A Study to Compare 3 Doses of a Hormonal Intra-uterine Device Containing Levonorgestrel and Indomethacin With a Hormonal Intra-uterine Device Containing Only Levonorgestrel to Assess the Effect and Safety of the Combined Components

Study Overview
=================
Brief Summary
-----------------
This study is the first study investigating the combined intrauterine administration of LNG (levonorgestrel) and IND (indomethacin). It is a combined proof-of-concept (PoC) and dose finding (DF) study in pre-menopausal women. It is designed to investigate the pharmacodynamics (PD) of BAY 987443 (i.e. IUS (intrauterine system) releasing LNG and IND), as well as pharmacokinetics (PK) of both active substances, safety and tolerability. In this study, Jaydess, as an LNG-only IUS, will be used as a comparator.

Official Title
-----------------
Multi-center, Randomized, Comparator-controlled, Single-blind, Parallel-Group Study to Investigate the Pharmacodynamics, Pharmacokinetics and Safety of an Intrauterine System (BAY987443) With Three Different Release Rates of Indomethacin and One Release Rate of Levonorgestrel, as Compared With Jaydess, in a Combined Proof-of-concept and Dose Finding Study in Healthy Pre-menopausal Women Treated for 90 Days

Conditions
-----------------
Contraception

Intervention / Treatment
-----------------
* Drug: BAY98-7443
* Drug: Levonogestrel (Skyla, BAY86-5028)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Agreement to use an acceptable non-hormonal method of contraception (i.e. male or female condom with or without spermicide; cap, diaphragm or sponge with spermicide) when sexually active. This applies during the pre-treatment cycle and directly following the treatment period until the end of the follow-up period. This is not required if safe contraception is achieved by a permanent method, such as bilateral fallopian tube blockage of the subject or vasectomy of the partner(s). Age at screening: 18-45 years inclusive Body mass index (BMI) at screening: ≥ 18 and ≤ 32 kg/m² No clinically relevant abnormal findings in the pre-treatment endometrial biopsy Adequate venous access (for frequent blood sampling) Exclusion Criteria: Menstrual disorders with unknown reason (not e.g. oligomenorrhea, hypomenorrhea amenorrhea due to hormonal treatment; not irregularities occurring during menarche). In case it is suspected that the woman is peri-menopausal, she should be excluded. Use of short-acting hormonal contraceptives/preparations containing sex hormones (oral, transdermal, intravaginal, IUS) during the pretreatment cycle Use of long-acting preparations containing sex hormones within the 40 weeks before the first screening examination (any long-acting injectable or implant) History of known or presence of suspected or known malignant tumors, especially any breast cancer, cervical carcinoma in situ or other progestin-sensitive cancer History of skin reactions, or other allergic-type reactions or known hypersensitivity reactions after taking aspirin, IND or other NSAIDs or to LNG, or any excipients of the IUSs Regular use of corticosteroids, irrespective of route of administration Known asthma bronchiale and aspirin-sensitive asthma Current or recurrent pelvic inflammatory disease Abnormal cervical smear within the last 6 month prior to screening Acute genital infection Known current thyroid disorders which require treatment (subjects with an euthyroid struma who do not need any treatment can participate)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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: BAY98-7443 (low IND dose)<br>Combi IUS Treatment, LNG (Levonorgestrel) with lowest dose of IND (indomethacin) | Drug: BAY98-7443<br>* Active ingredient content (in mg IND/LNG): low dose 6.5 / 13.5; middle dose 12.5 / 13.5; high dose 15.4 / 13.5<br>|
| Experimental: BAY98-7443 (middle IND dose)<br>Combi IUS Treatment, LNG with medium dose of IND | Drug: BAY98-7443<br>* Active ingredient content (in mg IND/LNG): low dose 6.5 / 13.5; middle dose 12.5 / 13.5; high dose 15.4 / 13.5<br>|
| Experimental: BAY98-7443 (high IND dose)<br>Combi IUS Treatment, LNG with highest dose of IND | Drug: BAY98-7443<br>* Active ingredient content (in mg IND/LNG): low dose 6.5 / 13.5; middle dose 12.5 / 13.5; high dose 15.4 / 13.5<br>|
| Active Comparator: Marketed comparator<br>Marketed comparator IUS | Drug: Levonogestrel (Skyla, BAY86-5028)<br>* Comparative LNG dose<br>* Other names: Jaydess;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of uterine bleeding/spotting (B/S) days during treatment | Recorded by participants with electronic diary | 90 days after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects showing endometrial histology typical for intrauterine LNG application in biopsies taken at the end of treatment |  | On day 90 after start of treatment | 
| Frequency of treatment emergent adverse events |  | 90 days after start of treatment |