Asthma
Conditions
Keywords
Dose ranging, Fluticasone Propionate, Dry Powder Inhaler (DPI), High Dose ICS, Asthma
Brief summary
The primary objective of this study is to evaluate the dose response, efficacy and safety of 4 different doses of fluticasone propionate (50, 100, 200, and 400mcg) delivered as Fluticasone Spiromax® Inhalation Powder (Fp Spiromax) when administered twice daily in subjects 12 years of age and older with severe persistent asthma who are uncontrolled on high dose ICS therapy.
Interventions
DRUGFp MDPI
Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate (Fp) dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. During the treatment period, participants were randomized to 50, 100, 200 or 400 mcg of Fp one inhalation twice a day for a total daily dose of 100, 200, 400 or 800 mcg. Study drug was administered in the morning and in the evening.
OTHERPlacebo MDPI
Placebo multidose dry powder inhaler (MDPI) in the morning and evening. Placebo MDPI was provided in devices identical in appearance to Fp MDPI.
DRUGFlovent Diskus
Flovent Diskus contains the active ingredient fluticasone propionate (Fp). Flovent Diskus 250 mcg was used twice a day, once in the morning and evening, for a total daily dose of 500 mcg of Fp. This therapy was not blinded as the inhaler device was different than the MDPI used in the other treatment arms.
DRUGalbuterol/salbutamol
A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent/assent signed and dated by the subject and/or parent /legal guardian before conducting any study related procedure. 2. Male or female 12 years and older, as of the Screening Visit. Male or female 18 years and older, as of the Screening Visit, in countries where local regulations or the regulatory status of study medication permit enrollment of adults only. 3. General good health, and free of any concomitant conditions or treatment that could interfere with study conduct, influence the interpretation of study observations/results, or put the subject at increased risk during the study. 4. Asthma Diagnosis: Asthma as defined by the National Institutes of Health (NIH). 5. Severity of Disease: • A best forced expiratory volume in one second (FEV1) of 40%-85% of the predicted normal value during the Screening Visit. NHANES III predicted values will be used for subjects aged ≥12 years and adjustments to predicted values will be made for African American subjects. ATS/ERS 2005 criteria for acceptability, reproducibility, and end of test must be met for spirometry 6. Reversibility of Disease: Demonstrated a ≥12% reversibility of FEV1 within 30 minutes following 2 inhalations of albuterol/salbutamol inhalation aerosol (if required, spacers are permitted for reversibility testing only) at the Screening Visit. If a subject fails to demonstrate an increase in FEV1 ≥12% then the subject is not eligible for the study and will not be allowed to re-screen. Reversibility values of 11.50 - 11.99 will be rounded to 12. Documented historical reversibility of ≥ 12 % within 3 months of the Screening Visit will be accepted. 7. Current Asthma Therapy: Subjects will be required to be on a short acting β2 agonist and inhaled corticosteroid for a minimum of 8 weeks before the Screening Visit and have been maintained on a stable dose of inhaled corticosteroids for four weeks prior to the Screening Visit at one of the following doses: * Fluticasone propionate HFA MDI ≥ 880 mcg/day * Fluticasone propionate DPI≥ 1000 mcg/day * Beclomethasone dipropionate DPI ≥ 2000 mcg/day * Beclomethasone dipropionate HFA (QVAR)≥ 640 mcg/day * Beclomethasone dipropionate HFA (Clenil Modulite)≥ 2000 mcg/day * Budesonide DPI ≥ 1600 mcg/day * Budesonide MDI ≥ 1600 mcg/day * Flunisolide ≥ 2000 mcg/day * Triamcinolone acetonide ≥ 2000 mcg /day * Mometasone furoate DPI ≥ 880 mcg/day * Ciclesonide HFA MDI ≥ 640 mcg/day Exception 1: Based upon the investigator's judgment that there is no inherent harm in changing the subject's current ICS/LABA therapy and the subject provides consent, subjects on inhaled Fluticasone propionate/salmeterol DPI ≥ 1000 mcg/day, or Fluticasone propionate/salmeterol HFA ≥ 880 mcg/day, or Fluticasone propionate/Formoterol ≥ 1000 mcg/day,or Beclomethasone dipropionate/Formoterol ≥ 400 mcg/day, or Budesonide/formoterol HFA ≥ 640 mcg/day, or Budesonide/formoterol DPI ≥ 800 mcg/day, or Mometasone furoate/formoterol MDI ≥ 800 mcg/day or subjects on a qualifying ICS dose plus a long-acting β2-agonists (LABA) administered via separate inhalers, may be switched to a qualifying dose of fluticasone propionate provided the subjects will not participate in the PK portion of the study. Exception 2: Subjects on a qualifying dose of fluticasone propionate who wish to participate in the PK portion of the study and who provide consent may have their fluticasone propionate switched to a different qualifying ICS (non-fluticasone propionate) at a pre-screening visit. The subject will be required to return to the clinic to complete the Screening Visit following a 1-week washout period. 8. Short-Acting β2-Agonists: All subjects must be able to replace their current short-acting β2-agonists with albuterol/salbutamol inhalation aerosol at the Screening Visit for use as needed for the duration of the study. The use of spacer devices with the metered dose inhaler (MDI) will not be allowed during the study with exception of it's use during reversibility testing at the Screening Visit. Nebulized albuterol/salbutamol will not be allowed at any time during the study. Subjects must be able to withhold all inhaled short-acting β2 sympathomimetic bronchodilators for at least 6 hours prior to all study visits. 9. If female, is currently not pregnant, breast feeding, or attempting to become pregnant, has a negative serum pregnancy test, and is of * Non-childbearing potential, defined as: * Before menarche, or * 1 year post-menopausal, or * Surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy), or * Congenital sterility, or * Diagnosed as infertile and not undergoing treatment to reverse infertility or is of * Child-bearing potential, willing to commit to using a consistent and acceptable method of birth control as defined below for the duration of the study: * Systemic contraception used for 1 month prior to screening, including birth control pills, transdermal patch (Ortho Evra®), vaginal ring (NuvaRing®), levonorgesterel (Norplant®), or injectable progesterone (Depo-Provera®), or * Double barrier methods (condoms, cervical cap, diaphragm, and vaginal contraceptive film with spermicide), or * Intrauterine device (IUD) or * Monogamous with a vasectomized male partner or is of * Child-bearing potential and not sexually active, willing to commit to using a consistent and acceptable method of birth control as defined above for the duration of the study, in the event the subject becomes sexually active 10. Capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements (visits, record-keeping, etc).
Exclusion criteria
1. History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures. 2. Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that is not resolved within 2 weeks of the Screening Visit. In addition, the subject must be excluded if such infection occurs between the Screening Visit and the Randomization Visit. 3. Any asthma exacerbation requiring oral corticosteroids within 1 month of the Screening Visit. A subject must not have had any hospitalization for asthma within 2 month prior to the Screening Visit. Note: An exacerbation of asthma is defined as any worsening of asthma requiring any treatment other than rescue albuterol/salbutamol HFA MDI and/or the subject's regular inhaled corticosteroid maintenance treatment. This includes requiring the use of systemic corticosteroids and/or emergency room visit or hospitalization, a change in the subject's regular inhaled corticosteroid maintenance treatment, or the addition of other asthma medications. 4. Presence of glaucoma, cataracts, ocular herpes simplex, or malignancy other than basal cell carcinoma. 5. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular (e.g., congestive heart failure, known aortic aneurysm, clinically significant cardiac arrhythmia or coronary heart disease), hepatic, renal, hematological, neuropsychological, endocrine (e.g., uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison's disease, Cushing's syndrome), gastrointestinal (e.g., poorly-controlled peptic ulcer, GERD), or pulmonary (e.g., chronic bronchitis, emphysema, bronchiectasis with the need for treatment, cystic fibrosis, bronchopulmonary dysplasia, chronic obstructive pulmonary disease). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which could affect the efficacy or safety analysis if the disease/condition exacerbated during the study. 6. Have any of the following conditions that, in the judgment of the investigator, might cause participation in this study to be detrimental to the subject, including, but not limited to: * Current malignancy excluding basal cell carcinoma; History of malignancy is acceptable only if the subject has been in remission for one year prior to the Screening Visit. (Remission is defined as no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to the Screening Visit) * Current or untreated tuberculosis; History of tuberculosis is acceptable only if a subject has received an approved prophylactic treatment regimen or an approved active treatment regimen and has had no evidence of active disease for a minimum of 2 years * Uncontrolled hypertension (systolic BP ≥160 or diastolic BP \>100) * Stroke within 3 months prior to the Screening Visit * Immunologic compromise 7. History of a positive test for HIV, hepatitis B or hepatitis C infection. 8. Untreated oral candidiasis at the Screening Visit. Subjects with clinical visual evidence of oral candidiasis and who agree to receive treatment and comply with appropriate medical monitoring may enter the study 9. History of any adverse reaction to any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the dry powder inhalers (Spiromax or Diskus) used in the study (i.e., lactose). 10. History of severe allergy to milk protein. 11. Use of systemic, oral or depot corticosteroids within 4 weeks prior to the Screening Visit * Use of topical corticosteroids (≤1% hydrocortisone cream) for dermatological disease is permitted * Use of intranasal corticosteroids or ocular corticosteroids at a stable dose for at least 4 weeks prior to the Screening Visit and throughout the study is permitted 12. Use of immunosuppressive medications within 4 weeks prior to the Screening Visit and during the study. 13. Immunotherapy for the treatment of allergy at a stable maintenance dose for at least 90 days prior to the Screening Visit and which will remain at a stable dose without escalation throughout the study is permitted. 14. Use of Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, ketoconazole, itraconazole) within 4 weeks prior to the Screening Visit. Strong and moderate CYP3A4 inhibitors are prohibited and weak CYP3A4 are allowed. 15. History of alcohol or drug abuse within two years preceding the Screening Visit. 16. Current smoker or a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). A subject may not have used tobacco products within the past one year (e.g., cigarettes, cigars, chewing tobacco, or pipe tobacco). 17. Study participation by clinical investigator site employees and/or their immediate relatives. 18. Study participation by more than one subject from the same household at the same time. However, after the study completion or discontinuation by one subject another subject from the same household may be screened. 19. Participation in any investigational drug study within the 30 days (starting at the final follow-up visit) preceding the Screening Visit or planned participation in another investigational drug study at any time during this study. 20. Pregnancy, nursing, or plans to become pregnant or donate gametes (ova or sperm) for in vitro fertilization during the study period or for 30 days following the subject's last study related visit (for eligible subjects only - if applicable). Eligible female subjects unwilling to employ appropriate contraceptive measures to ensure that pregnancy will not occur during the study will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | Baseline (Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12 | Trough FEV1 was measured electronically by spirometry at morning (AM) investigational site visits, before administration of the AM dose of study drug, and before albuterol/salbutamol administration. The highest FEV1 value from 3 acceptable and 2 reproducible maneuvers was used. All FEV1 data were submitted to a central reading center for evaluation. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline FEV1 + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t) | Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose | — |
| Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Day 1 to Week 12 | An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. |
| Patients With Positive Swab Test Results for Oral Candidiasis | Screening (Days -21 to -14), Randomization (Day 1), Weeks 1, 2, 3, 4, 6, 8, 10, 12 | Oropharyngeal examinations for visual evidence of oral candidiasis were conducted at each visit. Any visual evidence of oral candidiasis during the oropharyngeal exam was evaluated by obtaining and analyzing a swab of the suspect area. This outcomes indicates how many patients had positive swab test results. The total number of patients who had oropharyngeal exams at each timepoint are specified in the timepoint field. Appropriate therapy was to be initiated immediately at the discretion of the investigator and was not to be delayed for culture confirmation. Subjects with a culture-positive infection could continue participation in the study on appropriate anti-infective therapy, provided this therapy was not prohibited by the protocol. |
| 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Baseline (Day 1), Week 12, Endpoint | 24-hour urinary cortisol excretion was determined from 24-hour pooled-urine samples; urine was refrigerated until return to the investigational site after each 24-hour collection period. Urine was collected within 7 days of Day 1 and within 7 days of Week 12. Urine cortisol sample collection was not required at endpoint visit for subjects who terminated early from the study. |
| Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12 | Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (non-missing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
| Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12 | Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. PM PEF baseline was defined as the average of recorded (nonmissing) PM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
| The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12 | Day 1 to Week 12 | The analysis of probability of remaining in the study at Week 12 used the time to patient withdrawal for worsening asthma. Worsening asthma was defined as: 1. clinic visit FEV1 below the FEV1 stability limit value calculated on Day 1. 2. any 7-day run-in or treatment window (using information from the patient diary) during which the subject experienced: * 3 or more days in which the highest PEF has fallen below the PEF stability limit calculated on Day 1 * 3 or more days in which ≥12 inhalations/day of albuterol/salbutamol was used * 2 or more days in which the subject experienced a nighttime asthma symptom score of \>2 3. clinical asthma exacerbation, defined as worsening asthma requiring any treatment other than study drug or rescue albuterol/salbutamol including the use of systemic corticosteroids and/or ER visit or hospitalization. Patients who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment. |
| Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods | Baseline (Day -6 to Day 1 predose), Treatment (Day 1 to Week 12) | The change from baseline in the percentage of rescue-free 24-hour periods was analyzed with a marginal (also called population averaged) logistic model, with the response being the proportion of rescue-free 24-hour periods. The model included 2 time points of measurement for each subject: the baseline (the last 7 days before the treatment period) and the treatment period. The model contained covariates for sex, age, and treatment. Rescue-free days were as indicated in patient diaries. Data values are estimated means. |
| Maximum Observed Plasma Concentration (Cmax) | Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose | — |
| Time Of Maximum Observed Plasma Concentration (Tmax) | Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12 | Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. PM PEF baseline was defined as the average of recorded (nonmissing) PM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model that included data for all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
| Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | Baseline (Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12 | Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (nonmissing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model which includes data from all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
| Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12 | Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (nonmissing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model that included data for all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
Countries
Australia, Bulgaria, Canada, Croatia, Germany, Greece, Hungary, Ireland, Israel, New Zealand, Poland, Romania, Russia, Serbia, South Africa, Spain, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
1238 subjects with asthma at 180 centers were screened for enrollment. 889 subjects met entry criteria and were enrolled into the run-in period of the study. Of the 349 subjects who were not enrolled, 337 were excluded on the basis of inclusion/exclusion criteria, 5 subjects withdrew consent, and for 6 the reason given was other.
Participants by arm
| Arm | Count |
|---|---|
| Fp MDPI 50 mcg Fluticasone propionate (Fp) 50 mcg per dose twice a day (for a total daily dose of 100 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 107 |
| Fp MDPI 100 mcg Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 107 |
| Fp MDPI 200 mcg Fluticasone propionate (Fp) 200 mcg per dose twice a day (for a total daily dose of 400 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 106 |
| Fp MDPI 400 mcg Fluticasone propionate (Fp) 400 mcg per dose twice a day (for a total daily dose of 800 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 107 |
| Placebo MDPI Placebo twice a day using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 106 |
| Flovent Diskus 250mcg Fluticasone propionate (Fp) 250 mcg per dose twice a day (for a total daily dose of 500 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in an open-label manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 107 |
| Total | 640 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Pre-Assignment Period (Run-In Placebo) | Inclusion/exclusion criteria | 49 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pre-Assignment Period (Run-In Placebo) | Lost to Follow-up | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pre-Assignment Period (Run-In Placebo) | Other | 15 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pre-Assignment Period (Run-In Placebo) | Randomization criteria not met | 166 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pre-Assignment Period (Run-In Placebo) | Withdrawal by Subject | 17 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Adverse Event | 0 | 1 | 1 | 1 | 1 | 1 | 0 |
| Treatment Period | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period | Met stopping criteria | 0 | 16 | 13 | 19 | 16 | 33 | 15 |
| Treatment Period | Noncompliance to study medication | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Treatment Period | Physician Decision | 0 | 1 | 1 | 1 | 1 | 0 | 0 |
| Treatment Period | Protocol Violation | 0 | 5 | 4 | 10 | 6 | 8 | 12 |
| Treatment Period | Sponsor request | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Treatment Period | Withdrawal by Subject | 0 | 1 | 1 | 0 | 2 | 4 | 2 |
Baseline characteristics
| Characteristic | Fp MDPI 100 mcg | Fp MDPI 200 mcg | Fp MDPI 400 mcg | Placebo MDPI | Flovent Diskus 250mcg | Fp MDPI 50 mcg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 48.7 years STANDARD_DEVIATION 12.48 | 47.7 years STANDARD_DEVIATION 14.18 | 50.9 years STANDARD_DEVIATION 13.32 | 49.8 years STANDARD_DEVIATION 12.87 | 49.2 years STANDARD_DEVIATION 13.26 | 47.9 years STANDARD_DEVIATION 14.59 | 49.0 years STANDARD_DEVIATION 13.46 |
| Age, Customized Adolescents (12-17 years) | 3 participants | 1 participants | 1 participants | 1 participants | 1 participants | 2 participants | 9 participants |
| Age, Customized Adults (18-64 years) | 99 participants | 90 participants | 90 participants | 94 participants | 96 participants | 94 participants | 563 participants |
| Age, Customized Adults (65-84 years) | 5 participants | 15 participants | 16 participants | 11 participants | 10 participants | 11 participants | 68 participants |
| Body Mass Index | 30.4 kg/m^2 STANDARD_DEVIATION 7.6 | 29.8 kg/m^2 STANDARD_DEVIATION 8.12 | 30.1 kg/m^2 STANDARD_DEVIATION 6.81 | 30.5 kg/m^2 STANDARD_DEVIATION 8.83 | 29.6 kg/m^2 STANDARD_DEVIATION 6.03 | 31.3 kg/m^2 STANDARD_DEVIATION 17.88 | 30.3 kg/m^2 STANDARD_DEVIATION 10.02 |
| Forced Expiratory Volume in 1 Second (FEV1) | 2.031 liters STANDARD_DEVIATION 0.551 | 1.999 liters STANDARD_DEVIATION 0.525 | 2.016 liters STANDARD_DEVIATION 0.636 | 1.984 liters STANDARD_DEVIATION 0.565 | 1.955 liters STANDARD_DEVIATION 0.529 | 2.108 liters STANDARD_DEVIATION 0.662 | 2.016 liters STANDARD_DEVIATION 0.579 |
| Height | 168.7 cm STANDARD_DEVIATION 9.14 | 168.4 cm STANDARD_DEVIATION 7.86 | 167.4 cm STANDARD_DEVIATION 9.67 | 168.1 cm STANDARD_DEVIATION 8.57 | 168.0 cm STANDARD_DEVIATION 8.33 | 169.4 cm STANDARD_DEVIATION 13.04 | 168.3 cm STANDARD_DEVIATION 9.58 |
| % Predicted Expiratory Volume In 1 Second | 63.1 percent predicted FEV1 STANDARD_DEVIATION 9.5 | 63.4 percent predicted FEV1 STANDARD_DEVIATION 12.1 | 65.3 percent predicted FEV1 STANDARD_DEVIATION 11.4 | 63.1 percent predicted FEV1 STANDARD_DEVIATION 10 | 62.5 percent predicted FEV1 STANDARD_DEVIATION 12.1 | 63.7 percent predicted FEV1 STANDARD_DEVIATION 10.9 | 63.5 percent predicted FEV1 STANDARD_DEVIATION 11 |
| Qualifying Airway Reversibility | 27.3 percentage increase in FEV1 STANDARD_DEVIATION 14.7 | 30.4 percentage increase in FEV1 STANDARD_DEVIATION 25.2 | 29.1 percentage increase in FEV1 STANDARD_DEVIATION 19.5 | 28.9 percentage increase in FEV1 STANDARD_DEVIATION 19.1 | 26.8 percentage increase in FEV1 STANDARD_DEVIATION 15.7 | 31.6 percentage increase in FEV1 STANDARD_DEVIATION 22.4 | 29.0 percentage increase in FEV1 STANDARD_DEVIATION 19.8 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants | 2 participants | 0 participants | 1 participants | 7 participants |
| Race/Ethnicity, Customized Black | 12 participants | 12 participants | 13 participants | 8 participants | 11 participants | 9 participants | 65 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 7 participants | 8 participants | 12 participants | 6 participants | 9 participants | 5 participants | 47 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 100 participants | 98 participants | 95 participants | 100 participants | 98 participants | 102 participants | 593 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 94 participants | 93 participants | 91 participants | 96 participants | 95 participants | 96 participants | 565 participants |
| Sex: Female, Male Female | 55 Participants | 66 Participants | 72 Participants | 65 Participants | 58 Participants | 63 Participants | 379 Participants |
| Sex: Female, Male Male | 52 Participants | 40 Participants | 35 Participants | 41 Participants | 49 Participants | 44 Participants | 261 Participants |
| Weight | 86.6 kg STANDARD_DEVIATION 22.9 | 84.4 kg STANDARD_DEVIATION 21.89 | 84.4 kg STANDARD_DEVIATION 20.56 | 86.2 kg STANDARD_DEVIATION 25.19 | 83.3 kg STANDARD_DEVIATION 16.76 | 86.7 kg STANDARD_DEVIATION 23.73 | 85.3 kg STANDARD_DEVIATION 21.95 |
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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 106 | 4 / 107 | 5 / 106 | 7 / 107 | 5 / 107 | 6 / 106 |
| serious Total, serious adverse events | 0 / 106 | 1 / 107 | 1 / 106 | 0 / 107 | 1 / 107 | 1 / 106 |
Outcome results
Primary
Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period
Trough FEV1 was measured electronically by spirometry at morning (AM) investigational site visits, before administration of the AM dose of study drug, and before albuterol/salbutamol administration. The highest FEV1 value from 3 acceptable and 2 reproducible maneuvers was used. All FEV1 data were submitted to a central reading center for evaluation. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline FEV1 + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
Population: Full analysis set, including participants who contributed at least once to the analysis. Based on blinded data review, data from one site are excluded due to good clinical practice (GCP) concerns. Flovent Diskus data was used for confirmatory and exploratory endpoints; FEV1 data for Flovent Diskus is reported in outcome #12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.059 liters | Standard Error 0.0269 |
| Fp MDPI 100 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.101 liters | Standard Error 0.0268 |
| Fp MDPI 200 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.109 liters | Standard Error 0.0278 |
| Fp MDPI 400 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.125 liters | Standard Error 0.0274 |
| Placebo MDPI | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.053 liters | Standard Error 0.0283 |
Comparison: A linear in log-dose trend contrast was constructed to evaluate the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo). A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 0.05 level. Specifically, the 2-sided linear in log-dose time-averaged trend test was first performed at the 0.05 level of significance.p-value: 0.0604Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.063795% CI: [-0.004, 0.149]mixed model for repeated measures
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.158595% CI: [-0.022, 0.133]mixed model for repeated measures
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.222195% CI: [-0.029, 0.124]mixed model for repeated measures
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: =0.869495% CI: [-0.07, 0.083]mixed model for repeated measures
Secondary
24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint
24-hour urinary cortisol excretion was determined from 24-hour pooled-urine samples; urine was refrigerated until return to the investigational site after each 24-hour collection period. Urine was collected within 7 days of Day 1 and within 7 days of Week 12. Urine cortisol sample collection was not required at endpoint visit for subjects who terminated early from the study.
Time frame: Baseline (Day 1), Week 12, Endpoint
Population: Urine cortisol analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fp MDPI 50 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Week 12 | 71.8 nmol/day | Standard Deviation 48.37 |
| Fp MDPI 50 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Endpoint | 71.0 nmol/day | Standard Deviation 48.31 |
| Fp MDPI 50 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Baseline | 65.3 nmol/day | Standard Deviation 42.69 |
| Fp MDPI 100 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Endpoint | 61.5 nmol/day | Standard Deviation 45.73 |
| Fp MDPI 100 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Week 12 | 61.5 nmol/day | Standard Deviation 45.73 |
| Fp MDPI 100 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Baseline | 63.8 nmol/day | Standard Deviation 44.7 |
| Fp MDPI 200 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Week 12 | 66.8 nmol/day | Standard Deviation 53.96 |
| Fp MDPI 200 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Baseline | 66.6 nmol/day | Standard Deviation 45.53 |
| Fp MDPI 200 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Endpoint | 65.8 nmol/day | Standard Deviation 53.33 |
| Fp MDPI 400 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Endpoint | 45.0 nmol/day | Standard Deviation 38.33 |
| Fp MDPI 400 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Week 12 | 46.2 nmol/day | Standard Deviation 38.67 |
| Fp MDPI 400 mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Baseline | 57.4 nmol/day | Standard Deviation 34.68 |
| Placebo MDPI | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Endpoint | 74.4 nmol/day | Standard Deviation 54.97 |
| Placebo MDPI | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Baseline | 74.3 nmol/day | Standard Deviation 43.54 |
| Placebo MDPI | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Week 12 | 69.2 nmol/day | Standard Deviation 49.56 |
| Flovent Diskus 250mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Week 12 | 58.5 nmol/day | Standard Deviation 43.75 |
| Flovent Diskus 250mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Baseline | 66.2 nmol/day | Standard Deviation 42.68 |
| Flovent Diskus 250mcg | 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint | Endpoint | 58.4 nmol/day | Standard Deviation 43.49 |
Secondary
Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t)
Time frame: Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
Population: Pharmacokinetic analysis set. Two participants in the Fp MDPI 100 mcg treatment arm did not have AUC data. PK tests not run on participants in the Placebo MDPI arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t) | 117.6 pg*hr/mL | Standard Deviation 145.79 |
| Fp MDPI 100 mcg | Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t) | 126.8 pg*hr/mL | Standard Deviation 33.73 |
| Fp MDPI 200 mcg | Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t) | 292.0 pg*hr/mL | Standard Deviation 162.28 |
| Fp MDPI 400 mcg | Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t) | 462.8 pg*hr/mL | Standard Deviation 262.45 |
| Flovent Diskus 250mcg | Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t) | 162.3 pg*hr/mL | Standard Deviation 74.79 |
Secondary
Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods
The change from baseline in the percentage of rescue-free 24-hour periods was analyzed with a marginal (also called population averaged) logistic model, with the response being the proportion of rescue-free 24-hour periods. The model included 2 time points of measurement for each subject: the baseline (the last 7 days before the treatment period) and the treatment period. The model contained covariates for sex, age, and treatment. Rescue-free days were as indicated in patient diaries. Data values are estimated means.
Time frame: Baseline (Day -6 to Day 1 predose), Treatment (Day 1 to Week 12)
Population: Full analysis set including participants who contributed at least once to the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods | 22.78 percentage of total 24 hour periods | Standard Error 4.016 |
| Fp MDPI 100 mcg | Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods | 26.41 percentage of total 24 hour periods | Standard Error 4.013 |
| Fp MDPI 200 mcg | Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods | 16.18 percentage of total 24 hour periods | Standard Error 3.662 |
| Fp MDPI 400 mcg | Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods | 28.05 percentage of total 24 hour periods | Standard Error 3.951 |
| Placebo MDPI | Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods | 27.15 percentage of total 24 hour periods | Standard Error 4.475 |
| Flovent Diskus 250mcg | Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods | 15.87 percentage of total 24 hour periods | Standard Error 3.75 |
Comparison: Estimates computed from a generalized linear logistic model with gender and age as covariates and allows correlation between estimates on the same subject. Interpretation of the estimates is that they are the average over the population at the average level of continuous covariate (age) averaged over discrete covariate (gender).p-value: 0.8811695% CI: [-11.12, 12.91]Regression, Linear
Comparison: Estimates computed from a generalized linear logistic model with gender and age as covariates and allows correlation between estimates on the same subject. Interpretation of the estimates is that they are the average over the population at the average level of continuous covariate (age) averaged over discrete covariate (gender).p-value: 0.0597795% CI: [-22.64, 0.68]Regression, Linear
Comparison: Estimates computed from a generalized linear logistic model with gender and age as covariates and allows correlation between estimates on the same subject. Interpretation of the estimates is that they are the average over the population at the average level of continuous covariate (age) averaged over discrete covariate (gender).p-value: 0.9042695% CI: [-13.02, 11.54]Regression, Linear
Comparison: Estimates computed from a generalized linear logistic model with gender and age as covariates and allows correlation between estimates on the same subject. Interpretation of the estimates is that they are the average over the population at the average level of continuous covariate (age) averaged over discrete covariate (gender).p-value: 0.473195% CI: [-16.57, 7.82]Regression, Linear
Secondary
Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period
Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. PM PEF baseline was defined as the average of recorded (nonmissing) PM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
Population: Full analysis set, including participants who contributed at least once to the analysis. Based on blinded data review, data from one site are excluded due to good clinical practice (GCP) concerns. Flovent Diskus data was used for confirmatory and exploratory endpoints; evening PEF data for Flovent Diskus is reported in outcome #14.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 3.81 liters/minute | Standard Error 4.183 |
| Fp MDPI 100 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 6.41 liters/minute | Standard Error 4.209 |
| Fp MDPI 200 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 7.45 liters/minute | Standard Error 4.335 |
| Fp MDPI 400 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 10.97 liters/minute | Standard Error 4.208 |
| Placebo MDPI | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 3.42 liters/minute | Standard Error 4.462 |
Comparison: A linear in log-dose trend contrast was constructed to evaluate the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo). A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 0.05 level. Specifically, the 2-sided linear in log-dose time-averaged trend test was first performed at the 0.05 level of significance.p-value: 0.2879Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.216695% CI: [-4.45, 19.56]Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.516795% CI: [-8.17, 16.23]Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.625895% CI: [-9.06, 15.05]Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.948795% CI: [-11.6, 12.39]Regression, Linear
Secondary
Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period
Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (non-missing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
Population: Full analysis set, including participants who contributed at least once to the analysis. Based on blinded data review, data from one site are excluded due to good clinical practice (GCP) concerns. Flovent Diskus data was used for confirmatory and exploratory endpoints; morning PEF data for Flovent Diskus is reported in outcome #13.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 10.48 liters/minute | Standard Error 4.299 |
| Fp MDPI 100 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 9.34 liters/minute | Standard Error 4.245 |
| Fp MDPI 200 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 10.03 liters/minute | Standard Error 4.42 |
| Fp MDPI 400 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 9.61 liters/minute | Standard Error 4.307 |
| Placebo MDPI | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 2.24 liters/minute | Standard Error 4.507 |
Comparison: A linear in log-dose trend contrast was constructed to evaluate the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo). A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 0.05 level. Specifically, the 2-sided linear in log-dose time-averaged trend test was first performed at the 0.05 level of significance.p-value: 0.1512Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.236195% CI: [-4.83, 19.56]Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.216995% CI: [-4.59, 20.15]Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.252395% CI: [-5.07, 19.26]Regression, Linear
Comparison: No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.p-value: 0.185895% CI: [-3.98, 20.45]Regression, Linear
Secondary
Maximum Observed Plasma Concentration (Cmax)
Time frame: Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
Population: Pharmacokinetic analysis set. Two participants in the Fp MDPI 100 mcg treatment arm did not have AUC data. PK tests not run on participants in the Placebo MDPI arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Maximum Observed Plasma Concentration (Cmax) | 19.1 pg/mL | Standard Deviation 15.53 |
| Fp MDPI 100 mcg | Maximum Observed Plasma Concentration (Cmax) | 26.5 pg/mL | Standard Deviation 6.16 |
| Fp MDPI 200 mcg | Maximum Observed Plasma Concentration (Cmax) | 55.2 pg/mL | Standard Deviation 29.12 |
| Fp MDPI 400 mcg | Maximum Observed Plasma Concentration (Cmax) | 83.0 pg/mL | Standard Deviation 44.32 |
| Flovent Diskus 250mcg | Maximum Observed Plasma Concentration (Cmax) | 32.5 pg/mL | Standard Deviation 13.92 |
Secondary
Patients With Positive Swab Test Results for Oral Candidiasis
Oropharyngeal examinations for visual evidence of oral candidiasis were conducted at each visit. Any visual evidence of oral candidiasis during the oropharyngeal exam was evaluated by obtaining and analyzing a swab of the suspect area. This outcomes indicates how many patients had positive swab test results. The total number of patients who had oropharyngeal exams at each timepoint are specified in the timepoint field. Appropriate therapy was to be initiated immediately at the discretion of the investigator and was not to be delayed for culture confirmation. Subjects with a culture-positive infection could continue participation in the study on appropriate anti-infective therapy, provided this therapy was not prohibited by the protocol.
Time frame: Screening (Days -21 to -14), Randomization (Day 1), Weeks 1, 2, 3, 4, 6, 8, 10, 12
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 8 | 0 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Day 1 | 0 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 6 | 0 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 1 | 0 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Screening | 0 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 4 | 1 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 2 | 0 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 3 | 0 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 12 | 0 participants |
| Fp MDPI 50 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 10 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 3 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Screening | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 6 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Day 1 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 8 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 10 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 1 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 12 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 2 | 0 participants |
| Fp MDPI 100 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 4 | 0 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 10 | 0 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 4 | 1 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 1 | 0 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 8 | 1 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 12 | 0 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 6 | 0 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 3 | 0 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 2 | 1 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Screening | 0 participants |
| Fp MDPI 200 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Day 1 | 1 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 6 | 1 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 8 | 0 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 3 | 4 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 10 | 1 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 1 | 0 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Screening | 0 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 12 | 1 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 2 | 2 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 4 | 1 participants |
| Fp MDPI 400 mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Day 1 | 0 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Screening | 0 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Week 4 | 0 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Week 1 | 1 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Week 8 | 0 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Week 6 | 0 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Week 3 | 0 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Day 1 | 1 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Week 12 | 0 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Week 2 | 0 participants |
| Placebo MDPI | Patients With Positive Swab Test Results for Oral Candidiasis | Week 10 | 0 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 2 | 0 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 12 | 1 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 1 | 1 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 8 | 1 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Screening | 0 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Day 1 | 1 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 4 | 0 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 6 | 0 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 3 | 0 participants |
| Flovent Diskus 250mcg | Patients With Positive Swab Test Results for Oral Candidiasis | Week 10 | 0 participants |
Secondary
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period
An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time frame: Day 1 to Week 12
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 31 participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 3 participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 4 participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AEs | 1 participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AEs | 1 participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 1 participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AEs | 1 participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 27 participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 1 participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AEs | 1 participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AEs | 1 participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AEs | 1 participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 6 participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 34 participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 1 participants |
| Fp MDPI 400 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 participants |
| Fp MDPI 400 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 1 participants |
| Fp MDPI 400 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 9 participants |
| Fp MDPI 400 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AEs | 1 participants |
| Fp MDPI 400 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AEs | 0 participants |
| Fp MDPI 400 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 41 participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 33 participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AEs | 1 participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 1 participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 5 participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AEs | 1 participants |
| Flovent Diskus 250mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 participants |
| Flovent Diskus 250mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 2 participants |
| Flovent Diskus 250mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AEs | 0 participants |
| Flovent Diskus 250mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AEs | 0 participants |
| Flovent Diskus 250mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 0 participants |
| Flovent Diskus 250mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 27 participants |
Secondary
The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12
The analysis of probability of remaining in the study at Week 12 used the time to patient withdrawal for worsening asthma. Worsening asthma was defined as: 1. clinic visit FEV1 below the FEV1 stability limit value calculated on Day 1. 2. any 7-day run-in or treatment window (using information from the patient diary) during which the subject experienced: * 3 or more days in which the highest PEF has fallen below the PEF stability limit calculated on Day 1 * 3 or more days in which ≥12 inhalations/day of albuterol/salbutamol was used * 2 or more days in which the subject experienced a nighttime asthma symptom score of \>2 3. clinical asthma exacerbation, defined as worsening asthma requiring any treatment other than study drug or rescue albuterol/salbutamol including the use of systemic corticosteroids and/or ER visit or hospitalization. Patients who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment.
Time frame: Day 1 to Week 12
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fp MDPI 50 mcg | The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12 | 0.6872 probability |
| Fp MDPI 100 mcg | The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12 | 0.6330 probability |
| Fp MDPI 200 mcg | The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12 | 0.5852 probability |
| Fp MDPI 400 mcg | The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12 | 0.6109 probability |
| Placebo MDPI | The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12 | 0.4722 probability |
| Flovent Diskus 250mcg | The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12 | 0.5657 probability |
Comparison: P-value for comparison of survival curve to placebop-value: 0.0341Log Rank
Comparison: P-value for comparison of survival curve to placebop-value: 0.034Log Rank
Comparison: P-value for comparison of survival curve to placebop-value: 0.0058Log Rank
Comparison: P-value for comparison of survival curve to placebop-value: 0.0018Log Rank
Comparison: P-value for comparison of survival curve to placebop-value: 0.1006Log Rank
Secondary
Time Of Maximum Observed Plasma Concentration (Tmax)
Time frame: Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
Population: Pharmacokinetic analysis set. Two participants in the Fp MDPI 100 mcg treatment arm did not have AUC data. PK tests not run on participants in the Placebo MDPI arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Time Of Maximum Observed Plasma Concentration (Tmax) | 1.0 hours | Standard Deviation 0.54 |
| Fp MDPI 100 mcg | Time Of Maximum Observed Plasma Concentration (Tmax) | 1.2 hours | Standard Deviation 1.85 |
| Fp MDPI 200 mcg | Time Of Maximum Observed Plasma Concentration (Tmax) | 2.2 hours | Standard Deviation 3.58 |
| Fp MDPI 400 mcg | Time Of Maximum Observed Plasma Concentration (Tmax) | 1.4 hours | Standard Deviation 2.6 |
| Flovent Diskus 250mcg | Time Of Maximum Observed Plasma Concentration (Tmax) | 1.8 hours | Standard Deviation 2.75 |
Other Pre-specified
Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm)
Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (nonmissing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model which includes data from all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
Population: Full analysis set, including participants who contributed at least once to the analysis. Based on blinded data review, data from one site are excluded due to good clinical practice (GCP) concerns.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 0.063 liters | Standard Error 0.027 |
| Fp MDPI 100 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 0.102 liters | Standard Error 0.0269 |
| Fp MDPI 200 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 0.113 liters | Standard Error 0.0279 |
| Fp MDPI 400 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 0.129 liters | Standard Error 0.0274 |
| Placebo MDPI | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 0.057 liters | Standard Error 0.0284 |
| Flovent Diskus 250mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 0.110 liters | Standard Error 0.0274 |
p-value: =0.616195% CI: [-0.057, 0.096]mixed model for repeated measures
p-value: 0.924595% CI: [-0.973, 0.08]mixed model for repeated measures
p-value: 0.843495% CI: [-0.083, 0.068]mixed model for repeated measures
p-value: 0.224195% CI: [-0.122, 0.029]mixed model for repeated measures
p-value: 0.182295% CI: [-0.13, 0.025]mixed model for repeated measures
Other Pre-specified
Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm)
Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. PM PEF baseline was defined as the average of recorded (nonmissing) PM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model that included data for all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
Population: Full analysis set, including participants who contributed at least once to the analysis. Based on blinded data review, data from one site are excluded due to good clinical practice (GCP) concerns.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 4.22 liters/minute | Standard Error 4.245 |
| Fp MDPI 100 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 6.52 liters/minute | Standard Error 4.275 |
| Fp MDPI 200 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 7.89 liters/minute | Standard Error 4.397 |
| Fp MDPI 400 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 11.72 liters/minute | Standard Error 4.271 |
| Placebo MDPI | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 3.35 liters/minute | Standard Error 4.518 |
| Flovent Diskus 250mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 12.4 liters/minute | Standard Error 4.309 |
p-value: 0.910195% CI: [-12.59, 11.22]Regression, Linear
p-value: 0.463495% CI: [-16.6, 7.57]Regression, Linear
p-value: 0.333395% CI: [-17.8, 6.05]Regression, Linear
p-value: 0.176395% CI: [-20.06, 3.69]Regression, Linear
p-value: 0.146995% CI: [-21.3, 3.19]Regression, Linear
Other Pre-specified
Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm)
Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (nonmissing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model that included data for all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
Population: Full analysis set, including participants who contributed at least once to the analysis. Based on blinded data review, data from one site are excluded due to good clinical practice (GCP) concerns.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 50 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 10.85 liters/minute | Standard Error 4.245 |
| Fp MDPI 100 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 9.39 liters/minute | Standard Error 4.193 |
| Fp MDPI 200 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 10.29 liters/minute | Standard Error 4.362 |
| Fp MDPI 400 mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 10.40 liters/minute | Standard Error 4.254 |
| Placebo MDPI | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 2.52 liters/minute | Standard Error 4.453 |
| Flovent Diskus 250mcg | Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus Treatment Arm) | 15.97 liters/minute | Standard Error 4.283 |
p-value: 0.356895% CI: [-17.42, 6.29]Regression, Linear
p-value: 0.353195% CI: [-17.67, 6.32]Regression, Linear
p-value: 0.272495% CI: [-18.35, 5.19]Regression, Linear
p-value: =0.396495% CI: [-16.95, 6.72]Regression, Linear
p-value: 0.029695% CI: [-25.57, -1.33]Regression, Linear