A randomized, double-blind, double-dummy, parallel- group, multi-center phase IIb study to assess the efficacy and safety of different dose combinations of an aromatase inhibitor and a progestin in an intravaginal ring versus placebo and leuprorelin / leuprolide acetate in women with symptomatic endometriosis over a 12-week treatment period

Endometriosis is a benign, estrogen-dependent gynecological disorder affecting
6-10% of reproductive age women. The disease is characterized by the presence
of endometrium-like tissue outside the uterine cavity (e.g. the ovaries,
peritoneum, rectovaginal space and other pelvic structures).
Dysmenorrhea, chronic pelvic pain, painful intercourse and infertility are the
most common symptoms of endometriosis which can have a significant impact on
subjects* lives as e.g. substantial morbidity, multiple operations and
decreased quality of life. In addition, the economic burden associated with
endometriosis treated in referral centers was found to be as high as other
chronic diseases like diabetes, Crohn*s disease or rheumatoid arthritis in 10
European countries (2). The high economic burden for the healthcare system was
similarly found for the United States (US) (3).
According to guidelines from the American Society of Reproductive Medicine
(ASRM) and the European Society of Human Reproduction and Endocrinology
(ESHRE), endometriosis-associated pain is medically treated by agents which are
supposed to induce atrophy of endometriotic lesions such as combined oral
contraceptives (COCs), progestins, danazol, and gonadotropin-releasing hormone
(GnRH) analogues (4,5). These treatment options are not considered
significantly different in terms of efficacy (1). Side effect profiles and
costs, however, differ considerably. Thus, COCs, although not approved for the
indication, are commonly used *off label* for the treatment of endometriosis.
In contrast, different progestins are approved in different countries for the
treatment of endometriosis, but are used to a much lower extent compared to
COCs.
Due to the lack of other effective medical treatments, after failure of COC or
progestin treatment there are currently no alternatives available for subjects
with endometriosis-associated pain which could be used long-term. GnRH
analogues have an unfavorable side-effect profile (e.g. hot flushes, bone loss)
and can only be used short term. Danazol is rarely used in clinical practice,
due to its side effect profile (e.g. acne, weight gain, hirsutism, voice
changes). Surgery, as the last option is associated with the inherent risk of
complications and a substantial relapse rate over time which is reported to
range from up to 50% - 75% after 2-5 years (6,1). Thus, there is a high medical
need for an efficacious, safe and tolerable treatment which could be used
long-term for women with symptomatic endometriosis, and especially for those
not sufficiently responding to COCs or progestins. To fill the gap of available
treatment options, Bayer seeks to develop anastrozole (ATZ) combined with
levonorgestrel (LNG) in an intravaginal ring (IVR; BAY 98-7196) for subjects
with endometriosis-associated pain which could be used for long-term treatment
and potentially avoid otherwise necessary surgeries.

- The studymedication in this clinical study was developed for long-term use in
patients with endometriosis associated pelvic pain to release the pain and to
avoid to otherwise necessary operation.

Primary objective
-To assess the dose-response relationship and demonstrate efficacy of BAY
98-7196 vs. placebo in women with symptomatic endometriosis

Secundairy objectives
- To identify at least 1 superior effective dose of BAY 98-7196 compared to
placebo
- To compare the efficacy of BAY 98-7196 versus leuprorelin / leuprolide
acetate descriptively
- To assess sustainability of treatment effect and recurrence of symptoms
- To evaluate the safety and tolerability of BAY 98-7196 in women with
symptomatic endometriosis
- To explore sub-populations (e.g. subjects with indication for treatment with
a gonadotropin-releasing hormone agonist or surgery as judged by the
investigator or by endometriosis history and symptom severity)
- collecting data on the effect of the intra-vaginal ring on the condoms and
condoms use.

it concerns a randomized, double-blind, double-dummy, parallel-group,
multi-center phase IIb study to assess the efficacy and safety of different
dose combinations of an aromatase inhibitor and a progestin in an intravaginal
ring versus placebo and leuprorelin / leuprolide acetate in women with
symptomatic endometriosis over a 12-week treatment period
All patients will be randomized in 6 different treatment arms in the ratio of
1:1:1:1:1:1 and all patients will receive an intra-vaginal ring and the
intramuscular injection.
The following arms were created:
1. Placebo A IVR + placebo intramuscular (i.m.) injection
2. LNG 170 mg IVR + placebo i.m.
injection; --> dose per day:
LNG (40µg)
3. ATZ 50 mg+ LNG 170 mg IVR + placebo i.m. injection;
--> dose per day: ATZ (300 µg) + LNG (40 µg)
4. ATZ 120 mg+ LNG 170 mg IVR + placebo i.m. injection:
--> dose per day: ATZ (600 µg) + LNG (40 µg)
5. ATZ 200 mg+ LNG 170 mg IVR + placebo i.m. injection:
--> dose per day: ATZ (1050 µg) + LNG (40 µg)
6. Placebo B IVR + leuprorelin / leuprolide acetate (11.25 mg - 3-month depot)
i.m. injection

The following arms were created:
1. Placebo A IVR + placebo intramuscular (i.m.) injection
2. LNG 170 mg IVR + placebo i.m.
injection; --> dose per day:
LNG (40µg)
3. ATZ 50 mg+ LNG 170 mg IVR + placebo i.m. injection;
--> dose per day: ATZ (300 µg) + LNG (40 µg)
4. ATZ 120 mg+ LNG 170 mg IVR + placebo i.m. injection:
--> dose per day: ATZ (600 µg) + LNG (40 µg)
5. ATZ 200 mg+ LNG 170 mg IVR + placebo i.m. injection:
--> dose per day: ATZ (1050 µg) + LNG (40 µg)
6. Placebo B IVR + leuprorelin / leuprolide acetate (11.25 mg - 3-month depot)
i.m. injection

There are at maximum 7 visits
The patient is asked to complete 2 questionnaires to score the pain the patient
is experiencing (NRS and VAS). Next to these painscore-questionnaires, the
patient is asked complete 5 times 2 questionnaires and 4 times 3 questionnaires.
All questionnaires evaluate the current health-status and the pain of the
patient. All questionnaires will be completed electronically.
The evaluate the every day status, the patient is asked to keep an electronic
diary.
The patient will receive a full physical examination (length, bloodpressure,
heartrate and temperature, etc) and gynecological examination.
The research personnel will contact the patient on a weekly basis form visit 3
until the end of the study to ask about the condoms and the condom-usage. The
patient will be asked whether there were any issue as slippages, breakages,
leakages or any other problems.