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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 06/15/2021.

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

Clinicaltrials.gov identifier NCT03940807

Recruitment Status Not yet recruiting

First Posted May 7, 2019

Last update posted March 15, 2021

Study Description

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

  • Condition or Disease:Adenomyosis
  • Intervention/Treatment: Drug: 11.25mg GnRH agonist
    Drug: 0.1 mg GnRH agonist
    Drug: 25 µg transdermal oestradiol
  • Phase: Phase 3
Detailed Description

N/A

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 674 participants
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: Phase III Trial to Assess Impact of Ultra-long Versus Long Down-regulation Protocol on IVF/ICSI Outcomes in Infertile Women Presenting With Adenomyosis.
  • Estimated Study Start Date: June 2021
  • Estimated Primary Completion Date: January 2025
  • Estimated Study Completion Date: January 2025
Arms and interventions
Arm Intervention/treatment
Experimental: Ultra-long protocol group
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
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.

Drug: 25 µg transdermal oestradiol
Add back therapy (transdermal estradiol, 25μg twice a week) will be administrated throughout down-regulation period.
Active Comparator: Long protocol group
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
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.
Outcome Measures
  • Primary Outcome Measures: 1. Number of live birth after first or second in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) attempt. [ Time Frame: 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: 1. Uterine volume change [ Time Frame: 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
  • 2. Occurrence of poor responders [ Time Frame: 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
  • 3. Concentration of serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l [ Time Frame: 14 days following follicular aspiration ]
    Biochemical pregnancy defined as serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l, 14 days following follicular aspiration
  • 4. Implantation rate [ Time Frame: 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
  • 5. Number of Participants with clinical pregnancy [ Time Frame: 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
  • 6. Number of Participants with clinical pregnancy with fetal heart beat [ Time Frame: 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
  • 7. Number of Participants with ongoing pregnancy [ Time Frame: 12 weeks of gestation ]
    Ongoing pregnancy defined as a live pregnancy on first trimester US examination performed at 12 weeks of gestation
  • 8. First trimester miscarriage occurrence [ Time Frame: 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
  • 9. Occurrence of menopause-like symptoms symptoms at the end of the GnRH agonist treatment [ Time Frame: after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group ]
    Using the Menopause Rating Scale
  • 10. Occurrence of neonatal complications [ Time Frame: Until 6 weeks post-partum ]
  • 11. Occurrence of any other Adverse Event [ Time Frame: Through study completion, an average of 1 year ]
  • 12. Occurrence of pregnancy and post-partum complications [ Time Frame: Until 6 weeks post-partum ]
Eligibility Criteria
  • Ages Eligible for Study: 18 to 40 Years (Adult)
  • Sexes Eligible for Study: Female
  • Accepts Healthy Volunteers: No
Criteria

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 (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.

Contacts and Locations
Contacts

Contact: Fabien Vidal, MD 05 67 77 13 70 vidal.fabien@chu-toulouse.fr

Contact: Celia Bettiol, CRA 05 67 77 13 87 bettiol.c@chu-toulouse.fr

Locations
Show 14 Study Locations
Sponsors and Collaborators

University Hospital, Toulouse

Investigators

Principal Investigator: Fabien Vidal CHU Toulouse

More Information
  • Responsible Party: University Hospital, Toulouse
  • ClinicalTrials.gov Identifier: NCT03940807 History of Changes
  • Other Study ID Numbers: RC31/17/0448
  • First Posted: May 7, 2019 Key Record Dates
  • Last Update Posted: March 15, 2021
  • Last Verified: March 2021
  • Individual Participant
    Data (IPD) Sharing
    Statement:
  • Plan to Share IPD: No
  • Studies a U.S. FDA-regulated Drug Product: No
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by University Hospital, Toulouse: Infertility GnRH
  • Additional relevant MeSH terms: Adenomyosis