Dienogest Versus GnRH-a Pre-treatment in Women With Endometriosis Undergoing IVF

Study Overview
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Brief Summary
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Endometriosis is a chronic gynecologic disease that affects approximately 10% of women in the reproductive age group . It is characterized by the presence of endometrial tissue outside the uterus, causing pelvic pain and subfertility. It is estimated that around 40% of infertile women have the diagnosis of endometriosis . Infertility secondary to endometriosis is thought to be multifactorial. Women with endometriosis often require in vitro fertilization (IVF). One medical intervention that has been shown to improve IVF outcomes in women with endometriosis is hormonal suppression with gonadotropic releasing hormone agonist (GnRH-a) for a period of 3 to 6 months . In recent years, the effectiveness of dienogest, a fourth-generation progestin, for endometriosis treatment has been demonstrated. Dienogest seems to be as effective as GnRH-a in improving endometriosis-related pelvic pain [4]. However, no study has yet assessed whether dienogest has any benefit in treating endometriosis associated infertility. The aim of our study is to evaluate the efficacy of dienogest versus GnRH-a in improving ongoing pregnancy rates in women undergoing IVF due to endometriosis. We will conduct a non-blinded randomized controlled trial. One group will receive dienogest 2mg daily for a period of 3 months followed by a standard IVF/Intracytoplasmic Sperm Injection (ICSI) cycle. The second group will receive one injection of 3.75mg of GnRH-a every 28 days for three doses followed by a standard IVF/ICSI cycle 3 months later. The third group will not receive any medical interventions before the planned IVF/ICSI cycle. We hypothesize that patients receiving dienogest will have similar ongoing pregnancy rates compared to patients receiving the GnRH-a injection. Secondary outcomes including number of gonadotropins consumed, number of stimulation days, number of metaphase II eggs retrieved, fertilization rate, embryo quality, miscarriage rate, clinical pregnancy rates, live birth rates and potential maternal and obstetrical complications will also be evaluated. We will also compare ongoing pregnancy rates between the groups receiving Dienogest and placebo, and GnRH agonist and placebo.

Official Title
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Dienogest Versus Gonadotropin Releasing Hormone Agonist Pre-treatment in Women With Endometriosis Undergoing in Vitro Fertilization

Conditions
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Endometriosis

Intervention / Treatment
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* Drug: Dienogest 2 MG
* Drug: gonapeptyl
* Procedure: IVF/IVF+ART


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary or secondary infertility Endometriosis, stage III - IV, confirmed surgically by laparoscopy or laparotomy and/or radiologically by the presence of endometrioma on pelvic ultrasound or magnetic resonance imaging (MRI) Normal uterine cavity assessed by hysteroscopy or hysterosalpingogram Normal hormonal profile: TSH, prolactin, fasting blood sugar Normal semen analysis and mild/moderate male factor (Total motile sperm count > 5 million/ml and/or normal WHO morphology >20%) First IVF cycle or history of failed IVF cycles Washout period of ≥6 months after any diagnostic or therapeutic surgery for endometriosis or after any medical treatment with Dienogest or GnRH agonist. Exclusion Criteria: • Low ovarian reserve defined by one of the following: low AMH ≤1.5ng/mL and/or basal day 3 FSH ≥ 10mIU/mL and/or basal day 3 Estradiol ≥ 60ng/mL and/or previous egg collection yield of ≤3 oocytes. • Absolute contraindications to dienogest, including: undiagnosed abnormal vaginal bleeding pregnancy and/or lactation active venous thromboembolic disorder history of or current arterial and cardiovascular disease (eg, MI, CVA) diabetes mellitus with vascular involvement history of or current severe hepatic disease where liver function tests remain abnormal history of or current hepatic neoplasia (benign or malignant) known or suspected sex-hormone-dependent malignancy ocular lesions due to ophthalmic vascular disease, such as partial or complete vision loss or defect in visual fields current or history of migraine with focal aura hypersensitivity or poor tolerance to dienogest

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 38 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dienogest<br>patients will receive daily dienogest (2mg) for a total of 3 months (84 days) | Drug: Dienogest 2 MG<br>* Dienogest is a fourth-generation progestin of 19-nortestosterone derivative, that has been shown to improve endometriosis associated pelvic pain. It is well tolerated with no androgenic, glucocorticoid or mineralocorticoid activity. Dienogest creates a hyperprogestogenic and hypoestrogenic environment that initially induces a secretory state and then a decidualization of the ectopic endometrium and finally its atrophy. It also inhibits aromatase and COX-2 expression as well as prostaglandin E2 production in endometriotic stromal cells. It also normalizes the activity of natural killer cells and decreases the release of interleukin-1b by macrophages. These anti-inflammatory properties further help in reducing the size of endometriotic lesions<br>Procedure: IVF/IVF+ART<br>* In-vitro fertilization +/- assisted reproductive technology<br>|
| Active Comparator: GnRH agonist<br>patients will receive a single GnRH-a injection (3.25mg) every 28 days for three months. | Drug: gonapeptyl<br>* gonadotropic releasing hormone agonist<br>Procedure: IVF/IVF+ART<br>* In-vitro fertilization +/- assisted reproductive technology<br>|
| Other: Control Group<br>patients will not receive any medical intervention and will proceed with their IFV/ICSI cycles. | Procedure: IVF/IVF+ART<br>* In-vitro fertilization +/- assisted reproductive technology<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy rate | pregnancy positive fetal cardiac activity with beyond 12 weeks of gestation (%) | 12 weeks of gestation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gonadotropin consumption (IU) | Gonadotropin consumption (IU) | 3 months | 
| stimulation (days) | Duration of stimulation (days) | up to 15 days | 
| metaphase II oocytes retrieved | Number of metaphase II oocytes retrieved at the time of egg collection (n). | 12 weeks of gestation | 
| Fertilization rate | the number of 2PN zygotes divided by the total number of mature metaphase II oocytes retrieved (%). | day 2 | 
| Embryo quality. | Embryo quality according to embryo grading at day 3 or day5 | day 3 or 5 | 
| Clinical pregnancy rate | the presence of a gestational sac, with or without cardiac activity, on ultrasound assessment (%). | 12 weeks of gestation | 
| Ongoing pregnancy rate -2 | pregnancy positive fetal cardiac activity with beyond 12 weeks of gestation (%) | 12 weeks of gestation |