Leiomyoma, Uterine Hemorrhage
Conditions
Brief summary
This study will evaluate the superiority of ulipristal acetate versus placebo for the treatment of abnormal uterine bleeding associated with uterine fibroids
Interventions
Ulipristal acetate (UPA) tablet.
DRUGPlacebo
Matching placebo tablet.
Sponsors
Allergan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Premenopausal women, 18-50 years, inclusive. * Cyclic abnormal uterine bleeding (heavy or prolonged). * Menstrual blood loss (MBL) of ≥ 80 mL as measured by the alkaline hematin method in the first 8 days of menses. * Minimum of one discrete leiomyoma observable by transvaginal ultrasound. * Endometrial biopsy without evidence of malignancy or atypical or non-atypical hyperplasia.
Exclusion criteria
* History of uterine surgery that would interfere with the study endpoints. * Known coagulation disorder including bleeding disorder or clotting disorder. * History of, or current uterine, cervix, ovarian, or breast cancer. * Alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or total bilirubin two times or greater than the upper limit of normal range.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 1 | Last 35 consecutive days on treatment in the 12-Week Treatment Course 1 | Participants recorded bleeding in a daily diary. Absence of bleeding was defined as no bleeding days (i.e., no entries for bleeding or heavy bleeding; however, spotting was allowed), during the last 35 consecutive days on treatment in Treatment Course 1. |
| Time to Absence of Bleeding on Treatment During Treatment Course 1 | From first dose up to the end of the 12-Week Treatment Course 1 | Time to absence of bleeding was defined as the duration in days from first dose to the first day in the time interval in which absence of bleeding occurs and persists through the last dose in the first treatment course. The persistence of absence of bleeding occurred for a minimum of 35 consecutive days counting backward from the last dose in Treatment Course 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Absence of Bleeding From Day 11 Through the End of Treatment Course 1 | Day 11 through the end of treatment in the 12-Week Treatment Course 1 | Participants recorded bleeding in a daily diary. Absence of bleeding was defined as no bleeding days (i.e., no entries for bleeding or heavy bleeding; however, spotting was allowed), from Day 11 to the end of treatment in Treatment Course 1. |
| Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 2 | Last 35 consecutive days on treatment in the 12-Week Treatment Course 2 | Participants recorded bleeding in a daily diary. Absence of bleeding was defined as no bleeding days (i.e., no entries for bleeding or heavy bleeding; however, spotting was allowed), during the last 35 consecutive days on treatment in Treatment Course 2. |
| Time to Absence of Bleeding on Treatment During Treatment Course 2 | From first dose up to the end of treatment in the 12-Week Treatment Course 2 | Time to absence of bleeding is defined as the duration in days from first dose in treatment course 2 to the first day in the time interval in which absence of bleeding occurs and persists through the last dose in the second treatment course. The persistence of absence of bleeding occurred for a minimum of 35 consecutive days counting backward from the last dose in Treatment Course 2. |
| Change From Baseline in Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) Revised Activities Subscale Score at the End of Treatment Course 1 | Baseline (Day 1-4) to End of 12-Week Treatment Course 1 | The UFS-QOL is a uterine fibroid-specific questionnaire consisting of 37 questions developed to evaluate symptoms of uterine fibroids and their impact on health-related quality of life in women with leiomyomas. The first 8 questions comprise the Symptom Severity subscale to assess symptoms experienced by women with uterine leiomyomas, the remaining 29 questions comprise 6 subscales (Concern, Activities, Energy/mood, Control, Self-consciousness, Sexual Function) which overall deal with women's feelings and experiences regarding impact of uterine leiomyoma symptoms on her life. Each item is scored between 1 and 5, where 1=none of the time or not at all and 5=all of the time or a very great deal. A Revised Activities subscale was created to include the most relevant items pertaining to physical and social activities with a total possible score of 0 to 100. Higher Revised Activities subscale scores indicate less impact on activities. A positive change from Baseline indicates improvement. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| UPA 5 mg:Placebo Ulipristal Acetate (UPA) 5 mg tablet plus matching placebo 10 mg tablet, orally, once daily for 12 weeks in Treatment Course 1; followed by a 2 menses drug-free interval; followed by matching placebo tablets (5 mg and 10 mg), orally, once daily for 12 weeks in Treatment Course 2. | 55 |
| UPA 10 mg:Placebo UPA 10 mg tablet plus matching placebo 5 mg tablet, orally, once daily for 12 weeks in Treatment Course 1; followed by a 2 menses drug-free interval; followed by matching placebo tablets (5 mg and 10 mg), orally, once daily for 12 weeks in Treatment Course 2. | 47 |
| UPA 5 mg:UPA 5 mg UPA 5 mg tablet plus matching placebo 10 mg tablet, orally, once daily in both Treatment Course 1 and Treatment Course 2. There was a 2 menses drug-free interval in between courses. | 107 |
| UPA 10 mg:UPA 10 mg UPA 10 mg tablet plus matching placebo 5 mg tablet, orally, once daily in both Treatment Course 1 and Treatment Course 2. There was a 2 menses drug-free interval in between courses. | 110 |
| Placebo:UPA 5 mg Matching placebo tablets (5 mg and 10 mg) orally, once daily for 12 weeks in Treatment Course 1; followed by a 2 menses drug-free interval; followed by UPA 5 mg tablet plus matching placebo 10 mg tablet, orally, once daily for 12 weeks in Treatment Course 2. | 55 |
| Placebo:UPA 10 mg Matching placebo tablets (5 mg and 10 mg), orally, once daily for 12 weeks in Treatment Course 1; followed by a 2 menses drug-free interval; followed by UPA 10 mg tablet plus matching placebo 5 mg tablet, orally, once daily for 12 weeks in Treatment Course 2. | 58 |
| Total | 432 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Off-Treatment Interval 1 | Adverse Event | 1 | 0 | 0 | 1 | 0 | 0 |
| Off-Treatment Interval 1 | Lack of Efficacy | 0 | 0 | 2 | 0 | 1 | 0 |
| Off-Treatment Interval 1 | Lost to Follow-up | 2 | 1 | 3 | 2 | 4 | 2 |
| Off-Treatment Interval 1 | Other Miscellaneous Reasons | 2 | 0 | 3 | 2 | 0 | 0 |
| Off-Treatment Interval 1 | Protocol Violation | 1 | 0 | 2 | 0 | 1 | 0 |
| Off-Treatment Interval 1 | Withdrawal of Consent | 4 | 3 | 5 | 10 | 2 | 3 |
| Off-Treatment Interval 2 | Lack of Efficacy | 0 | 1 | 1 | 0 | 0 | 0 |
| Off-Treatment Interval 2 | Lost to Follow-up | 0 | 0 | 3 | 2 | 2 | 2 |
| Off-Treatment Interval 2 | Other Miscellaneous Reasons | 0 | 3 | 1 | 4 | 0 | 1 |
| Off-Treatment Interval 2 | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 |
| Off-Treatment Interval 2 | Withdrawal of Consent | 4 | 0 | 5 | 4 | 0 | 1 |
| Treatment Course 1 | Adverse Event | 1 | 4 | 3 | 4 | 1 | 2 |
| Treatment Course 1 | Lost to Follow-up | 2 | 4 | 3 | 3 | 2 | 4 |
| Treatment Course 1 | Protocol Violation | 0 | 0 | 1 | 1 | 0 | 0 |
| Treatment Course 1 | Withdrawal of Consent | 1 | 1 | 1 | 5 | 3 | 2 |
| Treatment Course 2 | Adverse Event | 0 | 4 | 2 | 1 | 0 | 1 |
| Treatment Course 2 | Lost to Follow-up | 1 | 0 | 1 | 1 | 0 | 1 |
| Treatment Course 2 | Withdrawal of Consent | 0 | 1 | 2 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo:UPA 10 mg | Total | UPA 5 mg:Placebo | UPA 10 mg:Placebo | UPA 5 mg:UPA 5 mg | UPA 10 mg:UPA 10 mg | Placebo:UPA 5 mg |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 40.7 years STANDARD_DEVIATION 4.6 | 41.0 years STANDARD_DEVIATION 5.6 | 41.5 years STANDARD_DEVIATION 5.7 | 41.8 years STANDARD_DEVIATION 5.2 | 40.9 years STANDARD_DEVIATION 6.6 | 41.0 years STANDARD_DEVIATION 5.3 | 40.8 years STANDARD_DEVIATION 5.1 |
| Sex: Female, Male Female | 58 Participants | 432 Participants | 55 Participants | 47 Participants | 107 Participants | 110 Participants | 55 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 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 | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 116 | 0 / 161 | 0 / 155 | 0 / 40 | 0 / 33 | 0 / 84 | 0 / 82 | 0 / 42 | 0 / 44 |
| other Total, other adverse events | 18 / 116 | 38 / 161 | 46 / 155 | 12 / 40 | 11 / 33 | 20 / 84 | 8 / 82 | 7 / 42 | 9 / 44 |
| serious Total, serious adverse events | 2 / 116 | 3 / 161 | 4 / 155 | 0 / 40 | 2 / 33 | 2 / 84 | 1 / 82 | 1 / 42 | 1 / 44 |
Outcome results
Primary
Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 1
Participants recorded bleeding in a daily diary. Absence of bleeding was defined as no bleeding days (i.e., no entries for bleeding or heavy bleeding; however, spotting was allowed), during the last 35 consecutive days on treatment in Treatment Course 1.
Time frame: Last 35 consecutive days on treatment in the 12-Week Treatment Course 1
Population: Intent-to-Treat (ITT) Population included all randomized participants. Data was summarized as per the treatment assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 1 | 0.0 percentage of participants |
| UPA 5 mg | Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 1 | 42.0 percentage of participants |
| UPA 10 mg | Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 1 | 54.8 percentage of participants |
Primary
Time to Absence of Bleeding on Treatment During Treatment Course 1
Time to absence of bleeding was defined as the duration in days from first dose to the first day in the time interval in which absence of bleeding occurs and persists through the last dose in the first treatment course. The persistence of absence of bleeding occurred for a minimum of 35 consecutive days counting backward from the last dose in Treatment Course 1.
Time frame: From first dose up to the end of the 12-Week Treatment Course 1
Population: ITT population included all randomized participants. Data was summarized per treatment assigned.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Absence of Bleeding on Treatment During Treatment Course 1 | NA days |
| UPA 5 mg | Time to Absence of Bleeding on Treatment During Treatment Course 1 | NA days |
| UPA 10 mg | Time to Absence of Bleeding on Treatment During Treatment Course 1 | 36.0 days |
Secondary
Change From Baseline in Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) Revised Activities Subscale Score at the End of Treatment Course 1
The UFS-QOL is a uterine fibroid-specific questionnaire consisting of 37 questions developed to evaluate symptoms of uterine fibroids and their impact on health-related quality of life in women with leiomyomas. The first 8 questions comprise the Symptom Severity subscale to assess symptoms experienced by women with uterine leiomyomas, the remaining 29 questions comprise 6 subscales (Concern, Activities, Energy/mood, Control, Self-consciousness, Sexual Function) which overall deal with women's feelings and experiences regarding impact of uterine leiomyoma symptoms on her life. Each item is scored between 1 and 5, where 1=none of the time or not at all and 5=all of the time or a very great deal. A Revised Activities subscale was created to include the most relevant items pertaining to physical and social activities with a total possible score of 0 to 100. Higher Revised Activities subscale scores indicate less impact on activities. A positive change from Baseline indicates improvement.
Time frame: Baseline (Day 1-4) to End of 12-Week Treatment Course 1
Population: Data was summarized as per treatment assigned and included all participants with data at both Baseline and Week 12 in Treatment Course 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) Revised Activities Subscale Score at the End of Treatment Course 1 | Baseline | 28.70 score on a scale | Standard Deviation 24.56 |
| Placebo | Change From Baseline in Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) Revised Activities Subscale Score at the End of Treatment Course 1 | Change from Baseline at Week 12 | 14.25 score on a scale | Standard Deviation 28.77 |
| UPA 5 mg | Change From Baseline in Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) Revised Activities Subscale Score at the End of Treatment Course 1 | Baseline | 27.52 score on a scale | Standard Deviation 24.05 |
| UPA 5 mg | Change From Baseline in Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) Revised Activities Subscale Score at the End of Treatment Course 1 | Change from Baseline at Week 12 | 50.19 score on a scale | Standard Deviation 32.07 |
| UPA 10 mg | Change From Baseline in Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) Revised Activities Subscale Score at the End of Treatment Course 1 | Baseline | 33.24 score on a scale | Standard Deviation 27 |
| UPA 10 mg | Change From Baseline in Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) Revised Activities Subscale Score at the End of Treatment Course 1 | Change from Baseline at Week 12 | 54.73 score on a scale | Standard Deviation 32.32 |
Secondary
Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 2
Participants recorded bleeding in a daily diary. Absence of bleeding was defined as no bleeding days (i.e., no entries for bleeding or heavy bleeding; however, spotting was allowed), during the last 35 consecutive days on treatment in Treatment Course 2.
Time frame: Last 35 consecutive days on treatment in the 12-Week Treatment Course 2
Population: Data was summarized as per the treatment assigned. Number of participants analyzed are participants with data available for analysis at the given timepoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 2 | 8.0 percentage of participants |
| UPA 5 mg | Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 2 | 40.5 percentage of participants |
| UPA 10 mg | Percentage of Participants With Absence of Bleeding During the Last 35 Consecutive Days on Treatment in Treatment Course 2 | 57.3 percentage of participants |
Secondary
Percentage of Participants With Absence of Bleeding From Day 11 Through the End of Treatment Course 1
Participants recorded bleeding in a daily diary. Absence of bleeding was defined as no bleeding days (i.e., no entries for bleeding or heavy bleeding; however, spotting was allowed), from Day 11 to the end of treatment in Treatment Course 1.
Time frame: Day 11 through the end of treatment in the 12-Week Treatment Course 1
Population: ITT population included all randomized participants. Data was summarized as per the treatment assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Absence of Bleeding From Day 11 Through the End of Treatment Course 1 | 0.0 percentage of participants |
| UPA 5 mg | Percentage of Participants With Absence of Bleeding From Day 11 Through the End of Treatment Course 1 | 34.6 percentage of participants |
| UPA 10 mg | Percentage of Participants With Absence of Bleeding From Day 11 Through the End of Treatment Course 1 | 55.4 percentage of participants |
Secondary
Time to Absence of Bleeding on Treatment During Treatment Course 2
Time to absence of bleeding is defined as the duration in days from first dose in treatment course 2 to the first day in the time interval in which absence of bleeding occurs and persists through the last dose in the second treatment course. The persistence of absence of bleeding occurred for a minimum of 35 consecutive days counting backward from the last dose in Treatment Course 2.
Time frame: From first dose up to the end of treatment in the 12-Week Treatment Course 2
Population: Data was summarized as per treatment assigned. Number of participants analyzed are participants with data available for analysis at the given timepoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Absence of Bleeding on Treatment During Treatment Course 2 | NA days |
| UPA 5 mg | Time to Absence of Bleeding on Treatment During Treatment Course 2 | NA days |
| UPA 10 mg | Time to Absence of Bleeding on Treatment During Treatment Course 2 | 7.5 days |