Leiomyoma
Conditions
Keywords
Uterine fibroids
Brief summary
The study is performed to assess the efficacy and safety of different doses of BAY1002670 in subjects with uterine fibroids. The dose-response relationship will be evaluated. Further, the study aims to establish a population pharmacokinetic/pharmacodynamic relationship for BAY1002670 in subjects with uterine fibroids. To assess the efficacy of BAY1002670 the interchangeability of menstrual pictogram and alkaline hematin method for the judgement of menstrual blood loss will be assessed.
Interventions
DRUGBAY1002670
Subjects received 4 milligram (mg) Vilaprisan (VPR) tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
DRUGPlacebo
Subjects received matching placebo tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
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 50 Years
Healthy volunteers
No
Inclusion criteria
* Signed and dated informed consent * Diagnosis of uterine fibroid(s) documented by transvaginal or abdominal ultrasound at screening with at least 1 fibroid with largest diameter 3.0 cm * 18 to 50 years of age at the time of screening * Heavy menstrual bleeding \>80 mL documented by MP during the bleeding episode following the screening visit * Normal or clinically insignificant cervical smear not requiring further follow-up * An endometrial biopsy performed at the screening visit 1 (Visit 1), without significant histological disorder such as endometrial hyperplasia or other significant endometrial pathology * Use of a non-hormonal barrier method of contraception starting at the bleeding episode following the screening visit 1 (Visit 1) until the end of the study * Good general health (except for findings related to uterine fibroids)
Exclusion criteria
* Pregnancy or lactation * Uterine fibroid with largest diameter \>10.0 cm * Hypersensitivity to any ingredient of the study drug * Laboratory values outside inclusion range before randomization and considered as clinically relevant * Hemoglobin values \<6 g/dL or any condition requiring immediate blood transfusion (subjects with hemoglobin values \<10.9 g/dL will receive iron supplementation) * Any diseases or conditions 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment | After end of the initial bleeding episode until the end of treatment, up to 12 weeks | Amenorrhea was defined as no scheduled or unscheduled bleeding/spotting after the end of the initial bleeding episode until end of treatment. Dose-response curve was estimated based on the primary endpoint. The 4 parameters characterizing the dose-response curve were reported in other pre-specified endpoints below. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Controlled Bleeding | During treatment period | Onset of controlled bleeding was defined by the first day, for which the MBL (assessed by MP, Version 2014) for all subsequent 28-day periods up to the end of the treatment period was less than 80 mL. Kaplan-Meier estimated time to onset of controlled bleeding (days) was reported. |
| Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | From baseline to end of follow-up | In the below table, N signifies subjects who were evaluable for the specific parameter at that timepoint for each arm, respectively. |
| Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | From baseline to end of follow-up period | Pelvic Magnetic resonance imagings (MRI), without contrast agents, were performed for volume measurements of the uterus and fibroids preferably using 1.5 Tesla scanners or higher. Images were sent to the imaging core laboratory for evaluation. Volume measurements of the uterus and fibroids were performed centrally by independent radiologist(s). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | At baseline | The ability of the MP to identify subjects with HMB (defined as \> 80 mL of blood loss during bleeding episode) per 28 days against the the current gold standard (i.e. AH method) was assessed. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MP method for detecting heavy menstrual bleeding were calculated against AH method. Sensitivity = true positive/(true positive + false negative)\*100; Specificity = true negative/(true negative + false positive)\*100; PPV = true positive/(true positive + false positive)\*100; NPV = true negative/(true negative + false negative)\*100. MP version 2014 was originally defined based on studies in healthy subjects. And MP version 2016 was developed for study population of women with heavy bleeding. |
| Percentage of Subjects With Amenorrhea (Defined as MBL < 2 mL) During the Last 28 Days of Treatment | Last 28 Days of Treatment | — |
| Exposure-response Analysis of Vilaprisan - Percentage of Subjects Achieving Maximum Effect (Emax) of Induced Amenorrhea | From start of the study treatment to Day 84 (treatment period) | Maximum effect of vilaprisan on induced amenorrhea during treatment period. Induced amenorrhea was defined as number of subjects with amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment. The nature of this exposure response analysis was the development of a model valid for the exposure response relationship over the entire range of available exposures (i.e. across all dose groups). Therefore, observations (exposure - induced amenorrhea) of all subjects need to be combined. |
| Estimated Dose-response Curve Based on Amenorrhea - ED50 | After end of the initial bleeding episode until the end of treatment | The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e\^\[{ED50-d)/δ\]}. ED50 is the dose at which 50% of Emax were achieved. |
| Estimated Dose-response Curve Based on Amenorrhea - δ | After end of the initial bleeding episode until the end of treatment | The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e\^\[{ED50-d)/δ\]}. δ is hill slope parameter which measures sensitivity of the response to the dose range of the drug, determining the steepness of the dose-response curve. |
| Percentage of Subjects With HMB Response During the Last 28 Days of Treatment | Last 28 Days of Treatment | — |
| Estimated Dose-response Curve Based on Amenorrhea - E0 and Emax | After end of the initial bleeding episode until the end of treatment | The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e\^\[{ED50-d)/δ\]}. E0 is the amenorrhea rate for placebo; Emax is the maximum effect attributable to the drug (compared with the basal effect with dose at d=0 \[placebo group\], the maximum increase of drug effect). |
| Steady-state Exposure Achieving Half-maximal Effect (EAUC50) of Induced Amenorrhea During Treatment Period of Vilaprisan | From start of the study treatment to Day 84 (treatment period) | Area-under-the-curve (AUC) of vilaprisan between 0 and 24 hours post-dose at steady-state achieving 50% of maximum effect of vilaprisan on induced amenorrhea during treatment period. Induced amenorrhea was defined as number of subjects with induced-amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment. The nature of this exposure response analysis was the development of a model valid for the exposure response relationship over the entire range of available exposures (i.e. across all dose groups). Therefore, observations (exposure - induced amenorrhea) of all subjects need to be combined. |
| Exposure-response Analysis of Vilaprisan - Predicted Percentage of Subjects Below 90% of the Maximum Probability of Induced Amenorrhea | From start of the study treatment to Day 84 (treatment period) | The final exposure-response model was used to simulate the percentage of subjects below 90% of the maximum probability of induced amenorrhea (that is, all days with bleeding intensity 1 = none) for the selected doses 1, 2 and 3 mg (see table below). |
Countries
Belgium, Bulgaria, Canada, Czechia, Finland, Germany, Hungary, Japan, Norway, Spain, Sweden, Switzerland, United States
Participant flow
Recruitment details
The study was conducted at multiple centers in 12 countries worldwide between 15 May 2014 (first subject first visit) and 04 May 2016 (last subject last visit).
Pre-assignment details
748 subjects were screened; 439 subjects were not randomized, the majority was screen failures. Therefore, 309 subjects were randomized.
Participants by arm
| Arm | Count |
|---|---|
| VPR 4 mg Subjects received 4 milligram (mg) VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization. | 60 |
| VPR 2 mg Subjects received 2 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization. | 61 |
| VPR 1 mg Subjects received 1 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization. | 61 |
| VPR 0.5 mg Subjects received 0.5 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization. | 60 |
| Placebo Subjects received matching placebo tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization. | 58 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 1 | 3 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 3 | 0 | 9 | 0 |
| Overall Study | Not treated | 2 | 0 | 2 | 2 | 3 |
| Overall Study | Other | 2 | 4 | 3 | 3 | 4 |
| Overall Study | Pregnancy | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Wish for pregnancy | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 5 | 1 | 5 | 6 |
Baseline characteristics
| Characteristic | Total | Placebo | VPR 4 mg | VPR 0.5 mg | VPR 1 mg | VPR 2 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 42.6 years STANDARD_DEVIATION 4.7 | 42.8 years STANDARD_DEVIATION 5.1 | 43.5 years STANDARD_DEVIATION 4.2 | 41.7 years STANDARD_DEVIATION 4.9 | 41.9 years STANDARD_DEVIATION 4.5 | 43 years STANDARD_DEVIATION 4.6 |
| Baseline menstrual blood loss by MP | 173.2 millilitre(s) STANDARD_DEVIATION 107.21 | 164.6 millilitre(s) STANDARD_DEVIATION 78.71 | 172.3 millilitre(s) STANDARD_DEVIATION 111.86 | 173.6 millilitre(s) STANDARD_DEVIATION 94.62 | 178.2 millilitre(s) STANDARD_DEVIATION 116.64 | 176.9 millilitre(s) STANDARD_DEVIATION 128.71 |
| Sex: Female, Male Female | 300 Participants | 58 Participants | 60 Participants | 60 Participants | 61 Participants | 61 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Volume of largest fibroid by US | 82.22 millilitre(s) STANDARD_DEVIATION 95.94 | 99.03 millilitre(s) STANDARD_DEVIATION 117.379 | 78.92 millilitre(s) STANDARD_DEVIATION 95.644 | 81.69 millilitre(s) STANDARD_DEVIATION 85.62 | 74.55 millilitre(s) STANDARD_DEVIATION 88.397 | 77.66 millilitre(s) STANDARD_DEVIATION 91.605 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 31 / 60 | 30 / 61 | 31 / 61 | 32 / 60 | 32 / 58 |
| serious Total, serious adverse events | 2 / 60 | 4 / 61 | 3 / 61 | 2 / 60 | 2 / 58 |
Outcome results
Primary
Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment
Amenorrhea was defined as no scheduled or unscheduled bleeding/spotting after the end of the initial bleeding episode until end of treatment. Dose-response curve was estimated based on the primary endpoint. The 4 parameters characterizing the dose-response curve were reported in other pre-specified endpoints below.
Time frame: After end of the initial bleeding episode until the end of treatment, up to 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VPR 4 mg | Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment | 60 Percentage of subjects |
| VPR 2 mg | Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment | 54.1 Percentage of subjects |
| VPR 1 mg | Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment | 55.7 Percentage of subjects |
| VPR 0.5 mg | Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment | 30 Percentage of subjects |
| Placebo | Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment | 1.7 Percentage of subjects |
Comparison: The placebo-adjusted amenorrhea rate was summarized by dose with unconditional 2-sided 95% confidence intervals for each active treatment group. This unconditional confidence interval was calculated by inverting 2 separate one-sided tests of half the nominal significance level each.95% CI: [44.55, 70.94]
Comparison: The placebo-adjusted amenorrhea rate was summarized by dose with unconditional 2-sided 95% confidence intervals for each active treatment group. This unconditional confidence interval was calculated by inverting 2 separate one-sided tests of half the nominal significance level each.95% CI: [38.8, 65.42]
Comparison: The placebo-adjusted amenorrhea rate was summarized by dose with unconditional 2-sided 95% confidence intervals for each active treatment group. This unconditional confidence interval was calculated by inverting 2 separate one-sided tests of half the nominal significance level each.95% CI: [40.41, 66.95]
Comparison: The placebo-adjusted amenorrhea rate was summarized by dose with unconditional 2-sided 95% confidence intervals for each active treatment group. This unconditional confidence interval was calculated by inverting 2 separate one-sided tests of half the nominal significance level each.95% CI: [15.92, 41.5]
Secondary
Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI
Pelvic Magnetic resonance imagings (MRI), without contrast agents, were performed for volume measurements of the uterus and fibroids preferably using 1.5 Tesla scanners or higher. Images were sent to the imaging core laboratory for evaluation. Volume measurements of the uterus and fibroids were performed centrally by independent radiologist(s).
Time frame: From baseline to end of follow-up period
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VPR 4 mg | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | End of treatment (N=47, 52, 58, 47, 48) | -41.4 mL |
| VPR 4 mg | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | Follow-up (N=45, 48, 55, 40, 41) | -26.9 mL |
| VPR 2 mg | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | End of treatment (N=47, 52, 58, 47, 48) | -27.2 mL |
| VPR 2 mg | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | Follow-up (N=45, 48, 55, 40, 41) | -15 mL |
| VPR 1 mg | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | End of treatment (N=47, 52, 58, 47, 48) | -18.9 mL |
| VPR 1 mg | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | Follow-up (N=45, 48, 55, 40, 41) | -9.7 mL |
| VPR 0.5 mg | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | Follow-up (N=45, 48, 55, 40, 41) | -9.3 mL |
| VPR 0.5 mg | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | End of treatment (N=47, 52, 58, 47, 48) | -14.9 mL |
| Placebo | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | End of treatment (N=47, 52, 58, 47, 48) | 4.9 mL |
| Placebo | Change in Volume of Largest Fibroid Compared to Baseline Measured by MRI | Follow-up (N=45, 48, 55, 40, 41) | 5.1 mL |
Secondary
Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method)
In the below table, N signifies subjects who were evaluable for the specific parameter at that timepoint for each arm, respectively.
Time frame: From baseline to end of follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VPR 4 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 1st period (N=46, 46, 47, 45, 45) | -79.83 mL | Standard Deviation 234.22 |
| VPR 4 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 3rd period (N=43, 45, 47, 43, 40) | -205.08 mL | Standard Deviation 214.8 |
| VPR 4 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 2ndperiod (N=44, 45, 47, 44, 44) | -203.43 mL | Standard Deviation 215.23 |
| VPR 2 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 2ndperiod (N=44, 45, 47, 44, 44) | -166.71 mL | Standard Deviation 149.57 |
| VPR 2 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 1st period (N=46, 46, 47, 45, 45) | -30.18 mL | Standard Deviation 106.82 |
| VPR 2 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 3rd period (N=43, 45, 47, 43, 40) | -173.38 mL | Standard Deviation 153.37 |
| VPR 1 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 2ndperiod (N=44, 45, 47, 44, 44) | -181.76 mL | Standard Deviation 111.98 |
| VPR 1 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 1st period (N=46, 46, 47, 45, 45) | -55.42 mL | Standard Deviation 109.29 |
| VPR 1 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 3rd period (N=43, 45, 47, 43, 40) | -185.77 mL | Standard Deviation 106.91 |
| VPR 0.5 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 1st period (N=46, 46, 47, 45, 45) | -44.14 mL | Standard Deviation 110.61 |
| VPR 0.5 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 3rd period (N=43, 45, 47, 43, 40) | -147.55 mL | Standard Deviation 138.4 |
| VPR 0.5 mg | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 2ndperiod (N=44, 45, 47, 44, 44) | -146.32 mL | Standard Deviation 136.97 |
| Placebo | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 2ndperiod (N=44, 45, 47, 44, 44) | -28.42 mL | Standard Deviation 113.93 |
| Placebo | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 1st period (N=46, 46, 47, 45, 45) | 17.22 mL | Standard Deviation 124.14 |
| Placebo | Change in Volume of Menstrual Blood Loss Per 28 Days From Baseline During Treatment by Reference Period (Assessed by Alkaline Hematin Method) | 3rd period (N=43, 45, 47, 43, 40) | -36.69 mL | Standard Deviation 117.98 |
Secondary
Time to Onset of Controlled Bleeding
Onset of controlled bleeding was defined by the first day, for which the MBL (assessed by MP, Version 2014) for all subsequent 28-day periods up to the end of the treatment period was less than 80 mL. Kaplan-Meier estimated time to onset of controlled bleeding (days) was reported.
Time frame: During treatment period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VPR 4 mg | Time to Onset of Controlled Bleeding | 2 Days |
| VPR 2 mg | Time to Onset of Controlled Bleeding | 2 Days |
| VPR 1 mg | Time to Onset of Controlled Bleeding | 3 Days |
| VPR 0.5 mg | Time to Onset of Controlled Bleeding | 2 Days |
| Placebo | Time to Onset of Controlled Bleeding | NA Days |
Other Pre-specified
Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB)
The ability of the MP to identify subjects with HMB (defined as \> 80 mL of blood loss during bleeding episode) per 28 days against the the current gold standard (i.e. AH method) was assessed. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MP method for detecting heavy menstrual bleeding were calculated against AH method. Sensitivity = true positive/(true positive + false negative)\*100; Specificity = true negative/(true negative + false positive)\*100; PPV = true positive/(true positive + false positive)\*100; NPV = true negative/(true negative + false negative)\*100. MP version 2014 was originally defined based on studies in healthy subjects. And MP version 2016 was developed for study population of women with heavy bleeding.
Time frame: At baseline
Population: An analysis set for the assessment of the interchangeability of the MP and the AH method to judge MBL included all screened subjects (except subjects in Japan) with any sanitary product data for which there is any matching pair of MP score and AH value available. A total of 399 subjects were included in this analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VPR 4 mg | Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | Version 2016: PPV | 70.6 Percentage |
| VPR 4 mg | Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | Version 2014: NPV | 78.7 Percentage |
| VPR 4 mg | Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | Version 2014: Sensitivity | 83.3 Percentage |
| VPR 4 mg | Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | Version 2014: Specificity | 77.3 Percentage |
| VPR 4 mg | Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | Version 2014: PPV | 82.1 Percentage |
| VPR 4 mg | Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | Version 2016: Sensitivity | 89.7 Percentage |
| VPR 4 mg | Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | Version 2016: Specificity | 54.5 Percentage |
| VPR 4 mg | Assessment of MP to Identify Subjects With Heavy Menstrual Bleeding (HMB) | Version 2016: NPV | 81.4 Percentage |
Other Pre-specified
Estimated Dose-response Curve Based on Amenorrhea - E0 and Emax
The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e\^\[{ED50-d)/δ\]}. E0 is the amenorrhea rate for placebo; Emax is the maximum effect attributable to the drug (compared with the basal effect with dose at d=0 \[placebo group\], the maximum increase of drug effect).
Time frame: After end of the initial bleeding episode until the end of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VPR 4 mg | Estimated Dose-response Curve Based on Amenorrhea - E0 and Emax | E0 | 0.82 Percentage |
| VPR 4 mg | Estimated Dose-response Curve Based on Amenorrhea - E0 and Emax | Emax | 57 Percentage |
Other Pre-specified
Estimated Dose-response Curve Based on Amenorrhea - ED50
The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e\^\[{ED50-d)/δ\]}. ED50 is the dose at which 50% of Emax were achieved.
Time frame: After end of the initial bleeding episode until the end of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VPR 4 mg | Estimated Dose-response Curve Based on Amenorrhea - ED50 | 0.5 mg |
Other Pre-specified
Estimated Dose-response Curve Based on Amenorrhea - δ
The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e\^\[{ED50-d)/δ\]}. δ is hill slope parameter which measures sensitivity of the response to the dose range of the drug, determining the steepness of the dose-response curve.
Time frame: After end of the initial bleeding episode until the end of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VPR 4 mg | Estimated Dose-response Curve Based on Amenorrhea - δ | 0.145 Slope |
Other Pre-specified
Exposure-response Analysis of Vilaprisan - Percentage of Subjects Achieving Maximum Effect (Emax) of Induced Amenorrhea
Maximum effect of vilaprisan on induced amenorrhea during treatment period. Induced amenorrhea was defined as number of subjects with amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment. The nature of this exposure response analysis was the development of a model valid for the exposure response relationship over the entire range of available exposures (i.e. across all dose groups). Therefore, observations (exposure - induced amenorrhea) of all subjects need to be combined.
Time frame: From start of the study treatment to Day 84 (treatment period)
Population: The exposure response analysis includes all verum treated subjects with valid PK concentration data and valid PD data and all placebo treated subjects with valid PD data (placebo: 50, 0.5 mg 50, 1.0 mg 56, 2.0 mg: 56, 4.0 mg: 55, in total 267).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VPR 4 mg | Exposure-response Analysis of Vilaprisan - Percentage of Subjects Achieving Maximum Effect (Emax) of Induced Amenorrhea | 59 Percentage of subjects |
Other Pre-specified
Exposure-response Analysis of Vilaprisan - Predicted Percentage of Subjects Below 90% of the Maximum Probability of Induced Amenorrhea
The final exposure-response model was used to simulate the percentage of subjects below 90% of the maximum probability of induced amenorrhea (that is, all days with bleeding intensity 1 = none) for the selected doses 1, 2 and 3 mg (see table below).
Time frame: From start of the study treatment to Day 84 (treatment period)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VPR 4 mg | Exposure-response Analysis of Vilaprisan - Predicted Percentage of Subjects Below 90% of the Maximum Probability of Induced Amenorrhea | 1 mg | 36 Percentage of subjects |
| VPR 4 mg | Exposure-response Analysis of Vilaprisan - Predicted Percentage of Subjects Below 90% of the Maximum Probability of Induced Amenorrhea | 2 mg | 2 Percentage of subjects |
| VPR 4 mg | Exposure-response Analysis of Vilaprisan - Predicted Percentage of Subjects Below 90% of the Maximum Probability of Induced Amenorrhea | 3 mg | 1 Percentage of subjects |
Other Pre-specified
Percentage of Subjects With Amenorrhea (Defined as MBL < 2 mL) During the Last 28 Days of Treatment
Time frame: Last 28 Days of Treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VPR 4 mg | Percentage of Subjects With Amenorrhea (Defined as MBL < 2 mL) During the Last 28 Days of Treatment | 83.33 Percentage of subjects |
| VPR 2 mg | Percentage of Subjects With Amenorrhea (Defined as MBL < 2 mL) During the Last 28 Days of Treatment | 88.52 Percentage of subjects |
| VPR 1 mg | Percentage of Subjects With Amenorrhea (Defined as MBL < 2 mL) During the Last 28 Days of Treatment | 85.25 Percentage of subjects |
| VPR 0.5 mg | Percentage of Subjects With Amenorrhea (Defined as MBL < 2 mL) During the Last 28 Days of Treatment | 65 Percentage of subjects |
| Placebo | Percentage of Subjects With Amenorrhea (Defined as MBL < 2 mL) During the Last 28 Days of Treatment | 8.62 Percentage of subjects |
Other Pre-specified
Percentage of Subjects With HMB Response During the Last 28 Days of Treatment
Time frame: Last 28 Days of Treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VPR 4 mg | Percentage of Subjects With HMB Response During the Last 28 Days of Treatment | 93.33 Percentage of subjects |
| VPR 2 mg | Percentage of Subjects With HMB Response During the Last 28 Days of Treatment | 96.72 Percentage of subjects |
| VPR 1 mg | Percentage of Subjects With HMB Response During the Last 28 Days of Treatment | 93.44 Percentage of subjects |
| VPR 0.5 mg | Percentage of Subjects With HMB Response During the Last 28 Days of Treatment | 81.67 Percentage of subjects |
| Placebo | Percentage of Subjects With HMB Response During the Last 28 Days of Treatment | 29.31 Percentage of subjects |
Other Pre-specified
Steady-state Exposure Achieving Half-maximal Effect (EAUC50) of Induced Amenorrhea During Treatment Period of Vilaprisan
Area-under-the-curve (AUC) of vilaprisan between 0 and 24 hours post-dose at steady-state achieving 50% of maximum effect of vilaprisan on induced amenorrhea during treatment period. Induced amenorrhea was defined as number of subjects with induced-amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment. The nature of this exposure response analysis was the development of a model valid for the exposure response relationship over the entire range of available exposures (i.e. across all dose groups). Therefore, observations (exposure - induced amenorrhea) of all subjects need to be combined.
Time frame: From start of the study treatment to Day 84 (treatment period)
Population: The exposure response analysis includes all verum treated subjects with valid PK concentration data and valid PD data and all placebo treated subjects with valid PD data (placebo: 50, 0.5 mg 50, 1.0 mg 56, 2.0 mg: 56, 4.0 mg: 55, in total 267).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VPR 4 mg | Steady-state Exposure Achieving Half-maximal Effect (EAUC50) of Induced Amenorrhea During Treatment Period of Vilaprisan | 36.93 mcg*h/L |