A randomized, parallel-group, double-blind placebo-controlled and open label active-controlled, multi-center study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids

Uterine fibroids are the leading cause for hysterectomy. Hysterectomy is the
only definitive treatment and eliminates the possibility of recurrence. In
North America, 275,000 women per year undergo hysterectomy as uterine fibroid
treatment. Many women seek an alternative to hysterectomy because they desire
future childbearing or wish to retain their uterus. For women who desire
uterine preservation, myomectomy is an alternative surgical procedure. The goal
is to remove visible and accessible fibroids and reconstruct the uterus.
However, the recurrence rate is substantial and up to 25% of patients require
repeat myomectomy or hysterectomy at a later stage. The medical need for
pharmacological alternatives to surgical or interventional treatment options is
considered high.
The selective progesterone receptor modulator vilaprisan (BAY 1002670) is a
promising new drugcandidate for the long-term treatment of uterine fibroids.
Evidence for efficacy is based on the clinical experience with other
progesterone receptor modulators, the potencies and selectivities of which are
lower compared to vilaprisan. If its pharmacologic properties can be translated
into significant therapeutic efficacy, options for medical treatment of
symptomatic uterine fibroids would considerably improve.

The primary objective of this study is
• To assess the efficacy of vilaprisan in subjects with uterine fibroids
compared to placebo.
The secondary objectives of this study are
• To assess the efficacy of vilaprisan in subjects with uterine fibroids
compared to ulipristal.
• To evaluate the safety of vilaprisan in subjects with uterine fibroids.

Randomized, parallel-group, double-blind, placebo-controlled and open label
active-controlled, multi-center design Screening period of up to 60 days.
Eligible subjects will be randomized to one of the following treatment groups:
Treatment groups A1, B1, C1, C3: 30 subjects each
Treatment groups A2, B2, C2: 6 subjects each

• A1: Vilaprisan 2 mg (12 weeks), vilaprisan 2 mg (12 weeks)
• A2: Placebo (12 weeks), vilaprisan 2 mg (12 weeks).

• B1: Vilaprisan 2 mg (12 weeks), 1 bleeding episode, vilaprisan 2 mg (12
weeks).
• B2: Placebo (12 weeks), 1 bleeding episode, vilaprisan 2 mg (12 weeks).

• C1: Ulipristal 5 mg (12 weeks), 2 bleeding episodes , ulipristal 5 mg (12
weeks)
• C2: Placebo (12 weeks), 2 bleeding episodes, ulipristal 5 mg (12 weeks)
• C3: Ulipristal 5 mg (12 weeks), 2 bleeding episodes, placebo (12 weeks)

After the end of treatment, subjects will be followed up for 12 weeks.

A1: Vilaprisan 2 mg (12 weeks), vilaprisan 2 mg (12 weeks)
A2: Placebo (12 weeks), vilaprisan 2 mg (12 weeks).

B1: Vilaprisan 2 mg (12 weeks), 1 bleeding episode, vilaprisan 2 mg (12
weeks).
B2: Placebo (12 weeks), 1 bleeding episode, vilaprisan 2 mg (12 weeks).

C1: Ulipristal 5 mg (12 weeks), 2 bleeding episodes , ulipristal 5 mg (12
weeks)
C2: Placebo (12 weeks), 2 bleeding episodes, ulipristal 5 mg (12 weeks)
C3: Ulipristal 5 mg (12 weeks), 2 bleeding episodes, placebo (12 weeks)

Patients have to undergo 10 site visits,
- 3 during the screening phase which is aimed to verify the inclusion and
exclusion criteria
- 6 visits during treatment (3 visits per treatment period)
- and a final visit at the end of the follow up period of 12 weeks.
The study duration for a single patient will be 12-13 months depending on the
treatment group.The following procedures are planned:
- 7 times blood samples for safety assessments and 4 times for PK - total blood
amount about 150 ml - During the collection of blood samples, pain and/or
bruising may occur at the needle site. Occasionally, an infection may occur
around the blood drawing site. An infection
may sometimes involve the vein and may on rare occasions be very serious and
require surgery. Lightheadedness and/or fainting occasionally occur during, or
shortly after, blood is drawn.
- 4 physical and 3 gynecological examinations
- transvaginal ultrasound at all visits
- cervical smear sampling at baseline and follow up - may cause discomfort and
spotting
- endometrial biopsy sampling at 3 visits - While the procedure is generally
considered safe, cramps or pelvic pain are common short-lived side effects. If
required painkillers can be used (please discuss with your study doctor). After
the procedure, you may experience some bleeding. A uterine perforation or
infection is a rare complication. Since a biopsy should not be taken during
pregnancy, a urine pregnancy test will be taken before each biopsy
- 4 times magnetic resonance imaging (MRI) without contrast agent

Throughout the whole study duration, patients are requested to use non-hormonal
methods of barrier contraception, Pregnancy tests will be performed at each
visit. A daily electronic diary has to be filled in.
The following side effects have been reported with the study drug in previous
studies:
For >10% of subjects of the overall study population after single or multiple
dosing with study drug, mild or moderate headache was reported. Less frequently
reported side effects >3% and <10% of subjects included nausea, fatigue and hot
flush. Ovarian cysts were observed during and after treatment in 11% of women
of reproductive age, and most of the cases spontaneously disappeared within a
few weeks. Less frequently were abdominal pain, menstrual cramps, and uterine
disorders. Transient ECG alterations at different dose levels without clinical
relevance were registered in some subjects. In less than 10% of the subjects
taking doses of the study drug, as compared to this study, liver
parameters were slightly above the reference range. Therefore, a close control
of liver parameters will take place during this study.
Due to the low number of study subjects who have taken the study drug so far,
the following side effects might be expected due to the nature of the study
drug and based on results from studies with drugs in the same compound class:
Endometrial changes: The inner lining of the uterus (endometrium) may thicken
or other changes in the endometrium may appear as a result of taking the study
drug. These changes are expected to disappear after treatment is stopped and
menstrual periods restart.
There can be no certainty that a patient will have any benefit from the study
drug, however it is expected that the study drug may decrease heavy menstrual
blood loss, other fibroid related symptoms, and fibroid size. The information
the study sponsor receives from this study may help to develop a better long
term treatment for uterine fibroid patients and to define the optimal dose of
the drug.