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

NCT03940807 | Withdrawn Phase 3

• 1 other identifier: RC31/17/0448
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 14

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

Conditions

Adenomyosis

Keywords

Infertility; GnRH

Outcome Measures

Primary Outcomes (1)

• Number of live birth after first or second in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) attempt.

  This outcome is defined as delivery of one or more live-born infant at \> 22 weeks of gestation.

  Up to 22 weeks of gestation

Secondary Outcomes (12)

• Uterine volume change

  after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group

• Occurrence of poor responders

  after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group

• Concentration of serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l

  14 days following follicular aspiration

• Implantation rate

  5 weeks after follicular aspiration

• Number of Participants with clinical pregnancy

  5 weeks after follicular aspiration

Study Arms (2)

Ultra-long protocol group

EXPERIMENTAL

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.

Drug: 11.25mg GnRH agonist; Drug: 25 µg transdermal oestradiol

Long protocol group

ACTIVE COMPARATOR

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.

Drug: 0.1 mg GnRH agonist

Interventions

11.25mg GnRH agonist DRUG

Ultra-long protocol group women will receive one intra-muscular administration of 11.25 mg GnRH agonist (triptorelin acetate) on the luteal phase of their menstrual cycle. Ovarian stimulation will be started after 90 days desensitization. After the desensitization period, all patients will undergo standardized ovarian stimulation, follicular aspiration, fertilization of all oocytes using either standard insemination or ICSI according to the features of sperm examination, fresh embryo transfer and luteal phase support.

Ultra-long protocol group

0.1 mg GnRH agonist DRUG

Long protocol group women will receive a 15-days pituitary down-regulation protocol that consists of daily subcutaneous injection of 0.1mg of GnRH agonist (triptorelin acetate) started on the luteal phase of their menstrual cycle. Ovarian stimulation will begin after 15 days desensitization. After the desensitization period, all patients will undergo standardized ovarian stimulation, follicular aspiration, fertilization of all oocytes using either standard insemination or ICSI according to the features of sperm examination, fresh embryo transfer and luteal phase support.

Long protocol group

25 µg transdermal oestradiol DRUG

Add back therapy (transdermal estradiol, 25μg twice a week) will be administrated throughout down-regulation period.

Ultra-long protocol group

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)
• infertility of any cause requiring IVF or ICSI
• infertility period of at least 1 year except for women with history of deep infiltrating endometriosis or bilateral salpingectomy
• age \>18 and \< 40 years
• 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
• first or second IVF or ICSI attempt
• absence of severe premature ovarian insufficiency defined by antral follicle count \< 8 and AMH \< 1ng/ml
• meet the criteria from the French law to be included in an assisted reproductive technique program
• informed written consent for both women and men
• social security cover for both women and men

You may not qualify if:

• absence of adenomyosis (defined as a thickening of the junctional zone to more than 12mm) on pelvic MRI
• other potential causes of implantation failure: leiomyoma, endometrial polyp, not removed hydrosalpinx, malformed uterus (unicornis, bicornis, septate, duplex), antiphospholipid syndrome
• medical contraindication to study treatments (GnRH agonist and add-back therapy)
• women taking prohibited concomitant treatments and not able to stop them for the study period
• 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
• patients subject to a judicial safeguard order, guardianship or trusteeship.

Sponsors & Collaborators

• University Hospital, Toulouse: lead

Study Sites (14)

CHU Angers

Angers, France

Location

Centre Aliénor d'Aquitaine

Bordeaux, France

Location

Hôpital Morvan

Brest, France

Location

Centre hospitalier intercommunal de Créteil

Créteil, France

Location

CHU Grenoble-Alpes

Grenoble, France

Location

CHU Limoges

Limoges, France

Location

Hôpital de la Conception Marseille

Marseille, France

Location

CHU Nice

Nice, France

Location

CHU Nîmes

Nîmes, France

Location

CHI Poissy

Poissy, France

Location

CHU Rouen Normandie

Rouen, France

Location

Centre hospitalier des 4 villes

Saint-Cloud, France

Location

CHU Strasbourg

Strasbourg, France

Location

CHU Toulouse

Toulouse, France

Location

MeSH Terms

Conditions

Adenomyosis; Infertility

Interventions

Gonadotropin-Releasing Hormone

Condition Hierarchy (Ancestors)

Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Fabien Vidal

  University Hospital, Toulouse

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 19, 2019
• First Posted: May 7, 2019
• Study Start: April 29, 2022
• Primary Completion: January 1, 2025
• Study Completion: January 1, 2025
• Last Updated: November 18, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (14)