg/g	Standard Deviation 3.4975
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 7: Week 12	10.268 mg/g	Standard Deviation 5.5748
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 5: Week 6	10.766 mg/g	Standard Deviation 5.3662
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Change from Baseline (Week 6)	-0.499 mg/g	Standard Deviation 3.4735
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]	Visit 3 (Baseline): Week 1	11.126 mg/g	Standard Deviation 5.5647

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.929495% CI: [-0.795, 0.87]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.52995% CI: [-0.587, 1.142]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.229195% CI: [-1.337, 0.321]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.217995% CI: [-0.311, 1.361]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 + Test 2 is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 + Test 2 is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.200295% CI: [-0.213, 1.016]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Control is equal to zero on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Control is NOT equal to zero on Visit 5 (Week 6). (mITT Population)p-value: 0.47695% CI: [-1.089, 0.509]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Control is equal to zero on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Control is NOT equal to zero on Visit 7 (Week 12). (mITT Population)p-value: 0.091495% CI: [-1.512, 0.113]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.970595% CI: [-1.122, 1.777]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.32895% CI: [-0.512, 2.465]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to Control on Visit 5 (Week 6). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to Control on Visit 5 (Week 6). (mITT Population)p-value: 0.995195% CI: [-1.667, 1.23]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.136795% CI: [-0.244, 2.693]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 + Test 2 is equal to Control on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 + Test 2 is NOT equal to Control on Visit 7 (Week 12). (mITT Population)p-value: 0.029495% CI: [0.111, 2.091]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to Test 2 on Visit 7 (Week 12). Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to Test 2 on Visit 7 (Week 12). (mITT Population)p-value: 0.679295% CI: [-1.424, 0.928]Mixed Models Analysis

Other Pre-specified

Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of urine nicotine equivalents (mg/g Cr) and absolute change from Baseline in Weeks 12, 18 and 24 are presented (Study ALCS-RA-17-11-EV). The first urine void of the day was collected at Visits 1, 3 and 5 of the ALCS-RA-17-11-EV study. Baseline samples were collected Week 1 of the ALCS-RA-16-06-EV study. Nicotine equivalents (μg/mL) = (nicotine \[ng/mL\]/162.23 \[mg/mmol\] + nicotinegluc (ng/mL)/338.36 \[mg/mmol\] + cotinine \[ng/mL\]/176.22 \[mg/mmol\] + cotininegluc \[ng/mL\]/352.34 \[mg/mmol\] + trans-3'-hydroxycotinine \[ng/mL\]/192.22 \[mg/mmol\] + trans-3'-hydroxycotinine-gluc \[ng/mL\]/368.34 \[mg/mmol\]) x 162.23 (mg/mmol) x 1 μg/1000 ng Urine creatinine concentration was measured in the urine collection and used to adjust the urine biomarker concentration value as follows: Urine biomarker (ng/g creatinine) = urine biomarker (pg/mL) x 100 / creatinine (mg/dL) Change from Baseline was calculated as follows: Absolute change from baseline = Post Product Use Value - Baseline Val

Time frame: 24 weeks total with measurement timepoints at Week 1/Baseline [ALCS-RA-16-06-EV study]), and Week 12, Week 18 and Week 24 [ALCS-RA-17-11-EV study]

Arm	Measure	Group	Value (MEAN)	Dispersion
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	10.107 mg/g	Standard Deviation 4.9952
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	10.412 mg/g	Standard Deviation 7.7828
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	12.421 mg/g	Standard Deviation 9.6385
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	10.621 mg/g	Standard Deviation 8.5013
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	0.305 mg/g	Standard Deviation 5.4615
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	2.360 mg/g	Standard Deviation 6.9077
Test 1	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	0.680 mg/g	Standard Deviation 5.902
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	2.103 mg/g	Standard Deviation 7.0107
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	1.266 mg/g	Standard Deviation 5.516
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	10.684 mg/g	Standard Deviation 5.2636
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	11.634 mg/g	Standard Deviation 7.8863
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	12.782 mg/g	Standard Deviation 7.1436
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	11.949 mg/g	Standard Deviation 7.0536
Test 2	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	1.281 mg/g	Standard Deviation 6.3017
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	11.205 mg/g	Standard Deviation 7.4173
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	11.773 mg/g	Standard Deviation 7.837
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	0.800 mg/g	Standard Deviation 5.4823
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	1.771 mg/g	Standard Deviation 6.5677
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	11.992 mg/g	Standard Deviation 8.6833
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	10.404 mg/g	Standard Deviation 5.1168
Test 1 + Test 2 Group	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	1.439 mg/g	Standard Deviation 6.5202
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 12)	-0.713 mg/g	Standard Deviation 3.9573
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 3: Week 18	10.841 mg/g	Standard Deviation 5.4127
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 18)	-0.976 mg/g	Standard Deviation 4.4242
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 5: Week 24	10.442 mg/g	Standard Deviation 4.5456
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Baseline: Week 1	11.813 mg/g	Standard Deviation 5.4517
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Change from Baseline (Week 24)	-1.372 mg/g	Standard Deviation 4.1783
Control	Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]	Visit 1: Week 12	11.101 mg/g	Standard Deviation 5.7563

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.401295% CI: [-0.86, 2.137]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.020195% CI: [0.343, 3.983]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.170995% CI: [-0.528, 2.948]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.030795% CI: [0.15, 3.035]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.069195% CI: [-0.126, 3.302]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.003495% CI: [0.838, 4.137]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 + Test 2 is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 + Test 2 is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.003495% CI: [0.622, 3.075]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Control is equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Control is NOT equal to zero on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.812395% CI: [-1.654, 1.299]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Control is equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Control is NOT equal to zero on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.587995% CI: [-2.226, 1.267]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Control is equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Control is NOT equal to zero on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.49195% CI: [-2.304, 1.111]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.967395% CI: [-1.967, 3.599]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.178795% CI: [-0.683, 5.968]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.524395% CI: [-1.406, 5.018]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to Control on Visit 1 (Week 12), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.395695% CI: [-0.966, 4.507]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to Control on Visit 3 (Week 18), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.38195% CI: [-1.16, 5.295]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.055795% CI: [-0.049, 6.216]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 + Test 2 is equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 1 + Test 2 is NOT equal to Control on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.019595% CI: [0.4, 4.49]Mixed Models Analysis

Comparison: Null hypothesis: Absolute change from Baseline for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. Alternate hypothesis: Absolute change from Baseline (Week 1) for Urine Nicotine Equivalents (mg/g creatinine) in Test 2 is NOT equal to Test 1 on Visit 5 (Week 24), relative to the start of the 12-week ALCS-RA-16-06-EV study. (mITT Population)p-value: 0.281795% CI: [-3.615, 1.06]Mixed Models Analysis

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

Biomarkers of Exposure and Biomarkers of Potential Harm in Adult Smokers Who Completely Switch to E-vapor Products

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Summary of Plasma sICAM-1 Absolute Change From Baseline (ng/mL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of Plasma sICAM-1 and Absolute Change From Baseline (ng/mL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Serum HDL-C Absolute Change From Baseline (mg/dL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of Serum HDL-C and Absolute Change From Baseline (mg/dL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Urine 11-dehydrothromboxane B2 Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of Urine 11-dehydrothromboxane B2 and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Urine 8-epi-prostaglandin F2alpha Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of Urine 8-epi-prostaglandin F2alpha and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Urine Total NNAL Absolute Change From Baseline (ng/g) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of Urine Total NNAL and Absolute Change From Baseline (ng/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Whole Blood COHB Absolute Change From Baseline (% Saturation) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of Whole Blood COHb and Absolute Change From Baseline (% Saturation) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Summary of Whole Blood WBC Absolute Change From Baseline (10^3 Cells/uL) by Study Group From Week 1 to Week 12 (mITT Population With Outliers Excluded) [ALCS-RA-16-06-EV]

Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of Whole Blood WBC Count and Absolute Change From Baseline (10^3 Cells/uL) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]

Frequency of eCO as Compliance Indicator, Weeks 12 (Study ALCS-RA-16-06-EV) and 24 (Study ALCS-RA-17-11-EV)

Percentage of Predicted FEV1 and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]

Percentage of Predicted FEV1/FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]

Percentage of Predicted FVC and Absolute Change From Baseline to Week 12 by Study Group (mITT Population) [ALCS-RA-16-06-EV]

Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 12 (mITT Population) [ALCS-RA-16-06-EV]

Summary of Urine Nicotine Equivalents and Absolute Change From Baseline (mg/g) by Study Group and Visit From Week 1 to Week 24 (mITT Population) [ALCS-RA-17-11-EV]