Uterine Fibroids
Conditions
Brief summary
To determine the safety, pharmacokinetics and efficacy of 4 doses (3, 6, 12, 24 mg) of Proellex in premenopausal women with uterine fibroids confirmed by ultrasound. Drug will be administered vaginally.
Detailed description
This study is a phase II, 5 arm study with a 12 week active dosing period. The study will be conducted in 2 stages. In the first stage, the first 6 women to be enrolled will be treated at the 12mg dose level, and in addition to the other required study assessments will be monitored with a 24-hour PK assessment on Day 14, and daily trough assessments for the first 14 days. If, at Visit 3, the Cmax or AUC of any subject treated at 12mg exceeds the mean observed for the highest safe oral dose administered in the ZP-204 study, all subjects enrolled at the 12mg level will be discontinued, no further patients will be treated at this dose level, and the 6mg vaginal dose will be assessed in a similar fashion. In the second stage, the remaining subjects will be randomized to a dose of 3, 6, 12 or 24 mg. For all subjects there will be a 4-6 week placebo run-in period, to establish baseline parameters (bleeding and quality of life) followed by treatment at one of three single-blind Proellex doses (3, 6 or 12 mg daily, administered vaginally in capsule form.) The primary efficacy endpoint will be bleeding assessed using the Pictorial Blood Loss Assessment Chart (PBAC) after 12 or 16 weeks of treatment. The secondary endpoints will be changes in size of uterine fibroids assessed by MRI and improvement in quality of life assessed using the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire (UFSQOL0. Safety endpoints include significant adverse events, changes in physical examination results, and/or clinical laboratory results significantly outside of normal range. For subjects enrolled in Stage 2, PK will be assessed after the first and last doses and trough levels every 2 weeks.
Interventions
DRUGProellex
vaginal suppository, daily, for 12 weeks
Sponsors
Repros Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 47 Years
Healthy volunteers
No
Inclusion criteria
* Healthy adult females between 18 and 47 years of age with uterine fibroids confirmed by ultrasound. * Normal transvaginal ultrasound (other than for presence of fibroids) * History of menstrual events occurring in regular cycles * Agreement not to attempt to become pregnant * 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 subject diary * Willing to discontinue hormonal contraceptives and consent to use of double barrier contraceptive techniques over the course of the study. * Has a negative pregnancy test at the Screening and Baseline visits An exception for the pregnancy test requirement will be granted for subjects reporting surgical sterilization in medical history * A Body Mass Index (BMI) between 18 and 39 inclusive * Is available for all treatment and follow-up visits.
Exclusion criteria
* Subject is a 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 * Subject is pregnant or lactating or is attempting or expecting to become pregnant during the 6 month study period * Women with abnormally high liver enzymes or liver disease. (ALT or AST exceeding 1.5xULN AND total bilirubin exceeding 1.5xULN at screening and confirmed on repeat). * Received an investigational drug in the 30 days prior to the screening for this study * Women with a history of PCOS * Concurrent use of any testosterone, progestin, androgen, estrogen, anabolic steroids, DHEA or hormonal products for at least 2 weeks prior to screening and during the study. * Use of oral contraceptives in the preceding 2 weeks. Use of Depo-Provera® in the preceding 6 months. * Has an IUD in place * Women currently using narcotics * Women currently taking spironolactone * Infectious disease screen is positive for HIV or Hepatitis A, B or C * Clinically significant abnormal findings on screening examination 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Vaginal Bleeding | 12 or 16 weeks | Change from baseline in vaginal bleeding assessed at the end of treatment (12 or 16 weeks) using a Pictorial Blood Loss Assessment Chart (PBAC), which measures volume (mL) of blood loss over a 28-day period Less blood loss represents an improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Levels of Proellex | 12 or 16 weeks | Determination of Cmax of Proellex at end of treatment |
| Uterine Fibroid Size | 12 or 16 weeks | Percent change in volume of confirmed uterine fibroids at end of treatment, assessed by MRI |
| Induction of Amenorrhea at End of Treatment | End of treatment | Percentage of subjects with induced amenorrhea during last 28 days on drug Amenorrhea was deemed to be achieved if no daily bleeding score was greater than 1 during the last 28 calendar days of the dosing period. A score of 1 was to be indicated if spotting was observed which did not require a sanitary product. Subjects that terminated early were deemed not to have achieved amenorrhea. |
| Endometrial Thickness | 12 or 16 weeks | Percent change in median endometrial thickness from baseline to end of treatment assessed by ultrasound determination of uterine stripe. |
| Change in Quality of Life | 12 or 16 weeks | Percentage change from baseline in median quality of life using uterine fibroid symptom and quality of life questionnaire (UFSQOL) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Proellex 3 mg Per Protocol Subjects will receive 3 mg Proellex daily, vaginally for 12 weeks.
Proellex: vaginal suppository, daily, for 12 weeks | 9 |
| Proellex 6 mg Per Protocol Subjects receiving 6 mg Proellex daily, vaginally for 12 weeks
Proellex: vaginal suppository, daily, for 12 weeks | 9 |
| Proellex 12 mg Per Protocol Subjects receiving 12 mg Proellex daily, vaginally for 12 or 16 weeks
Proellex: vaginal suppository, daily, for 12 weeks Includes subjects from both arms 1 and 3 (PK group and non-PK groups) | 12 |
| 24 mg Proellex 24 mg vaginal Proellex daily
Proellex: vaginal suppository, daily, for 16 weeks | 10 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Proellex 3 mg Per Protocol | Proellex 6 mg Per Protocol | Proellex 12 mg Per Protocol | 24 mg Proellex | Total |
|---|---|---|---|---|---|
| Age, Continuous | 38.7 years STANDARD_DEVIATION 6.3 | 39.9 years STANDARD_DEVIATION 6.9 | 39.8 years STANDARD_DEVIATION 4.8 | 40.9 years STANDARD_DEVIATION 5.2 | 39.8 years STANDARD_DEVIATION 5.6 |
| Region of Enrollment United States | 9 participants | 9 participants | 12 participants | 10 participants | 40 participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 12 Participants | 10 Participants | 40 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 9 | 4 / 9 | 6 / 12 | 3 / 10 |
| serious Total, serious adverse events | 0 / 9 | 1 / 9 | 0 / 12 | 1 / 10 |
Outcome results
Primary
Change From Baseline in Vaginal Bleeding
Change from baseline in vaginal bleeding assessed at the end of treatment (12 or 16 weeks) using a Pictorial Blood Loss Assessment Chart (PBAC), which measures volume (mL) of blood loss over a 28-day period Less blood loss represents an improvement.
Time frame: 12 or 16 weeks
Population: MITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Proellex 3 mg Per Protocol | Change From Baseline in Vaginal Bleeding | -83.5 mL |
| Proellex 6 mg Per Protocol | Change From Baseline in Vaginal Bleeding | -36.0 mL |
| Proellex 12 mg Per Protocol | Change From Baseline in Vaginal Bleeding | -63.5 mL |
| 24 mg Proellex | Change From Baseline in Vaginal Bleeding | -39.5 mL |
Secondary
Blood Levels of Proellex
Determination of Cmax of Proellex at end of treatment
Time frame: 12 or 16 weeks
Population: Subjects with end of treatment PK assessment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Proellex 3 mg Per Protocol | Blood Levels of Proellex | 11.1 ng/dL | Standard Deviation 5.1 |
| Proellex 6 mg Per Protocol | Blood Levels of Proellex | 14.1 ng/dL | Standard Deviation 6.6 |
| Proellex 12 mg Per Protocol | Blood Levels of Proellex | 11.6 ng/dL | Standard Deviation 2 |
| 24 mg Proellex | Blood Levels of Proellex | 7.4 ng/dL | Standard Deviation 5.3 |
| 24 mg Proellex | Blood Levels of Proellex | 10.2 ng/dL | Standard Deviation 8.6 |
Secondary
Change in Quality of Life
Percentage change from baseline in median quality of life using uterine fibroid symptom and quality of life questionnaire (UFSQOL)
Time frame: 12 or 16 weeks
Population: MITT. Note: lower score is improvement
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Proellex 3 mg Per Protocol | Change in Quality of Life | -67.9 Percent change |
| Proellex 6 mg Per Protocol | Change in Quality of Life | -8.5 Percent change |
| Proellex 12 mg Per Protocol | Change in Quality of Life | -98.2 Percent change |
| 24 mg Proellex | Change in Quality of Life | -100.0 Percent change |
Secondary
Endometrial Thickness
Percent change in median endometrial thickness from baseline to end of treatment assessed by ultrasound determination of uterine stripe.
Time frame: 12 or 16 weeks
Population: Safety population, data based on subjects with both baseline and end of treatment assessments
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Proellex 3 mg Per Protocol | Endometrial Thickness | 60.8 Percent change |
| Proellex 6 mg Per Protocol | Endometrial Thickness | -25.8 Percent change |
| Proellex 12 mg Per Protocol | Endometrial Thickness | 39.3 Percent change |
| 24 mg Proellex | Endometrial Thickness | 32.3 Percent change |
Secondary
Induction of Amenorrhea at End of Treatment
Percentage of subjects with induced amenorrhea during last 28 days on drug Amenorrhea was deemed to be achieved if no daily bleeding score was greater than 1 during the last 28 calendar days of the dosing period. A score of 1 was to be indicated if spotting was observed which did not require a sanitary product. Subjects that terminated early were deemed not to have achieved amenorrhea.
Time frame: End of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proellex 3 mg Per Protocol | Induction of Amenorrhea at End of Treatment | 55.6 Percentage of particpants |
| Proellex 6 mg Per Protocol | Induction of Amenorrhea at End of Treatment | 0 Percentage of particpants |
| Proellex 12 mg Per Protocol | Induction of Amenorrhea at End of Treatment | 66.7 Percentage of particpants |
| 24 mg Proellex | Induction of Amenorrhea at End of Treatment | 40.0 Percentage of particpants |
Secondary
Uterine Fibroid Size
Percent change in volume of confirmed uterine fibroids at end of treatment, assessed by MRI
Time frame: 12 or 16 weeks
Population: MITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Proellex 3 mg Per Protocol | Uterine Fibroid Size | -9.9 Percentage change |
| Proellex 6 mg Per Protocol | Uterine Fibroid Size | -13.4 Percentage change |
| Proellex 12 mg Per Protocol | Uterine Fibroid Size | -21.9 Percentage change |
| 24 mg Proellex | Uterine Fibroid Size | -3.5 Percentage change |