E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Infertilty in women with adenomyosis. |
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E.1.1.1 | Medical condition in easily understood language |
Infertilty in women with adenomyosis. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the impact of ultra-long protocol versus long protocol on the live birth rate after first or second IVF/ICSI attempt in infertile women with adenomyosis. |
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E.2.2 | Secondary objectives of the trial |
To compare ultra-long and long protocols efficacy after first or second IVF/ICSI in terms of:
-uterine volume reduction following pituitary down-regulation
-low responders rate
-biochemical pregnancy
-implantation rate
-clinical pregnancy
-clinical pregnancy with fetal heart beat
-ongoing pregnancy at the end of first trimester
-first trimester miscarriage
To assess treatment safety and tolerability in both arms in terms of specific menopause-like symptoms at the end of down-regulation treatment,
To assess Adverse Events occurrence during down-regulation treatment, during IVF/ICSI attempt, during pregnancy (including ectopic pregnancy occurrence) and at delivery (maternal and perinatal complications for mother and child until 6 weeks post-partum).
To assess placental malposition occurrence (defined as the presence of placenta previa or accreta diagnosed on third trimester US examination or at time of delivery).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) suspected adenomyosis on high quality TV US or focal or diffuse adenomyosis defined as a thickening of the JZ to more than 12mm on previous MRI (<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 (AMH, estradiol, FSH, 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
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E.4 | Principal exclusion criteria |
1) absence of adenomyosis (defined as a thickening of the JZ 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)history of previous prolonged GnRH agonist treatment (> 3 months) within 6 months prior study treatment start
5) women taking prohibited concomitant treatments and not able to stop them for the study period
6) 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
7) positive plasma viral load for HIV, HCV or HBV for one (or both) in the couple during the year before inclusion
8) participation in another research study including an exclusion period which has not expired at the time of screening
9) patients subject to a judicial safeguard order, guardianship or trusteeship.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is a live birth after first or second IVF/ICSI attempt defined as delivery of one or more live-born infant. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From 22 weeks of gestation |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
-Uterine volume reduction between Ultra sound measurements: at baseline and at time of ovarian stimulation onset
-Occurrence of poor responders defined as women with <3 matures follicles or serum estradiol <500
-Biochemical pregnancy defined as serum ßhCG ≥ 100 IU/l
-Implantation rate defined as the ratio ”number of gestational sacs/number of transferred embryos” on transvaginal ultrasound
-Clinical pregnancy defined as the presence of one or more gestational sacs on transvaginal ultrasound
-Clinical pregnancy with fetal heart beat defined as the presence of at least one fetus with heart beat on transvaginal ultrasound
-Ongoing pregnancy defined as a live pregnancy on first trimester ultrasound examination
-First trimester miscarriage occurrence defined as a pregnancy loss before 12 weeks of gestation among patients with a clinical pregnancy
Secondary safety endpoints include:
-Occurrence of menopause-like symptoms using the Menopause Rating Scale
-Occurrence of ovarian hyperstimulation syndrome (OHS)
-Occurrence of pregnancy and post-partum complications
-Occurrence of neonatal complications
-Occurrence of any other adverse Event
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Uterine volume reduction:at baseline and at time of ovarian stimulation onset
-Occurrence of poor responders:at the time of ovulation triggering
-Biochemical pregnancy:14 days following follicular aspiration
-Implantation rate and clinical pregnancy:5 weeks after follicular aspiration
-Clinical pregnancy with fetal heart beat:7 weeks after embryo transfer
-Ongoing pregnancy:at 12 weeks of gestation
-First trimester miscarriage occurrence:before 12 weeks of gestation
-Occurrence of menopause-like symptoms:at the end of the GnRH agonist treatment
-Occurrence of ovarian hyperstimulation syndrome
-Occurrence of pregnancy, neonatal and post-partum complications: until 6 weeks post-partum
-Occurrence of any other Adverse Event: during the entire study period |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |