Uterine Fibroids
Conditions
Keywords
Heavy menstrual bleeding
Brief summary
The primary objective of this study was to show superiority of vilaprisan in the treatment of heavy menstrual bleeding (HMB) in subjects with uterine fibroids compared to placebo The secondary objectives of this study were to additionally evaluate the efficacy and safety of vilaprisan in subjects with uterine fibroids
Interventions
Orally, coated tablet 2 mg, once daily
DRUGPlacebo
Orally, coated tablet, once daily
Sponsors
Bayer
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Women, 18 years or older in good general health * Diagnosis of uterine fibroid(s) documented by ultrasound at screening with at least 1 fibroid with largest diameter more than 30 mm and less than 120 mm * Heavy menstrual bleeding (HMB) in at least 2 bleeding periods during the screening period each with blood loss volume of \>80.00 mL documented by the alkaline hematin (AH) method * An endometrial biopsy performed during the screening period without significant histological disorder such as endometrial hyperplasia (including simple hyperplasia) or other significant endometrial pathology * Use of an acceptable non-hormonal method of contraception (ie, either male condom, cap, diaphragm or sponge, each in combination with spermicide) starting at Visit 1 until the end of the study
Exclusion criteria
* Pregnancy or lactation (less than 3 months since delivery, abortion, or lactation before start of treatment) * Hypersensitivity to any ingredient of the study drug * Hemoglobin values ≤6 g/dL or any condition requiring immediate blood transfusion (subjects with hemoglobin values ≤10.9 g/dL will be recommended to use iron supplementation) * Any diseases, conditions, or medications that can compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study drug * Any diseases or conditions that might interfere with the conduct of the study or the interpretation of the results * Abuse of alcohol, drugs or medicines (e.g. laxatives) * Use of other treatments that might interfere with the conduct of the study or the interpretation of results * Undiagnosed abnormal genital bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Amenorrhea | The last 28 days of treatment period 1 | Amenorrhea was defined as menstrual blood loss (MBL) \< 2 mL during the last 28 days of treatment. The evaluation of MBL was based on the Alkaline hematin (AH) method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Amenorrhea | In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks) | Onset of amenorrhea was defined by the first day for which the MBL for all subsequent 28-day periods up to the end of a treatment period was \<2 mL (amenorrhea defined similar to primary endpoint and assessed by the AH method). |
| Time to Onset of Controlled Bleeding | In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks) | Onset of controlled bleeding was defined by the first day for which the MBL for all subsequent 28-day periods up to the end of a treatment period was \<80.00 mL (assessed by the AH method). |
| Number of Participants With Heavy Menstrual Bleeding (HMB) Response | The last 28 days of treatment period 1 and treatment period 2 | HMB was defined as MBL \<80.00 mL during the last 28 days of treatment and \>50% reduction compared to baseline (assessed by the AH method). |
| Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Up to 36 weeks | Number of participants with endometrial histology findings, e.g. benign endometrium, malignant neoplasm, hyperplasia without atypia, hyperplasia with atypia and endometrial polyps. |
| Change From Baseline of Endometrial Thickness | In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks) | Ultrasound examinations were performed. Endometrial thickness was measured in the medio-sagittal section as double-layer in millimeters. Summary statistics for change from baseline in endometrial thickness was provided in below table. |
| Number of Participants With Absence of Bleeding (Spotting Allowed) | The last 28 days of treatment period 1 and treatment period 2 | Absence of bleeding was defined as no scheduled or unscheduled bleeding (spotting allowed) during the last 28 days of a treatment period based on subjects' daily responses to the UF-DBD (Uterine Fibroid Daily Bleeding Diary). |
Countries
Czechia, Japan, Russia, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 87 study centers in USA, Japan, Czech Republic, Russia, and Ukraine between 24-Jan-2018 (first participant first visit) and 30-Jun-2021 (last participant last visit).
Pre-assignment details
Overall, 481 participants were screened, of them, 378 (78.6%) participants were not randomized to treatment. The majority of these (n=286) were screen failures. Of the 103 participants who were randomized, 91 participants received study treatment. Full analysis set (FAS) consisted of all randomized subjects, excluding randomized subjects who did not start treatment period 1 (never received study drug) due to the study being closed prematurely (7 \[6.8%\]), and included 96 (93.2%) subjects.
Participants by arm
| Arm | Count |
|---|---|
| Vilaprisan (A1) Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode. | 32 |
| Placebo+Vilaprisan (B1) Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode. | 33 |
| Vilaprisan+Placebo (B2) Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode. | 31 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow-up Period | Other | 0 | 0 | 1 |
| Follow-up Period | Withdrawal by Subject | 0 | 0 | 1 |
| Post-treatment Period 1 | Adverse Event | 0 | 0 | 1 |
| Post-treatment Period 1 | Other | 4 | 3 | 4 |
| Post-treatment Period 1 | Physician Decision | 2 | 3 | 0 |
| Post-treatment Period 1 | Study terminated by sponsor | 11 | 10 | 11 |
| Post-treatment Period 1 | Withdrawal by Subject | 5 | 0 | 0 |
| Treatment Period 1 | Adverse Event | 0 | 1 | 0 |
| Treatment Period 1 | Lost to Follow-up | 0 | 0 | 1 |
| Treatment Period 1 | Other | 1 | 2 | 3 |
| Treatment Period 1 | Protocol Violation | 0 | 2 | 0 |
| Treatment Period 1 | Study terminated by sponsor | 3 | 1 | 1 |
| Treatment Period 1 | Withdrawal by Subject | 0 | 2 | 4 |
| Treatment Period 2 | Adverse Event | 2 | 1 | 1 |
| Treatment Period 2 | Lost to Follow-up | 1 | 1 | 0 |
| Treatment Period 2 | Other | 1 | 1 | 0 |
| Treatment Period 2 | Withdrawal by Subject | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Vilaprisan (A1) | Placebo+Vilaprisan (B1) | Vilaprisan+Placebo (B2) | Total |
|---|---|---|---|---|
| Age, Continuous | 43.1 Years STANDARD_DEVIATION 5.5 | 42.7 Years STANDARD_DEVIATION 6 | 43.8 Years STANDARD_DEVIATION 4.3 | 43.2 Years STANDARD_DEVIATION 5.3 |
| Endometrial thickness | 12.8 Millimeters STANDARD_DEVIATION 4.5 | 12.8 Millimeters STANDARD_DEVIATION 2.9 | 11.9 Millimeters STANDARD_DEVIATION 3.9 | 12.5 Millimeters STANDARD_DEVIATION 3.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 30 Participants | 26 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 11 Participants | 11 Participants | 33 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 7 Participants | 8 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 13 Participants | 15 Participants | 10 Participants | 38 Participants |
| Sex: Female, Male Female | 32 Participants | 33 Participants | 31 Participants | 96 Participants |
| Sex: Female, Male Male | 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 30 | 0 / 30 | 0 / 31 | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 18 / 31 | 19 / 30 | 16 / 30 | 10 / 31 | 12 / 30 | 12 / 30 |
| serious Total, serious adverse events | 1 / 31 | 4 / 30 | 0 / 30 | 7 / 31 | 8 / 30 | 3 / 30 |
Outcome results
Primary
Number of Participants With Amenorrhea
Amenorrhea was defined as menstrual blood loss (MBL) \< 2 mL during the last 28 days of treatment. The evaluation of MBL was based on the Alkaline hematin (AH) method.
Time frame: The last 28 days of treatment period 1
Population: FAS population with evaluable data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vilaprisan (A1) | Number of Participants With Amenorrhea | 29 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants With Amenorrhea | 1 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants With Amenorrhea | 25 Participants |
Comparison: Vilaprisan (A1) and Vilaprisan+Placebo (B2) combined vs. Placebo+Vilaprisan (B1) in treatment period 1p-value: <0.000195% CI: [0.72, 0.93]Cochran-Mantel-Haenszel
Secondary
Change From Baseline of Endometrial Thickness
Ultrasound examinations were performed. Endometrial thickness was measured in the medio-sagittal section as double-layer in millimeters. Summary statistics for change from baseline in endometrial thickness was provided in below table.
Time frame: In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks)
Population: SAF was analyzed. Overall number of participants analyzed represents number of participants without missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vilaprisan (A1) | Change From Baseline of Endometrial Thickness | Treatment period 1 | -2.5 Millimeters | Standard Deviation 4.1 |
| Vilaprisan (A1) | Change From Baseline of Endometrial Thickness | Treatment period 2 | -5.3 Millimeters | Standard Deviation 7.6 |
| Placebo+Vilaprisan (B1) | Change From Baseline of Endometrial Thickness | Treatment period 1 | -2.8 Millimeters | Standard Deviation 2.6 |
| Placebo+Vilaprisan (B1) | Change From Baseline of Endometrial Thickness | Treatment period 2 | -3.5 Millimeters | Standard Deviation 4.1 |
| Vilaprisan+Placebo (B2) | Change From Baseline of Endometrial Thickness | Treatment period 1 | -3.1 Millimeters | Standard Deviation 3.7 |
| Vilaprisan+Placebo (B2) | Change From Baseline of Endometrial Thickness | Treatment period 2 | -0.4 Millimeters | Standard Deviation 4.1 |
Secondary
Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis)
Number of participants with endometrial histology findings, e.g. benign endometrium, malignant neoplasm, hyperplasia without atypia, hyperplasia with atypia and endometrial polyps.
Time frame: Up to 36 weeks
Population: Samples with sufficient tissue for analysis in SAF population was analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vilaprisan (A1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Adequate endometrial tissue | 31 Participants |
| Vilaprisan (A1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Benign Endometrium | 31 Participants |
| Vilaprisan (A1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Hyperplasia WHO 2014, no atypia | 0 Participants |
| Vilaprisan (A1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Hyperplasia WHO 2014, atypia | 0 Participants |
| Vilaprisan (A1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Malignant Neoplasm | 0 Participants |
| Vilaprisan (A1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Endometrial Polyps | 2 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Endometrial Polyps | 0 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Adequate endometrial tissue | 30 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Hyperplasia WHO 2014, atypia | 0 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Malignant Neoplasm | 0 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Benign Endometrium | 30 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Hyperplasia WHO 2014, no atypia | 0 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Benign Endometrium | 26 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Hyperplasia WHO 2014, no atypia | 0 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Endometrial Polyps | 1 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Hyperplasia WHO 2014, atypia | 0 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Adequate endometrial tissue | 26 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants by Endometrial Biopsy Main Results (Majority Read, Main Diagnosis) | Malignant Neoplasm | 0 Participants |
Secondary
Number of Participants With Absence of Bleeding (Spotting Allowed)
Absence of bleeding was defined as no scheduled or unscheduled bleeding (spotting allowed) during the last 28 days of a treatment period based on subjects' daily responses to the UF-DBD (Uterine Fibroid Daily Bleeding Diary).
Time frame: The last 28 days of treatment period 1 and treatment period 2
Population: FAS population with valuable data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vilaprisan (A1) | Number of Participants With Absence of Bleeding (Spotting Allowed) | Treatment period 1 | 29 Participants |
| Vilaprisan (A1) | Number of Participants With Absence of Bleeding (Spotting Allowed) | Treatment period 2 | 6 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants With Absence of Bleeding (Spotting Allowed) | Treatment period 1 | 2 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants With Absence of Bleeding (Spotting Allowed) | Treatment period 2 | 8 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants With Absence of Bleeding (Spotting Allowed) | Treatment period 1 | 25 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants With Absence of Bleeding (Spotting Allowed) | Treatment period 2 | 1 Participants |
Secondary
Number of Participants With Heavy Menstrual Bleeding (HMB) Response
HMB was defined as MBL \<80.00 mL during the last 28 days of treatment and \>50% reduction compared to baseline (assessed by the AH method).
Time frame: The last 28 days of treatment period 1 and treatment period 2
Population: FAS population with valuable data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vilaprisan (A1) | Number of Participants With Heavy Menstrual Bleeding (HMB) Response | Treatment period 1 | 30 Participants |
| Vilaprisan (A1) | Number of Participants With Heavy Menstrual Bleeding (HMB) Response | Treatment period 2 | 6 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants With Heavy Menstrual Bleeding (HMB) Response | Treatment period 1 | 7 Participants |
| Placebo+Vilaprisan (B1) | Number of Participants With Heavy Menstrual Bleeding (HMB) Response | Treatment period 2 | 9 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants With Heavy Menstrual Bleeding (HMB) Response | Treatment period 1 | 26 Participants |
| Vilaprisan+Placebo (B2) | Number of Participants With Heavy Menstrual Bleeding (HMB) Response | Treatment period 2 | 1 Participants |
Secondary
Time to Onset of Amenorrhea
Onset of amenorrhea was defined by the first day for which the MBL for all subsequent 28-day periods up to the end of a treatment period was \<2 mL (amenorrhea defined similar to primary endpoint and assessed by the AH method).
Time frame: In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks)
Population: FAS population with valuable data. In treatment period 2, participants who did not start the respective treatment period or had less than 28 days of treatment are included among censored observations.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vilaprisan (A1) | Time to Onset of Amenorrhea | Treatment period 1 | 3 Days |
| Vilaprisan (A1) | Time to Onset of Amenorrhea | Treatment period 2 | 3 Days |
| Placebo+Vilaprisan (B1) | Time to Onset of Amenorrhea | Treatment period 1 | NA Days |
| Placebo+Vilaprisan (B1) | Time to Onset of Amenorrhea | Treatment period 2 | 4 Days |
| Vilaprisan+Placebo (B2) | Time to Onset of Amenorrhea | Treatment period 1 | 3 Days |
| Vilaprisan+Placebo (B2) | Time to Onset of Amenorrhea | Treatment period 2 | NA Days |
Secondary
Time to Onset of Controlled Bleeding
Onset of controlled bleeding was defined by the first day for which the MBL for all subsequent 28-day periods up to the end of a treatment period was \<80.00 mL (assessed by the AH method).
Time frame: In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks)
Population: FAS population with valuable data. In treatment period 2, participants who did not start the respective treatment period or had less than 28 days of treatment are included among censored observations.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vilaprisan (A1) | Time to Onset of Controlled Bleeding | Treatment period 1 | 1 Days |
| Vilaprisan (A1) | Time to Onset of Controlled Bleeding | Treatment period 2 | 1.5 Days |
| Placebo+Vilaprisan (B1) | Time to Onset of Controlled Bleeding | Treatment period 1 | NA Days |
| Placebo+Vilaprisan (B1) | Time to Onset of Controlled Bleeding | Treatment period 2 | 1 Days |
| Vilaprisan+Placebo (B2) | Time to Onset of Controlled Bleeding | Treatment period 1 | 1 Days |
| Vilaprisan+Placebo (B2) | Time to Onset of Controlled Bleeding | Treatment period 2 | NA Days |