ZK283197 for Treatment of Vasomotor Symptoms

Study Overview
=================
Brief Summary
-----------------
The primary goal of the planned study is to investigate the efficacy and safety of ZK 283197 in the dosage of 2 and 3 mg ingested once daily during a period of 8 weeks for the treatment of hot flushes. In order to be able to assess the efficacy of the test substance, this is compared with the efficacy of 1 mg Estradiol and placebo. The comparator Estradiol is a certified hormone preparation, which is already used for the treatment of hot flushes as standard treatment. After passing the screening, volunteers will start with a run-in phase followed by a 8 weeks treatment and a follow-up phase. 112 postmenopausal women with hot flushes and without relevant prior diseases will participate in three European countries (2 study sites in Germany, 1 study site in Great Britain and 1 study site in The Netherlands) in this study.

Official Title
-----------------
A Double-blind, Randomized, Placebo and Active Controlled, Multicenter Study to Investigate Efficacy and Safety After Oral Administration of 2 and 3 mg ZK 283197, 1 mg 17ß-estradiol and Placebo Once Daily for 8 Weeks in Postmenopausal Women With Hot Flushes

Conditions
-----------------
Vasomotor System

Intervention / Treatment
-----------------
* Drug: BAY 86-5310 (ZK 283197)
* Drug: Placebo
* Drug: 17ß-estradiol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women with at least 35 moderate to severe hot flushes in seven consecutive days Body mass index (BMI) : 20 - 30 kg/m² (inclusive) Postmenopausal status Exclusion Criteria: Contraindication for use for hormonal therapy Prior hysterectomy Hormonal therapy or intrauterine hormone releasing device within 4 weeks prior to study entry or any long-acting injectable or implant up to 6 months prior to study entry Repeated intake of medications affecting study aim

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZK 283197, 3 mg<br>Postmenopausal women with hot flushes received 3 mg (3 x 1 mg tablets) ZK 283197, administered orally once daily over 8 weeks | Drug: BAY 86-5310 (ZK 283197)<br>* 3 mg (3 x 1 mg tablet) or 2 mg (2 x 1 mg tablet) ZK 283197 in respective treatment group, once daily p.o. over 8 weeks<br>|
| Placebo Comparator: Matching placebo<br>Postmenopausal women with hot flushes received placebo (3 tablets) orally once daily over 8 weeks | Drug: Placebo<br>* Placebo, once daily p.o. over 8 weeks<br>|
| Experimental: ZK 283197, 2 mg<br>Postmenopausal women with hot flushes received 2 mg (2 x 1 mg tablet) ZK 283197 plus 1 placebo tablet, once daily orally over 8 weeks | Drug: BAY 86-5310 (ZK 283197)<br>* 3 mg (3 x 1 mg tablet) or 2 mg (2 x 1 mg tablet) ZK 283197 in respective treatment group, once daily p.o. over 8 weeks<br>|
| Active Comparator: 17ß-estradiol<br>Postmenopausal women with hot flushes received 1 mg (2 x 0.5 mg tablet) 17ß-estradiol plus 1 placebo tablet, once daily orally over 8 weeks | Drug: 17ß-estradiol<br>* 1 mg (2 x 0.5 mg tablet) 17ß-estradiol, once daily p.o. over 8 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative change in frequency of moderate to severe hot flushes per week between baseline and Week 8 of the treatment phase |  | Between baseline and Week 8 of the treatment phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events |  | From Week 1 of treatment until end of Follow-up period (approximately 12 weeks) | 
| Exposure-response relationship | A generalized linear model was applied to explore the dependence of the number of hot flushes in Week 8 to (i) the dose of ZK 283197, (ii) the AUC of ZK 283197, (iii) the maximum concentration Cmax of ZK 283197 and (iv) the average concentration Cave of ZK 283197 | At week 8 | 
| Change from baseline to all treatment weeks in frequency and severity of moderate to severe hot flushes |  | From baseline up to 8 weeks | 
| Change from baseline to all treatment weeks in severity and frequency of all hot flushes |  | From baseline up to 8 weeks | 
| Trough levels at every visit |  | Before 1st administration and at Week 1, 2, 4, 6 and 8 | 
| AUC(0-24h) | Area under the curve from administration to 24 h after administration | Pre-dose and up to 24 h post-dose (measured between Week 4-8) | 
| Cmax | Maximum serum concentration | Pre-dose and up to 24 h post-dose (measured between Week 4-8) | 
| tmax | Time to reach maximum drug concentration | Pre-dose and up to 24 h post-dose (measured between Week 4-8) | 
| Cmin | Minimum serum concentration | Pre-dose and up to 24 h post-dose (measured between Week 4-8) | 
| Cave | Average serum concentration | Pre-dose and up to 24 h post-dose (measured between Week 4-8) | 
| Vaginal cytology | The epithelial maturation index/value and the karyopycnotic index were assessed | Between baseline and Week 8 | 
| Endometrial thickness | Transvaginal ultrasound was performed to demonstrate the absence of relevant endometrium growth | Fom baseline to Week 8 | 
| Endometrial histology |  | Between baseline and Week 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hot flushes, Therapy of hot flushes, 17ß-estradiol (E2), Hormone replacement therapy