Endometriosis
Conditions
Keywords
Elagolix, Endometriosis associated pain, Dysmenorrhea (DYS), Non-menstrual pelvic pain (NMPP), ORILISSA
Brief summary
The objective of this study is to evaluate safety and efficacy of elagolix in the management of moderate to severe endometriosis-associated pain in adult premenopausal female participants including the safety and efficacy of elagolix in combination with concomitant hormonal add-back therapy.
Interventions
Tablets
Tablet
DRUGElagolix
Tablet
Tablets
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 49 Years
Healthy volunteers
No
Inclusion criteria
* Participant is a premenopausal female 18 to 49 years of age (inclusive) at the time of Screening. * Participant has a documented surgical diagnosis (e.g., laparoscopy or laparotomy) of endometriosis established by visualization within 10 years prior to entry into Washout or Screening. * Participant must agree to use only protocol specified rescue analgesics during the Screening and Treatment Periods for endometriosis-associated pain. * Participant must have the following documented in the e-Diary during the last 35 days prior to Study Day 1: 1. At least 2 days of moderate or severe dysmenorrhea (DYS) AND either 2. At least 2 days of moderate or severe non-menstrual pelvic pain (NMPP) and an average NMPP score of at least 1.0, OR 3. At least 4 days of moderate or severe NMPP and an average NMPP score of at least 0.5.
Exclusion criteria
* Participant has chronic pelvic pain that is not caused by endometriosis, that requires chronic analgesic therapy, which would interfere with the assessment of endometriosis-related pain. * Participant is using any systemic corticosteroids for over 14 days within 3 months prior to Screening or is likely to require treatment with systemic corticosteroids during the course of the study. Over-the-counter and prescription topical, inhaled or intranasal corticosteroids are allowed. * Participant has a history of any major depression or post-traumatic stress disorder (PTSD) within 2 years of the screening visit or other major psychiatric disorder at any time. * Participant has a history of suicide attempts or answered yes to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) within the last 1 year at Screening or prior to randomization on Day 1. * Participant has any history of osteoporosis or other metabolic bone disease or any condition that would interfere with obtaining adequate dual energy x-ray absorptiometry (DXA) measurements * Screening DXA results of the lumbar spine (L1-L4), femoral neck or total hip bone mineral density (BMD) corresponding to less than 2.0 or more standard deviations below normal. * Participant has either: 1. a newly diagnosed, clinically significant medical condition that requires therapeutic intervention (e.g., new onset hypertension), that has not been stabilized 30 days prior to randomization on Day 1 OR 2. a clinically significant medical condition that is anticipated to require intervention during the course of study participation (e.g., anticipated major elective surgery) OR 3. an unstable medical condition that makes the subject an unsuitable candidate for the study in the opinion of the Investigator, (including, but not limited to, uncontrolled diabetes mellitus, uncontrolled hypertension, epilepsy requiring anti-epileptic medication, unstable angina, confirmed inflammatory bowel disease, hyperprolactinemia, clinically significant infection or injury). * Participant has any conditions contraindicated with use of E2/NETA.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Co-Primary Endpoint: Percentage of Participants With a Response for Dysmenorrhea (DYS) at Months 6 and 12 Based on Daily Assessment | Month 6, Month 12 | Participants recorded rescue analgesic use for endometriosis-associated pain daily and DYS (pain during menstruation ) and its impact on daily activities each day of their period in an electronic diary (e-Diary). DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over 35 days prior to each visit. Response was defined as a reduction of -0.92 or more from baseline in DYS as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a \< 15% increase in average rescue analgesic pill count and no additional analgesic). |
| Co-Primary Endpoint: Percentage of Participants With a Response for Non-menstrual Pelvic Pain (NMPP) at Months 6 and 12 Based on Daily Assessment | Month 6, Month 12 | Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over the 35 days prior to each visit. Response was defined as a reduction of -0.55 or greater from baseline for NMPP as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a \< 15% increase in average pill count of rescue analgesics and no additional analgesics). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in DYS at Month 3 Based on Daily Assessment | Baseline, Month 3 | Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: 0: No discomfort 1. Mild discomfort but I was easily able to do the things I usually do 2. Moderate discomfort or pain that made it difficult to do some of the things I usually do 3. Severe pain that made it difficult to do the things I usually do. Pain scores were averaged over the 35 days prior to each visit. |
| Change From Baseline in Non-menstrual Pelvic Pain (NMPP) at Month 12 Based on Daily Assessment | Baseline, Month 12 | Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over the 35 days prior to each visit. |
| Change From Baseline in NMPP at Month 6 Based on Daily Assessment | Baseline, Month 6 | Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over the 35 days prior to each visit. |
| Change From Baseline in NMPP at Month 3 Based on Daily Assessment | Baseline, Month 3 | Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over the 35 days prior to each visit. |
| Change From Baseline to Month 6 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score | Baseline, Month 6 | The PROMIS Fatigue Short Form 6a is self-administered and composed of 6 questions to evaluate fatigue over the past 7 days. All questions employ the following five response options: 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always. The PROMIS Fatigue 6a score is calculated as a T-score, which is a standardized score with a mean of 50 (based on the average for the United States general population) and a standard deviation (SD) of 10. Higher scores indicate higher levels of fatigue. A decrease in score (negative change from baseline) indicates improvement in fatigue. |
| Change From Baseline in Dyspareunia (DYSP) at Month 12 Based on Daily Assessment | Baseline, Month 12 | Participants assessed DYSP each day in an e-Diary according to the following response options: * 0: None; No discomfort during sexual intercourse * 1: Mild; Able to tolerate the discomfort during sexual intercourse * 2: Moderate; Intercourse was interrupted due to pain * 3: Severe; Avoided intercourse because of pain * Not applicable; I was not sexually active for reasons other than endometriosis or did not have sexual intercourse. Pain scores were averaged over the 35 days prior to each visit. Responses of Not Applicable were excluded. |
| Change From Baseline in DYS at Month 12 Based on Daily Assessment | Baseline, Month 12 | Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores were averaged over the 35 days prior to each visit. |
| Change From Baseline in DYSP at Month 3 Based on Daily Assessment | Baseline, Month 3 | Participants assessed DYSP each day in an e-Diary according to the following response options: * 0: None; No discomfort during sexual intercourse * 1: Mild; Able to tolerate the discomfort during sexual intercourse * 2: Moderate; Intercourse was interrupted due to pain * 3: Severe; Avoided intercourse because of pain * Not applicable; I was not sexually active for reasons other than endometriosis or did not have sexual intercourse. Pain scores were averaged over the 35 days prior to each visit. Responses of Not Applicable were excluded. |
| Change From Baseline to Month 12 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score | Baseline, Month 12 | The PROMIS Fatigue Short Form 6a is self-administered and composed of 6 questions to evaluate fatigue over the past 7 days. All questions employ the following five response options: 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always. The PROMIS Fatigue 6a score is calculated as a T-score, which is a standardized score with a mean of 50 (based on the average for the United States general population) and a standard deviation (SD) of 10. Higher scores indicate higher levels of fatigue. A decrease in score (negative change from baseline) indicates improvement in fatigue. |
| Change From Baseline in Endometriosis-Associated Pain Score at Month 12 Assessed With Numeric Rating Scale (NRS) | Baseline, Month 12 | The NRS measured endometriosis-associated pain with and without menstruation on an 11-point scale from 0 = no pain to 10 = worst pain ever. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit. |
| Change From Baseline in Endometriosis-Associated Pain Score at Month 6 Assessed With NRS | Baseline, Month 6 | The NRS measured endometriosis-associated pain with and without menstruation on an 11-point scale from 0 = no pain to 10 = worst pain ever. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit. |
| Change From Baseline in Endometriosis-Associated Pain Score at Month 3 Assessed With NRS | Baseline, Month 3 | The NRS measured endometriosis-associated pain with and without menstruation on an 11-point scale from 0 = no pain to 10 = worst pain ever. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit. |
| Change From Baseline in DYSP at Month 6 Based on Daily Assessment | Baseline, Month 6 | Participants assessed DYSP each day in an e-Diary according to the following response options: * 0: None; No discomfort during sexual intercourse * 1: Mild; Able to tolerate the discomfort during sexual intercourse * 2: Moderate; Intercourse was interrupted due to pain * 3: Severe; Avoided intercourse because of pain * Not applicable; I was not sexually active for reasons other than endometriosis or did not have sexual intercourse. Pain scores were averaged over the 35 days prior to each visit. Responses of Not Applicable were excluded. |
| Change From Baseline in DYS at Month 6 Based on Daily Assessment | Baseline, Month 6 | Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: 0: No discomfort 1. Mild discomfort but I was easily able to do the things I usually do 2. Moderate discomfort or pain that made it difficult to do some of the things I usually do 3. Severe pain that made it difficult to do the things I usually do. Pain scores were averaged over the 35 days prior to each visit. |
Countries
Canada, Puerto Rico, United States
Participant flow
Recruitment details
A total of 679 subjects were treated at 137 sites in 2 countries (US \[including Puerto Rico\] and Canada). Of the 679 subjects who were treated on study, 299 subjects discontinued study drug prematurely during the Placebo-Controlled Treatment Period and 240 discontinued study drug prematurely during the Open-Label Treatment Period.
Pre-assignment details
Participants were randomly assigned on Study Day 1 in a 4:1:2 ratio as follows: * elagolix 200 mg twice daily (BID) plus estradiol/norethindrone acetate (E2/NETA) 1 mg/0.5 mg once daily (QD) * elagolix 200 mg BID * placebo Data are presented for the 12-month Placebo-Controlled Treatment Period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo for the 12-month placebo-controlled Treatment Period, followed by elagolix 200 mg BID plus E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period. | 193 |
| Elagolix / Elagolix + E2/NETA Elagolix 200 mg BID alone for the first 6 months of the 12-month placebo-controlled Treatment Period and elagolix 200 mg BID+E2/NETA 1 mg/0.5 mg QD for the second 6 months, followed by elagolix 200 mg BID + E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period. | 97 |
| Elagolix + E2/NETA Elagolix 200 mg BID + E2/NETA 1 mg/0.5 mg QD for the 12-month placebo-controlled Treatment Period, followed by elagolix 200 mg BID plus E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period. | 389 |
| Total | 679 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Period | Adverse Event | 3 | 2 | 7 |
| Double-Blind Period | Lost to Follow-up | 2 | 3 | 9 |
| Double-Blind Period | Non-compliance with study procedures | 0 | 2 | 4 |
| Double-Blind Period | Other | 10 | 3 | 17 |
| Double-Blind Period | Pregnancy | 5 | 0 | 0 |
| Double-Blind Period | Requires surgery or invasive intervention for treatment of endometriosis | 2 | 0 | 1 |
| Double-Blind Period | Withdrawal by Subject | 14 | 2 | 14 |
| Follow-Up Period | Adverse Event | 16 | 8 | 37 |
| Follow-Up Period | COVID-19 logistical restrictions | 1 | 0 | 0 |
| Follow-Up Period | Exclusionary medications | 1 | 1 | 5 |
| Follow-Up Period | Lost to Follow-up | 28 | 15 | 50 |
| Follow-Up Period | Non-compliance with study procedures | 4 | 1 | 6 |
| Follow-Up Period | Other | 14 | 10 | 31 |
| Follow-Up Period | Pregnancy | 7 | 0 | 18 |
| Follow-Up Period | Requires surgery or invasive intervention for treatment of endometriosis | 3 | 1 | 2 |
| Follow-Up Period | Withdrawal by Subject | 18 | 11 | 55 |
| Open-Label Period | Adverse Event | 1 | 2 | 2 |
| Open-Label Period | Exclusionary medications | 0 | 0 | 1 |
| Open-Label Period | Lost to Follow-up | 1 | 2 | 8 |
| Open-Label Period | Non-compliance with study procedures | 1 | 1 | 2 |
| Open-Label Period | Other | 1 | 1 | 6 |
| Open-Label Period | Requires surgery or invasive intervention for treatment of endometriosis | 0 | 0 | 2 |
| Open-Label Period | Withdrawal by Subject | 12 | 5 | 24 |
| Screening Period | Other | 1 | 0 | 0 |
| Screening Period | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Elagolix / Elagolix + E2/NETA | Elagolix + E2/NETA |
|---|---|---|---|---|
| Age, Continuous | 32.5 years STANDARD_DEVIATION 6.69 | 33.1 years STANDARD_DEVIATION 6.72 | 32.5 years STANDARD_DEVIATION 6.44 | 32.3 years STANDARD_DEVIATION 6.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 106 Participants | 37 Participants | 11 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 573 Participants | 156 Participants | 86 Participants | 331 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 99 Participants | 31 Participants | 19 Participants | 49 Participants |
| Race (NIH/OMB) More than one race | 12 Participants | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 561 Participants | 159 Participants | 74 Participants | 328 Participants |
| Sex/Gender, Customized Female | 679 Participants | 193 Participants | 97 Participants | 389 Participants |
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 | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 194 | 0 / 98 | 0 / 389 | 0 / 194 | 0 / 98 | 0 / 389 | 0 / 106 | 0 / 59 | 0 / 215 | 0 / 194 | 0 / 98 | 0 / 389 |
| other Total, other adverse events | 1 / 194 | 0 / 98 | 1 / 389 | 89 / 194 | 74 / 98 | 236 / 389 | 60 / 106 | 32 / 59 | 125 / 215 | 2 / 194 | 3 / 98 | 6 / 389 |
| serious Total, serious adverse events | 0 / 194 | 0 / 98 | 1 / 389 | 8 / 194 | 2 / 98 | 14 / 389 | 7 / 106 | 2 / 59 | 10 / 215 | 2 / 194 | 0 / 98 | 1 / 389 |
Outcome results
Primary
Co-Primary Endpoint: Percentage of Participants With a Response for Dysmenorrhea (DYS) at Months 6 and 12 Based on Daily Assessment
Participants recorded rescue analgesic use for endometriosis-associated pain daily and DYS (pain during menstruation ) and its impact on daily activities each day of their period in an electronic diary (e-Diary). DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over 35 days prior to each visit. Response was defined as a reduction of -0.92 or more from baseline in DYS as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a \< 15% increase in average rescue analgesic pill count and no additional analgesic).
Time frame: Month 6, Month 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment at given time point. Last observation carried forward. Per protocol, the primary comparison for the co-primary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Co-Primary Endpoint: Percentage of Participants With a Response for Dysmenorrhea (DYS) at Months 6 and 12 Based on Daily Assessment | Month 6 | 23.7 percentage of participants |
| Placebo | Co-Primary Endpoint: Percentage of Participants With a Response for Dysmenorrhea (DYS) at Months 6 and 12 Based on Daily Assessment | Month 12 | 29.1 percentage of participants |
| Elagolix + E2/NETA | Co-Primary Endpoint: Percentage of Participants With a Response for Dysmenorrhea (DYS) at Months 6 and 12 Based on Daily Assessment | Month 6 | 62.8 percentage of participants |
| Elagolix + E2/NETA | Co-Primary Endpoint: Percentage of Participants With a Response for Dysmenorrhea (DYS) at Months 6 and 12 Based on Daily Assessment | Month 12 | 63.8 percentage of participants |
Comparison: Month 6p-value: <0.00195% CI: [3.711, 8.176]Regression, Logistic
Comparison: Month 12p-value: <0.00195% CI: [2.968, 6.331]Regression, Logistic
Primary
Co-Primary Endpoint: Percentage of Participants With a Response for Non-menstrual Pelvic Pain (NMPP) at Months 6 and 12 Based on Daily Assessment
Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over the 35 days prior to each visit. Response was defined as a reduction of -0.55 or greater from baseline for NMPP as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a \< 15% increase in average pill count of rescue analgesics and no additional analgesics).
Time frame: Month 6, Month 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment at given time point. Last observation carried forward. Per protocol, the primary comparison for the co-primary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Co-Primary Endpoint: Percentage of Participants With a Response for Non-menstrual Pelvic Pain (NMPP) at Months 6 and 12 Based on Daily Assessment | Month 6 | 36.8 percentage of participants |
| Placebo | Co-Primary Endpoint: Percentage of Participants With a Response for Non-menstrual Pelvic Pain (NMPP) at Months 6 and 12 Based on Daily Assessment | Month 12 | 42.3 percentage of participants |
| Elagolix + E2/NETA | Co-Primary Endpoint: Percentage of Participants With a Response for Non-menstrual Pelvic Pain (NMPP) at Months 6 and 12 Based on Daily Assessment | Month 6 | 51.3 percentage of participants |
| Elagolix + E2/NETA | Co-Primary Endpoint: Percentage of Participants With a Response for Non-menstrual Pelvic Pain (NMPP) at Months 6 and 12 Based on Daily Assessment | Month 12 | 54.3 percentage of participants |
Comparison: Month 6p-value: <0.00195% CI: [1.275, 2.605]Regression, Logistic
Comparison: Month 12p-value: 0.00795% CI: [1.146, 2.326]Regression, Logistic
Secondary
Change From Baseline in DYS at Month 12 Based on Daily Assessment
Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in DYS at Month 12 Based on Daily Assessment | -0.73 score on a scale | Standard Error 0.077 |
| Elagolix + E2/NETA | Change From Baseline in DYS at Month 12 Based on Daily Assessment | -1.73 score on a scale | Standard Error 0.055 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: <0.00195% CI: [-1.18, -0.809]mixed model repeated measures (MMRM)
Secondary
Change From Baseline in DYS at Month 3 Based on Daily Assessment
Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: 0: No discomfort 1. Mild discomfort but I was easily able to do the things I usually do 2. Moderate discomfort or pain that made it difficult to do some of the things I usually do 3. Severe pain that made it difficult to do the things I usually do. Pain scores were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 3
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in DYS at Month 3 Based on Daily Assessment | -0.56 score on a scale | Standard Error 0.069 |
| Elagolix + E2/NETA | Change From Baseline in DYS at Month 3 Based on Daily Assessment | -1.54 score on a scale | Standard Error 0.049 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: <0.00195% CI: [-1.156, -0.823]MMRM
Secondary
Change From Baseline in DYS at Month 6 Based on Daily Assessment
Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: 0: No discomfort 1. Mild discomfort but I was easily able to do the things I usually do 2. Moderate discomfort or pain that made it difficult to do some of the things I usually do 3. Severe pain that made it difficult to do the things I usually do. Pain scores were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 6
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in DYS at Month 6 Based on Daily Assessment | -0.62 score on a scale | Standard Error 0.072 |
| Elagolix + E2/NETA | Change From Baseline in DYS at Month 6 Based on Daily Assessment | -1.64 score on a scale | Standard Error 0.05 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: <0.00195% CI: [-1.19, -0.845]MMRM
Secondary
Change From Baseline in Dyspareunia (DYSP) at Month 12 Based on Daily Assessment
Participants assessed DYSP each day in an e-Diary according to the following response options: * 0: None; No discomfort during sexual intercourse * 1: Mild; Able to tolerate the discomfort during sexual intercourse * 2: Moderate; Intercourse was interrupted due to pain * 3: Severe; Avoided intercourse because of pain * Not applicable; I was not sexually active for reasons other than endometriosis or did not have sexual intercourse. Pain scores were averaged over the 35 days prior to each visit. Responses of Not Applicable were excluded.
Time frame: Baseline, Month 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Dyspareunia (DYSP) at Month 12 Based on Daily Assessment | -0.60 score on a scale | Standard Error 0.079 |
| Elagolix + E2/NETA | Change From Baseline in Dyspareunia (DYSP) at Month 12 Based on Daily Assessment | -0.70 score on a scale | Standard Error 0.058 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: 0.28495% CI: [-0.298, 0.088]MMRM
Secondary
Change From Baseline in DYSP at Month 3 Based on Daily Assessment
Participants assessed DYSP each day in an e-Diary according to the following response options: * 0: None; No discomfort during sexual intercourse * 1: Mild; Able to tolerate the discomfort during sexual intercourse * 2: Moderate; Intercourse was interrupted due to pain * 3: Severe; Avoided intercourse because of pain * Not applicable; I was not sexually active for reasons other than endometriosis or did not have sexual intercourse. Pain scores were averaged over the 35 days prior to each visit. Responses of Not Applicable were excluded.
Time frame: Baseline, Month 3
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in DYSP at Month 3 Based on Daily Assessment | -0.40 score on a scale | Standard Error 0.064 |
| Elagolix + E2/NETA | Change From Baseline in DYSP at Month 3 Based on Daily Assessment | -0.62 score on a scale | Standard Error 0.045 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: 0.00595% CI: [-0.375, -0.066]MMRM
Secondary
Change From Baseline in DYSP at Month 6 Based on Daily Assessment
Participants assessed DYSP each day in an e-Diary according to the following response options: * 0: None; No discomfort during sexual intercourse * 1: Mild; Able to tolerate the discomfort during sexual intercourse * 2: Moderate; Intercourse was interrupted due to pain * 3: Severe; Avoided intercourse because of pain * Not applicable; I was not sexually active for reasons other than endometriosis or did not have sexual intercourse. Pain scores were averaged over the 35 days prior to each visit. Responses of Not Applicable were excluded.
Time frame: Baseline, Month 6
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in DYSP at Month 6 Based on Daily Assessment | -0.54 score on a scale | Standard Error 0.076 |
| Elagolix + E2/NETA | Change From Baseline in DYSP at Month 6 Based on Daily Assessment | -0.63 score on a scale | Standard Error 0.053 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: 0.28695% CI: [-0.279, 0.083]MMRM
Secondary
Change From Baseline in Endometriosis-Associated Pain Score at Month 12 Assessed With Numeric Rating Scale (NRS)
The NRS measured endometriosis-associated pain with and without menstruation on an 11-point scale from 0 = no pain to 10 = worst pain ever. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Endometriosis-Associated Pain Score at Month 12 Assessed With Numeric Rating Scale (NRS) | -3.25 score on a scale | Standard Error 0.263 |
| Elagolix + E2/NETA | Change From Baseline in Endometriosis-Associated Pain Score at Month 12 Assessed With Numeric Rating Scale (NRS) | -4.39 score on a scale | Standard Error 0.186 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: <0.00195% CI: [-1.774, -0.508]MMRM
Secondary
Change From Baseline in Endometriosis-Associated Pain Score at Month 3 Assessed With NRS
The NRS measured endometriosis-associated pain with and without menstruation on an 11-point scale from 0 = no pain to 10 = worst pain ever. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 3
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Endometriosis-Associated Pain Score at Month 3 Assessed With NRS | -2.33 score on a scale | Standard Error 0.225 |
| Elagolix + E2/NETA | Change From Baseline in Endometriosis-Associated Pain Score at Month 3 Assessed With NRS | -3.79 score on a scale | Standard Error 0.161 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: <0.00195% CI: [-2.002, -0.915]MMRM
Secondary
Change From Baseline in Endometriosis-Associated Pain Score at Month 6 Assessed With NRS
The NRS measured endometriosis-associated pain with and without menstruation on an 11-point scale from 0 = no pain to 10 = worst pain ever. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 6
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Endometriosis-Associated Pain Score at Month 6 Assessed With NRS | -2.74 score on a scale | Standard Error 0.248 |
| Elagolix + E2/NETA | Change From Baseline in Endometriosis-Associated Pain Score at Month 6 Assessed With NRS | -4.12 score on a scale | Standard Error 0.174 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: <0.00195% CI: [-1.978, -0.788]MMRM
Secondary
Change From Baseline in NMPP at Month 3 Based on Daily Assessment
Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 3
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in NMPP at Month 3 Based on Daily Assessment | -0.49 score on a scale | Standard Error 0.046 |
| Elagolix + E2/NETA | Change From Baseline in NMPP at Month 3 Based on Daily Assessment | -0.65 score on a scale | Standard Error 0.032 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: 0.00495% CI: [-0.27, -0.05]MMRM
Secondary
Change From Baseline in NMPP at Month 6 Based on Daily Assessment
Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 6
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in NMPP at Month 6 Based on Daily Assessment | -0.57 score on a scale | Standard Error 0.051 |
| Elagolix + E2/NETA | Change From Baseline in NMPP at Month 6 Based on Daily Assessment | -0.78 score on a scale | Standard Error 0.036 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: <0.00195% CI: [-0.329, -0.085]MMRM
Secondary
Change From Baseline in Non-menstrual Pelvic Pain (NMPP) at Month 12 Based on Daily Assessment
Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: * 0: No discomfort * 1: Mild discomfort but I was easily able to do the things I usually do * 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do * 3: Severe pain that made it difficult to do the things I usually do. Pain scores and analgesic use were averaged over the 35 days prior to each visit.
Time frame: Baseline, Month 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Mixed-effects model repeated measures (MMRM) analysis. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Non-menstrual Pelvic Pain (NMPP) at Month 12 Based on Daily Assessment | -0.64 score on a scale | Standard Error 0.06 |
| Elagolix + E2/NETA | Change From Baseline in Non-menstrual Pelvic Pain (NMPP) at Month 12 Based on Daily Assessment | -0.86 score on a scale | Standard Error 0.042 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: 0.00295% CI: [-0.367, -0.08]MMRM
Secondary
Change From Baseline to Month 12 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score
The PROMIS Fatigue Short Form 6a is self-administered and composed of 6 questions to evaluate fatigue over the past 7 days. All questions employ the following five response options: 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always. The PROMIS Fatigue 6a score is calculated as a T-score, which is a standardized score with a mean of 50 (based on the average for the United States general population) and a standard deviation (SD) of 10. Higher scores indicate higher levels of fatigue. A decrease in score (negative change from baseline) indicates improvement in fatigue.
Time frame: Baseline, Month 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Observed cases. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Month 12 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score | -6.43 T-score | Standard Error 0.949 |
| Elagolix + E2/NETA | Change From Baseline to Month 12 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score | -8.92 T-score | Standard Error 0.665 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: 0.03295% CI: [-4.773, -0.216]ANCOVA
Secondary
Change From Baseline to Month 6 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score
The PROMIS Fatigue Short Form 6a is self-administered and composed of 6 questions to evaluate fatigue over the past 7 days. All questions employ the following five response options: 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always. The PROMIS Fatigue 6a score is calculated as a T-score, which is a standardized score with a mean of 50 (based on the average for the United States general population) and a standard deviation (SD) of 10. Higher scores indicate higher levels of fatigue. A decrease in score (negative change from baseline) indicates improvement in fatigue.
Time frame: Baseline, Month 6
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with an assessment. Observed cases. Per protocol, the primary comparison for the secondary endpoints was between the elagolix plus E2/NETA and placebo arms only.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Month 6 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score | -4.71 T-score | Standard Error 0.739 |
| Elagolix + E2/NETA | Change From Baseline to Month 6 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score | -7.22 T-score | Standard Error 0.514 |
Comparison: Ranked secondary endpoints were tested following a fixed-sequence testing procedure. Testing began with testing each of the co-primary endpoints using alpha of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo. If both co-primary endpoints achieved statistical significance with elagolix plus E2/NETA as compared to placebo, continued testing was performed for the ranked secondary endpoints following a fixed-sequence testing procedure in the order of endpoints presented.p-value: 0.00595% CI: [-4.283, -0.746]ANCOVA