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

Endometriosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03142035
• Other study ID #: OGY.DC.03
• Status: Recruiting
• Phase: N/A
• Start date: October 22, 2017
• Est. completion date: February 22, 2023

Study information

• Verified date: May 2022
• Source: American University of Beirut Medical Center
• Contact: Dina Chamsi, MD
• Phone: 961-01350000
• Email: dc09[@]aub.edu.lb
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 189
• Est. completion date: February 22, 2023
• Est. primary completion date: February 22, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 38 Years

Eligibility

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

Related Conditions & MeSH terms

• Endometriosis

Intervention

Drug:
• Dienogest 2 MG
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
• gonapeptyl
gonadotropic releasing hormone agonist

Procedure:
• IVF/IVF+ART
In-vitro fertilization +/- assisted reproductive technology

Locations

Country	Name	City	State
Lebanon	American University of Beirut Medical center	Beirut

Sponsors (1)

Lead Sponsor	Collaborator
American University of Beirut Medical Center

Country where clinical trial is conducted

Lebanon, 

References & Publications (23)

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Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002 Jun;77(6):1148-55. — View Citation

Bizzarri N, Remorgida V, Leone Roberti Maggiore U, Scala C, Tafi E, Ghirardi V, Salvatore S, Candiani M, Venturini PL, Ferrero S. Dienogest in the treatment of endometriosis. Expert Opin Pharmacother. 2014 Sep;15(13):1889-902. doi: 10.1517/14656566.2014.943734. Epub 2014 Jul 29. Review. — View Citation

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Matson PL, Yovich JL. The treatment of infertility associated with endometriosis by in vitro fertilization. Fertil Steril. 1986 Sep;46(3):432-4. — View Citation

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Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004635. Review. — View Citation

Simón C, Gutiérrez A, Vidal A, de los Santos MJ, Tarín JJ, Remohí J, Pellicer A. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod. 1994 Apr;9(4):725-9. — View Citation

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Toya M, Saito H, Ohta N, Saito T, Kaneko T, Hiroi M. Moderate and severe endometriosis is associated with alterations in the cell cycle of granulosa cells in patients undergoing in vitro fertilization and embryo transfer. Fertil Steril. 2000 Feb;73(2):344-50. — View Citation

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* Note: There are 23 references in all — Click here to view all references

Outcome

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