Impact of Ultra-long Versus Long Down-regulation Protocol on IVF/ICSI in Adenomyosis

Phase 3

Withdrawn

• Conditions: Adenomyosis
• Interventions: Drug: 11.25mg GnRH agonist; Drug: 0.1 mg GnRH agonist; Drug: 25 µg transdermal oestradiol

• Registration Number: NCT03940807
• Lead Sponsor: University Hospital, Toulouse

Brief Summary

Adenomyosis is a benign condition defined as the invasion of ectopic endometrium into the myometrium, resulting in smooth muscle hyperplasia and endometrial inflammation, commonly associated with endometriosis and uterine fibroids.

Heterogeneity among studies regarding diagnostic criteria and therapeutic management has fed the debate surrounding the impact of adenomyosis on assisted reproductive therapy outcomes. Nevertheless, recent data support that adenomyosis impairs reproductive outcomes associated with in vitro fertilization (IVF). According to several experimental data, prolonged exposure to gonadotropin releasing hormone (GnRH) agonists may overcome part of the detrimental impact of adenomyosis on fertility outcome. Overall, GnRH agonist treatment resulted in decreased local production of cytochrome P450 aromatase, decreased intrauterine concentration of free radicals and reduced inflammatory response and angiogenesis in endometrium, myometrium and adenomyosis lesions. At the same time, GnRH agonists affect neither endometrial capacity to support invasion nor invasive potential of the blastocyst in the early stages of implantation.

For IVF, 2 main protocols based on GnRH agonist pituitary down-regulation are available:

* the long protocol involving a 15 days pituitary down-regulation;

* the ultra-long protocol involving a 3 months pituitary down-regulation. Most studies using ultra-long protocol reported similar IVF outcomes in adenomyosis patients and control groups. Conversely, studies involving long or GnRH antagonist protocols demonstrated a significant reduction in clinical and ongoing pregnancy rates in adenomyosis patients compared to control subjects. Thus supporting that ultra-long protocol may be beneficial to improve IVF outcomes in the setting of adenomyosis.This is what investigators would like to demonstrate in this study

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-04-19
• Study First Submitted QC: 2019-05-03
• Study First Posted: 2019-05-07
• Study Start: 2022-04-29
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-14
• Last Update Posted: 2022-11-18
• Primary Completion: 2025-01
• Study Completion: 2025-01

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: Female
• Target Recruitment: Not specified

Inclusion Criteria

1. suspected adenomyosis on high quality transvaginal ultrasound or focal or diffuse adenomyosis defined as a thickening of the junctional zone to more than 12mm on previous magnetic resonance Imaging (<6 months)
2. infertility of any cause requiring IVF or ICSI
3. infertility period of at least 1 year except for women with history of deep infiltrating endometriosis or bilateral salpingectomy
4. age >18 and < 40 years
5. complete fertility workup comprising for women hormone serum measurement (anti-mullerian hormone (AMH), estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH)), high quality transvaginal ultrasound and, when applicable, hysterosalpingography, diagnostic laparoscopy or hysteroscopy
6. first or second IVF or ICSI attempt
7. absence of severe premature ovarian insufficiency defined by antral follicle count < 8 and AMH < 1ng/ml
8. meet the criteria from the French law to be included in an assisted reproductive technique program
9. informed written consent for both women and men
10. social security cover for both women and men

Exclusion Criteria

1. absence of adenomyosis (defined as a thickening of the junctional zone to more than 12mm) on pelvic MRI
2. other potential causes of implantation failure: leiomyoma, endometrial polyp, not removed hydrosalpinx, malformed uterus (unicornis, bicornis, septate, duplex), antiphospholipid syndrome
3. medical contraindication to study treatments (GnRH agonist and add-back therapy)
4. women taking prohibited concomitant treatments and not able to stop them for the study period
5. medical contraindication to assisted reproductive technique and/or pregnancy including: uncontrolled type I and II diabetes; undiagnosed liver disease or dysfunction; renal insufficiency; history of deep venous thrombosis, pulmonary embolism or cerebrovascular accident; uncontrolled hypertension; known symptomatic heart disease; history of or suspected cervical carcinoma, endometrial carcinoma, ovarian carcinoma or breast carcinoma; undiagnosed vaginal bleeding; genetic abnormalities
6. positive plasma viral load for human immunodeficiency virus(HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) for one (or both) in the couple during the year before inclusion
7. participation in another research study including an exclusion period which has not expired at the time of screening
8. patients subject to a judicial safeguard order, guardianship or trusteeship.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ultra-long protocol group	11.25mg GnRH agonist	All women will receive one intra-muscular administration of 11.25 mg Gonadotropin Releasing Hormone (GnRH) agonist (triptorelin acetate) on luteal phase of their menstrual cycle. Add back therapy (transdermal estradiol, 25μg twice a week) will be administrated throughout down-regulation period. Ovarian stimulation will be started after 90 days desensitization.
Long protocol group	0.1 mg GnRH agonist	All women will receive a 15-days pituitary down-regulation protocol that consists of daily subcutaneous application of 0.1mg of GnRH agonist (triptorelin acetate) started on luteal phase of their menstrual cycle. Ovarian stimulation will begin after 15 days desensitization.
Ultra-long protocol group	25 µg transdermal oestradiol	All women will receive one intra-muscular administration of 11.25 mg Gonadotropin Releasing Hormone (GnRH) agonist (triptorelin acetate) on luteal phase of their menstrual cycle. Add back therapy (transdermal estradiol, 25μg twice a week) will be administrated throughout down-regulation period. Ovarian stimulation will be started after 90 days desensitization.

Primary Outcome Measures

Name	Time	Method
Number of live birth after first or second in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) attempt.	Up to 22 weeks of gestation	This outcome is defined as delivery of one or more live-born infant at \> 22 weeks of gestation.

Secondary Outcome Measures

Name	Time	Method
Occurrence of poor responders	after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group	Occurrence of poor responders defined as women with \<3 matures follicles or serum estradiol \<500 at the time of ovulation triggering
Implantation rate	5 weeks after follicular aspiration	Implantation rate defined as the ratio "number of gestational sacs/number of transferred embryos" on TV US performed 5 weeks after follicular aspiration
Number of Participants with clinical pregnancy	5 weeks after follicular aspiration	Clinical pregnancy defined as the presence of one or more gestational sacs on transvaginal ultrasound performed 5 weeks after follicular aspiration, including ectopic pregnancy
Number of Participants with ongoing pregnancy	12 weeks of gestation	Ongoing pregnancy defined as a live pregnancy on first trimester US examination performed at 12 weeks of gestation
Occurrence of any other Adverse Event	Through study completion, an average of 1 year
Concentration of serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l	14 days following follicular aspiration	Biochemical pregnancy defined as serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l, 14 days following follicular aspiration
Uterine volume change	after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group	Uterine volume reduction between ultrasound measurements at baseline and at time of ovarian stimulation onset
First trimester miscarriage occurrence	Before 12 weeks of gestation	First trimester miscarriage occurrence defined as a pregnancy loss before 12 weeks of gestation among patients with a clinical pregnancy
Occurrence of neonatal complications	Until 6 weeks post-partum
Number of Participants with clinical pregnancy with fetal heart beat	7 weeks after embryo transfer	Clinical pregnancy with fetal heart beat defined as the presence of at least one fetus with heart beat on transvaginal ultrasound performed 7 weeks after embryo transfer
Occurrence of menopause-like symptoms symptoms at the end of the GnRH agonist treatment	after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group	Using the Menopause Rating Scale
Occurrence of pregnancy and post-partum complications	Until 6 weeks post-partum

Trial Locations

Locations (14)

CHU Angers; 🇫🇷 Angers, France

Centre Aliénor d'Aquitaine; 🇫🇷 Bordeaux, France

Hôpital Morvan; 🇫🇷 Brest, France

Centre hospitalier intercommunal de Créteil; 🇫🇷 Créteil, France

CHU Grenoble-Alpes; 🇫🇷 Grenoble, France

CHU Limoges; 🇫🇷 Limoges, France

Hôpital de la Conception Marseille; 🇫🇷 Marseille, France

CHU Nice; 🇫🇷 Nice, France

CHU Nîmes; 🇫🇷 Nîmes, France

CHI Poissy; 🇫🇷 Poissy, France

CHU Rouen Normandie; 🇫🇷 Rouen, France

Centre hospitalier des 4 villes; 🇫🇷 Saint-Cloud, France

CHU Strasbourg; 🇫🇷 Strasbourg, France

CHU Toulouse; 🇫🇷 Toulouse, France