Bay1002670, Fibroids, Safety and Efficacy EU,US,Can, Jap

Leiomyoma Clinical Trial

— ASTEROID 1  

Official title:

A Randomized, Parallel-group, Double-blind, Placebo Controlled, Multi-center Study to Assess the Efficacy and Safety of Different Doses of BAY1002670 in Subjects With Uterine Fibroids Over 3 Months

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02131662
• Other study ID #: 15788
• Secondary ID: 2013-003945-40
• Status: Completed
• Phase: Phase 2
• First received: May 5, 2014
• Last updated: November 6, 2017
• Start date: May 15, 2014
• Est. completion date: May 4, 2016

Study information

• Verified date: November 2017
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 309
• Est. completion date: May 4, 2016
• Est. primary completion date: May 4, 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Leiomyoma

Intervention

Drug:
• BAY1002670
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.
• BAY1002670
Subjects received 2 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
• BAY1002670
Subjects received 1 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
• BAY1002670
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.
• Placebo
Subjects received matching placebo tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Canada,  Czechia,  Finland,  Germany,  Hungary,  Japan,  Norway,  Spain,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	From start of the study treatment to Day 84 (treatment period)
Other	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.	From start of the study treatment to Day 84 (treatment period)
Other	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).	From start of the study treatment to Day 84 (treatment period)
Other	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.	At baseline
Other	Percentage of Subjects With Amenorrhea (Defined as MBL < 2 mL) During the Last 28 Days of Treatment		Last 28 Days of Treatment
Other	Percentage of Subjects With HMB Response During the Last 28 Days of Treatment		Last 28 Days of Treatment
Other	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 d. The model is defined as p(d)=E0 + Emax/{1+ e^[{ED50-d)/d]}. 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).	After end of the initial bleeding episode until the end of treatment
Other	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 d. The model is defined as p(d)=E0 + Emax/{1+ e^[{ED50-d)/d]}. ED50 is the dose at which 50% of Emax were achieved.	After end of the initial bleeding episode until the end of treatment
Other	Estimated Dose-response Curve Based on Amenorrhea - d	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 d. The model is defined as p(d)=E0 + Emax/{1+ e^[{ED50-d)/d]}. d 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.	After end of the initial bleeding episode until the end of treatment
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.	After end of the initial bleeding episode until the end of treatment, up to 12 weeks
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.	From baseline to end of follow-up
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.	During treatment period
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).	From baseline to end of follow-up period

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