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

Primary Purpose

Adenomyosis

Status
Withdrawn
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
11.25mg GnRH agonist
0.1 mg GnRH agonist
25 µg transdermal oestradiol
Sponsored by
University Hospital, Toulouse
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adenomyosis focused on measuring Infertility, GnRH

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • CHU Angers
  • Centre Aliénor d'Aquitaine
  • Hôpital Morvan
  • Centre hospitalier intercommunal de Créteil
  • CHU Grenoble-Alpes
  • CHU Limoges
  • Hôpital de la Conception Marseille
  • CHU Nice
  • CHU Nîmes
  • CHI Poissy
  • CHU Rouen Normandie
  • Centre hospitalier des 4 villes
  • CHU Strasbourg
  • CHU Toulouse

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ultra-long protocol group

Long protocol group

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Uterine volume change
Uterine volume reduction between ultrasound measurements at baseline and at time of ovarian stimulation onset
Occurrence of poor responders
Occurrence of poor responders defined as women with <3 matures follicles or serum estradiol <500 at the time of ovulation triggering
Concentration of serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l
Biochemical pregnancy defined as serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l, 14 days following follicular aspiration
Implantation rate
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
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 clinical pregnancy with fetal heart beat
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
Number of Participants with ongoing pregnancy
Ongoing pregnancy defined as a live pregnancy on first trimester US examination performed at 12 weeks of gestation
First trimester miscarriage occurrence
First trimester miscarriage occurrence defined as a pregnancy loss before 12 weeks of gestation among patients with a clinical pregnancy
Occurrence of menopause-like symptoms symptoms at the end of the GnRH agonist treatment
Using the Menopause Rating Scale
Occurrence of neonatal complications
Occurrence of any other Adverse Event
Occurrence of pregnancy and post-partum complications

Full Information

First Posted
April 19, 2019
Last Updated
November 14, 2022
Sponsor
University Hospital, Toulouse
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1. Study Identification

Unique Protocol Identification Number
NCT03940807
Brief Title
Impact of Ultra-long Versus Long Down-regulation Protocol on IVF/ICSI in Adenomyosis
Acronym
ADENOFIV
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.
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Withdrawn
Why Stopped
Principal investigator departure
Study Start Date
April 29, 2022 (Actual)
Primary Completion Date
January 2025 (Anticipated)
Study Completion Date
January 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Toulouse

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenomyosis
Keywords
Infertility, GnRH

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ultra-long protocol group
Arm Type
Experimental
Arm Description
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.
Arm Title
Long protocol group
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
11.25mg GnRH agonist
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
0.1 mg GnRH agonist
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
25 µg transdermal oestradiol
Intervention Description
Add back therapy (transdermal estradiol, 25μg twice a week) will be administrated throughout down-regulation period.
Primary Outcome Measure Information:
Title
Number of live birth after first or second in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) attempt.
Description
This outcome is defined as delivery of one or more live-born infant at > 22 weeks of gestation.
Time Frame
Up to 22 weeks of gestation
Secondary Outcome Measure Information:
Title
Uterine volume change
Description
Uterine volume reduction between ultrasound measurements at baseline and at time of ovarian stimulation onset
Time Frame
after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group
Title
Occurrence of poor responders
Description
Occurrence of poor responders defined as women with <3 matures follicles or serum estradiol <500 at the time of ovulation triggering
Time Frame
after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group
Title
Concentration of serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l
Description
Biochemical pregnancy defined as serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l, 14 days following follicular aspiration
Time Frame
14 days following follicular aspiration
Title
Implantation rate
Description
Implantation rate defined as the ratio "number of gestational sacs/number of transferred embryos" on TV US performed 5 weeks after follicular aspiration
Time Frame
5 weeks after follicular aspiration
Title
Number of Participants with clinical pregnancy
Description
Clinical pregnancy defined as the presence of one or more gestational sacs on transvaginal ultrasound performed 5 weeks after follicular aspiration, including ectopic pregnancy
Time Frame
5 weeks after follicular aspiration
Title
Number of Participants with clinical pregnancy with fetal heart beat
Description
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
Time Frame
7 weeks after embryo transfer
Title
Number of Participants with ongoing pregnancy
Description
Ongoing pregnancy defined as a live pregnancy on first trimester US examination performed at 12 weeks of gestation
Time Frame
12 weeks of gestation
Title
First trimester miscarriage occurrence
Description
First trimester miscarriage occurrence defined as a pregnancy loss before 12 weeks of gestation among patients with a clinical pregnancy
Time Frame
Before 12 weeks of gestation
Title
Occurrence of menopause-like symptoms symptoms at the end of the GnRH agonist treatment
Description
Using the Menopause Rating Scale
Time Frame
after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group
Title
Occurrence of neonatal complications
Time Frame
Until 6 weeks post-partum
Title
Occurrence of any other Adverse Event
Time Frame
Through study completion, an average of 1 year
Title
Occurrence of pregnancy and post-partum complications
Time Frame
Until 6 weeks post-partum

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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 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 participation in another research study including an exclusion period which has not expired at the time of screening patients subject to a judicial safeguard order, guardianship or trusteeship.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fabien Vidal
Organizational Affiliation
CHU Toulouse
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Angers
City
Angers
Country
France
Facility Name
Centre Aliénor d'Aquitaine
City
Bordeaux
Country
France
Facility Name
Hôpital Morvan
City
Brest
Country
France
Facility Name
Centre hospitalier intercommunal de Créteil
City
Créteil
Country
France
Facility Name
CHU Grenoble-Alpes
City
Grenoble
Country
France
Facility Name
CHU Limoges
City
Limoges
Country
France
Facility Name
Hôpital de la Conception Marseille
City
Marseille
Country
France
Facility Name
CHU Nice
City
Nice
Country
France
Facility Name
CHU Nîmes
City
Nîmes
Country
France
Facility Name
CHI Poissy
City
Poissy
Country
France
Facility Name
CHU Rouen Normandie
City
Rouen
Country
France
Facility Name
Centre hospitalier des 4 villes
City
Saint-Cloud
Country
France
Facility Name
CHU Strasbourg
City
Strasbourg
Country
France
Facility Name
CHU Toulouse
City
Toulouse
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No

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

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