Safety and Efficacy of Telapristone Acetate (Proellex®) in the Treatment of Pre-Menopausal Women With Confirmed, Symptomatic Endometriosis

Study Overview
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Brief Summary
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The primary purpose of this study is to determine the safety and efficacy of two oral doses of telapristone acetate administered to premenopausal women with pelvic pain associated with endometriosis confirmed within the last seven years and using prescription analgesics for symptomatic pain.

Detailed Description
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This study is a phase 2, 3-arm-study with an 18-week active dosing period and an option for participants to receive 2 additional 16-week cycles of active treatment at their randomized dose [6 mg or 12 mg/day]. Placebo participants who elect additional treatment will receive treatment at 12 mg/day. The treatment dose will remain double-blind. The study will be conducted in 3 stages. The first stage is a no treatment baseline assessment period. This stage will last as long as it takes to record at least one full menstrual cycle (ovulation until ovulation). For stage 2, following the run-in stage, at Visit 3, 60 participants will be randomized into one of 3 arms in a 1-1-1 fashion. The start of dosing should commence as soon as possible after ovulation following the end of the previous menstrual event. For stage 3, participants who are eligible to receive additional cycles of treatment and who elect to continue treatment will be scheduled within a week before the second expected menses (+/- 2 days), following the off-drug interval. Participants will receive 2 cycles of treatment separated by an off-drug interval (ODI), after which they will be followed until menses has returned.

Official Title
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A Phase 2, Multi-Center, Three-Arm, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of 6 and 12 mg Proellex® (Telapristone Acetate) Administered Orally in the Treatment of Premenopausal Women With Confirmed Symptomatic Endometriosis

Conditions
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Endometriosis

Intervention / Treatment
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* Drug: Placebo
* Drug: Telapristone acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult females between 18 and 47 years of age using prescription analgesics for endometriosis pain and with a Biberoglu Behrman Symptom Severity Scale (BBSS) score ≥7 at screening (assessed over the previous 28 days). Endometriosis diagnosis must have been surgically confirmed within 7 years. A laparoscopic diagnosis is acceptable. Participants must have a history of at least 3 regular menstrual cycles in which symptoms of endometriosis occurred immediately prior to screening. Normal or abnormal but non-clinically significant transvaginal ultrasound. History of menstrual events occurring in regular cycles. Agreement not to attempt to become pregnant during the trial. Agreement to limit alcohol consumption to no more than 2 drinks per week and to avoid alcohol consumption within 48 hours before each visit. Ability to complete a daily electronic participant diary and study procedures in compliance with the protocol. Women of child-bearing potential must be willing to use double-barrier contraception during the study and for 30 days after discontinuation of study medication. Acceptable double-barrier methods are: male condom with spermicide; male condom with diaphragm; diaphragm containing spermicide plus additional intra-vaginal spermicide. Has a negative pregnancy test at the Screening and Baseline visits, and subsequent study visits. A Body Mass Index (BMI) between 18 and 39 inclusive. Is available for all treatment and follow-up visits. Exclusion Criteria: Post-menopausal woman, defined as either; six (6) months or more (immediately prior to screening visit) without a menstrual period, or prior hysterectomy and/or oophorectomy. Pregnant or lactating or is attempting or expecting to become pregnant during the 6-7 month study period. Women with abnormally high liver enzymes or liver disease [alanine transaminase (ALT) or aspartate aminotransferase (AST) exceeding 2 x upper limit of normal (ULN) and total bilirubin exceeding 1.5 x ULN at screening and confirmed on repeat]. Received an investigational drug in the 30 days prior to the screening for this study. History of polycystic ovary syndrome (PCOS). Concurrent use of any testosterone, androgen, anabolic steroids, dehydroepiandrosterone (DHEA) or hormonal products for at least 2 weeks prior to screening and during the study. Oral contraceptive use for control of endometriosis symptoms is acceptable for the first 28-days of the study. Use of Depo-Provera® in the preceding 6 months. Use of Gonadotrophin releasing hormone (GnRH) as (e.g. Lupron Depot) within 3 months of the first dose of study drug (Lupron Depot must have a wash-out period of 3 months after the period of duration of the Lupron dose). Has an intrauterine device (IUD) in place. Copper IUDs (non-hormone containing will be permitted). Presence of intramural fibroids that impact the endometrial stripe, submucosal fibroids (any size), or endometrial polyps. Subserosal and intramural fibroids with no impact on the endometrial stripe are acceptable. Presence of endometrioma(s). Present history or condition that causes non-endometriosis related dyspareunia (e.g. vulvar vestibulitis). Past or present history of thrombophlebitis or thromboembolic disorders. Known or suspected carcinoma of the breast or reproductive organs. History of abnormal electrocardiogram (ECG) that, in the opinion of the investigator, is clinically significant and will prevent the participant from completing the study, including a QTc (corrected QT interval) of greater than 450 milliseconds (ms). Cervical dysplasia classified as Atypical Squamous Cells of Undetermined Significance (ASCUS) associated with high-risk human papilloma virus (HPV) or Low/High Grade Squamous Intraepithelial Lesion (LGSIL or HGSIL). History of abnormal endometrial biopsy including the presence of Endometrial Intraepithelial Neoplasia (EIN). Recent history (within past 6 months) of alcoholism or drug abuse. Known active infection with Human Immunodeficiency Virus (HIV), Hepatitis A, B or C. Previous history of auto-immune disease and/or positive antinuclear antigen (ANA). Endometrial stripe ≥18 mm in thickness at Visit 1. Women currently taking cimetidine or spironolactone. Clinically significant abnormal findings on screening examination and laboratory assessments or any condition which in the opinion of the investigator would interfere with the participant's ability to comply with the study instructions or endanger the participant if she took part in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 47 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Following the Stage 1 no treatment baseline assessment period, placebo matching capsules, orally, once daily for 18 weeks in Stage 2. Eligible participants had the option to receive 2 additional 16-week cycles of active treatment at 12 milligrams (mg)/day separated by an off-drug interval (ODI) in Stage 3. | Drug: Placebo<br>* Placebo matching capsules, orally, once daily for 18 weeks.<br>|
| Experimental: Telapristone acetate 6 mg<br>Following the Stage 1 no treatment baseline assessment period, telapristone acetate (Proellex®) 6 mg capsules, orally once daily for 18 weeks in Stage 2. Eligible participants had the option to receive 2 additional 16-week cycles of active treatment at 6 mg/day separated by an ODI in Stage 3. | Drug: Telapristone acetate<br>* Telapristone acetate capsules, orally once daily for 18 weeks.<br>* Other names: Proellex®;|
| Experimental: Telapristone acetate 12 mg<br>Following the Stage 1 no treatment baseline assessment period, telapristone acetate (Proellex®) 12 mg capsules, orally once daily for 18 weeks. Eligible participants had the option to receive 2 additional 16-week cycles of active treatment at 12 mg/day separated by an ODI in Stage 3. | Drug: Telapristone acetate<br>* Telapristone acetate capsules, orally once daily for 18 weeks.<br>* Other names: Proellex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Individual Biberoglu Behrman Symptom Severity Scale (BBSS) Score for Dysmenorrhea | The BBSS scale defined dysmenorrhea according to the loss of work efficiency and need for bed rest. The dysmenorrhea was graded on a scale from 0 to 3 where, 0 = None; 1 = Mild (some loss in work efficiency); 2 = Moderate (in bed part of the day, occasional loss of work efficiency); 3 = Severe (in bed one or more days, incapacitation), with higher scores indicating more severe symptoms. Participants were provided with a daily diary to record information about participant-reported scores for endometriosis pain each day. Daily scores were standardized to a 28-day period for each interval (Baseline, On-drug Cycle 1 and Off-drug Cycle 1) calculated as the sum of scores in the interval divided by the number of the days in the interval multiplied by 28. A negative change from Baseline indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to the last day of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) and at the end of Off-drug Cycle 1 (Off-drug Cycle 1 is 3 weeks following On-drug Cycle 1) | 
| Change From Baseline in Individual BBSS Score for Dyspareunia | The BBSS scale defined deep dyspareunia according to the limitation of sexual activity. The dyspareunia was graded on a scale from 0 to 3 where, 0= None (no discomfort); 1= Mild (tolerated discomfort); 2= Moderate (intercourse painful to the point of interruption); 3= Severe (intercourse avoided because of pain), with higher scores indicating more severe symptoms. Participants were provided with a daily diary to record information about participant-reported scores for endometriosis pain each day. Daily scores were standardized to a 28-day period for each interval (Baseline, On-drug Cycle 1 and Off-drug Cycle 1) calculated as the sum of scores in the interval divided by the number of the days in the interval multiplied by 28. A negative change from Baseline indicates improvement.. | Baseline (28-day Baseline Menstrual Cycle) to the last day of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) and at the end of Off-drug Cycle 1 (Off-drug Cycle 1 is 3 weeks following On-drug Cycle 1) | 
| Change From Baseline in Individual BBSS Score for Non-Menstrual Pelvic Pain | The BBSS scale defined non-menstrual pelvic pain according to various degrees of discomfort and use of analgesics. The non-menstrual pelvic pain was graded on a scale from 0 to 3 where, 0= None (absence of pain); 1= Mild (occasional pelvic discomfort); 2= Moderate (noticeable discomfort for most of the cycle); 3= Severe (pain persisting during the cycle or requiring strong analgesics), with higher scores indicating more severe symptoms. Participants were provided with a daily diary to record information about participant-reported scores for endometriosis pain each day. Daily scores were standardized to a 28-day period for each interval (Baseline, On-drug Cycle 1 and Off-drug Cycle 1) calculated as the sum of scores in the interval divided by the number of the days in the interval multiplied by 28. A negative change from Baseline indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to the last day dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) and to the end of Off-drug Cycle 1 (Off-drug Cycle 1 is 3 weeks following On-drug Cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Prescription Analgesics Usage | An analgesic was any member of the group of drugs used to achieve analgesia, relief from pain. Prescription analgesics are analgesics prescribed by the physician. Participants were provided with a daily diary to record the number of pills of non-narcotic prescription and narcotic analgesics taken for endometriosis-related pain symptoms each day. Daily number of pills were standardized to a 28-day period for each interval (Baseline and On-drug Cycle 1) calculated as the sum of pills in the interval divided by the number of the days in the interval multiplied by 28. A negative change from Baseline indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to the last day of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) | 
| Percentage Change From Baseline in Prescription Analgesics Usage | An analgesic was any member of the group of drugs used to achieve analgesia, relief from pain. Prescription analgesics are analgesics prescribed by the physician. Participants were provided with a daily diary to record the number of pills of non-narcotic prescription and narcotic analgesics taken for endometriosis-related pain symptoms each day. Daily number of pills were standardized to a 28-day period for each interval (Baseline and last 28-days On-drug Cycle 1) calculated as the sum of pills in the interval divided by the number of the days in the interval multiplied by 28.The percent change from baseline in the analgesic usage was determined by subtracting the baseline analgesic usage from the analgesic usage during the last nominal 28 day menstrual cycle, divided by the baseline analgesic usage, and multiplied by 100%. A negative percent change from Baseline indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to last 28 days of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) | 
| Change From Baseline in Non-Prescription Analgesics Usage | An analgesic was any member of the group of drugs used to achieve analgesia, relief from pain. Nonprescription analgesics are over-the-counter (OTC) analgesics. Participants were provided with a daily diary to record the number of pills of OTC drugs taken for endometriosis-related pain symptoms each day. Daily number of pills were standardized to a 28-day period for each interval (Baseline and On-drug Cycle 1) calculated as the sum of pills in the interval divided by the number of the days in the interval multiplied by 28. A negative change from Baseline indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to last day of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) | 
| Percentage Change From Baseline in Non-Prescription Analgesics Usage | An analgesic was any member of the group of drugs used to achieve analgesia, relief from pain. Nonprescription analgesics are OTC analgesics. Participants were provided with a daily diary to record the number of pills of over the counter drugs taken for endometriosis-related pain symptoms each day. Daily number of pills were standardized to a 28-day period for each interval (Baseline and last 28-days On-drug Cycle 1) calculated as the sum of pills in the interval divided by the number of the days in the interval multiplied by 28. The percent change from baseline in the analgesic usage was determined by subtracting the baseline analgesic usage from the analgesic usage during the last nominal 28 day menstrual cycle, divided by the baseline analgesic usage, and multiplied by 100%. A negative percent change indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to last 28 days of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) | 
| Change From Baseline in Total Analgesics Usage | An analgesic was any member of the group of drugs used to achieve analgesia, relief from pain. The total analgesics is comprised of prescription and non-prescription analgesics. Participants were provided with a daily diary to record the number of pills of OTC and prescription analgesics taken for endometriosis-related pain symptoms each day. The daily number of pills were standardized to a 28-day period for each interval (Baseline and On-drug Cycle 1) calculated as the sum of pills in the interval divided by the number of the days in the interval multiplied by 28. A negative change from Baseline indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to last day of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) | 
| Percentage Change From Baseline in Total Analgesics Usage | An analgesic was any member of the group of drugs used to achieve analgesia, relief from pain. The total analgesics is comprised of prescription and non-prescription analgesics. Participants were provided with a daily diary to record the number of pills of OTC and prescription analgesics taken for endometriosis-related pain symptoms each day. Daily number of pills were standardized to a 28-day period for each interval (Baseline and last 28-days On-drug Cycle 1) calculated as the sum of pills in the interval divided by the number of the days in the interval multiplied by 28. The percent change from baseline in the analgesic usage was determined by subtracting the baseline analgesic usage from the analgesic usage during the last nominal 28-day menstrual cycle, divided by the baseline analgesic usage, and multiplied by 100%. A negative percent change indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to last 28 days of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) | 
| Change From Baseline in BBSS Physician-Reported Scores | BBSS Physician-Reported Scores included two scores: Pelvic Tenderness Score (PTS) and Induration Score (IS). PTS was graded on a scale from 0 to 3 where, 0= None; 1= Mild (minimal tenderness on palpation); 2= Moderate (extensive tenderness on palpation); 3= Severe (unable to palpate because of tenderness). IS was graded on a scale from 0 to 3 where, 0= None; 1= Mild (uterus freely mobile, induration on the cul-de-sac); 2= Moderate (thickened and indurated adnexa and cul-de-sac, restricted uterine mobility); 3= Severe (nodular adnexa and cul-de-sac, uterus frequently frozen), with higher scores indicating more severe symptoms. A negative change from Baseline indicates improvement. Data from On-drug cycle and Off-drug interval (ODI) were reported. | Baseline (Day 1) to last day of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) and at the end of Off-drug Cycle 1 (Off-drug Cycle 1 is 3 weeks following On-drug Cycle 1) | 
| Change From Baseline in Participant-Reported Pain Using Visual Analog Scale (VAS) Pain Score | A 100-millimeter (mm) VAS was used to grade the severity of dysmenorrhea, and non-menstrual pelvic pain. The lowest value indicated the absence of pain and the highest value indicated pain as bad as it could be; a score of 1-50 was considered mild pain, 51-80 moderate pain and 81-100 severe pain. A negative change from Baseline indicates improvement. Participants were provided with a daily diary to record information about participant-reported scores for endometriosis pain. | Baseline (Day 1) to last day of dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) and at the end of Off-drug Cycle 1 (Off-drug Cycle 1 is 3 weeks following On-drug Cycle 1) | 
| Change From Baseline in Participant-Reported Pain Using a Numerical Rating Scale (NRS) | NRS is a valid and reliable clinical measure to assess pain intensity. Sex Avoidance Pain (SAP) and Endometriosis Pain (EP) were assessed using NRS-11 to measure pain based on pain ratings given by participants on the scale of 0 to 10 where, 0 represents no pain and 10 represents the worst pain possible. Participants were provided with a daily diary to record information about participant-reported scores for endometriosis pain each day. Daily scores were standardized to a 28-day period for each interval (Baseline, On-drug Cycle 1 and Off-drug Cycle 1) calculated as the sum of scores in the interval divided by the number of the days in the interval multiplied by 28. A negative change from Baseline indicates improvement. | Baseline (28-day Baseline Menstrual Cycle) to the last day dosing in Cycle 1 (On-drug Cycle 1 is 18 weeks) and to the end of Off-drug Cycle 1 (Off-drug Cycle 1 is 3 weeks following On-drug Cycle 1) |