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AdenomyosisPhase 3ADENOFIVNCT03940807

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

A Phase 3 study testing 11.25mg GnRH agonist, 0.1 mg GnRH agonist and 25 µg transdermal oestradiol in people with Adenomyosis, run by University Hospital, Toulouse at 14 sites in France.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 40 years, women only
Conditions the study is for
Adenomyosis
What is being tested?
11.25mg GnRH agonist, 0.1 mg GnRH agonist and 25 µg transdermal oestradiol
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
14 sitesFrance
Study dates
29 Apr 2022to Jan 2025
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 40 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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
Show all 10Show fewer
  • 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

Who cannot join

  • 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.

Trial locations and contacts

14 sites in 1 country.

14 sites in 1 country

France14 sites

  • CHU Angers

    Angers

  • Centre Aliénor d'Aquitaine

    Bordeaux

  • Hôpital Morvan

    Brest

  • Centre hospitalier intercommunal de Créteil

    Créteil

  • CHU Grenoble-Alpes

    Grenoble

  • CHU Limoges

    Limoges

  • Hôpital de la Conception Marseille

    Marseille

  • CHU Nice

    Nice

  • CHU Nîmes

    Nîmes

  • CHI Poissy

    Poissy

  • CHU Rouen Normandie

    Rouen

  • Centre hospitalier des 4 villes

    Saint-Cloud

  • CHU Strasbourg

    Strasbourg

  • CHU Toulouse

    Toulouse

Other trials in France

About this study

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.

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.

Read more

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
Being tested
11.25mg GnRH agonist, 0.1 mg GnRH agonist, 25 µg transdermal oestradiol
Keywords
Infertility, GnRH
Medical subject headings
Adenomyosis, Infertility

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 11.25mg GnRH agonistDrug

    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.

  • 0.1 mg GnRH agonistDrug

    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.

  • 25 µg transdermal oestradiolDrug

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

Study groups in NCT03940807
Study groupRoleWhat they receive
Ultra-long protocol groupExperimentalAll 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.
Receives: Drug: 11.25mg GnRH agonist; Drug: 25 µg transdermal oestradiol
Long protocol groupActive comparatorAll 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.
Receives: Drug: 0.1 mg GnRH agonist

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 22 weeks of gestation

Secondary outcomes (12)

  1. Uterine volume change

    Uterine volume reduction between ultrasound measurements at baseline and at time of ovarian stimulation onset

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

  2. 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

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

  3. 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

    Measured: 14 days following follicular aspiration

  4. 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

    Measured: 5 weeks after follicular aspiration

  5. 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

    Measured: 5 weeks after follicular aspiration

  6. 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

    Measured: 7 weeks after embryo transfer

  7. Number of Participants with ongoing pregnancy

    Ongoing pregnancy defined as a live pregnancy on first trimester US examination performed at 12 weeks of gestation

    Measured: 12 weeks of gestation

  8. First trimester miscarriage occurrence

    First trimester miscarriage occurrence defined as a pregnancy loss before 12 weeks of gestation among patients with a clinical pregnancy

    Measured: Before 12 weeks of gestation

  9. Occurrence of menopause-like symptoms symptoms at the end of the GnRH agonist treatment

    Using the Menopause Rating Scale

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

  10. Occurrence of neonatal complications

    Measured: Until 6 weeks post-partum

  11. Occurrence of any other Adverse Event

    Measured: Through study completion, an average of 1 year

  12. Occurrence of pregnancy and post-partum complications

    Measured: Until 6 weeks post-partum

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 May 2019
  2. Study start29 Apr 2022
  3. Primary completionJan 2025 (estimated)
  4. Study completionJan 2025 (estimated)

Why it stopped: Principal investigator departure

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03940807
Sponsor's protocol ID
RC31/17/0448
Acronym
ADENOFIV
Status last verified
Nov 2022
First submitted
19 Apr 2019
Last updated
18 Nov 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing 11.25mg GnRH agonist, 0.1 mg GnRH agonist and 25 µg transdermal oestradiol in people with Adenomyosis, run by University Hospital, Toulouse at 14 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 18 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03940807.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2022.

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