Phase III Trial to Assess Impact of Ultra-long Versus Long Down-regulation Protocol on IVF/ICSI Outcomes in Infertile Women Presenting With Adenomyosis.
试验速览
- 阶段
- 3 期
- 状态
- 撤回
- 试验地点
- 14
- 主要终点
- Number of live birth after first or second in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) attempt.
研究概览
简要总结
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: 11.25mg GnRH agonist (Drug)
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.
干预措施: 25 µg transdermal oestradiol (Drug)
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.
干预措施: 0.1 mg GnRH agonist (Drug)
结局指标
主要结局
Number of live birth after first or second in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) attempt.
时间窗: Up to 22 weeks of gestation
This outcome is defined as delivery of one or more live-born infant at \> 22 weeks of gestation.
次要结局
- Number of Participants with clinical pregnancy(5 weeks after follicular aspiration)
- Occurrence of poor responders(after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group)
- Implantation rate(5 weeks after follicular aspiration)
- Number of Participants with ongoing pregnancy(12 weeks of gestation)
- Occurrence of any other Adverse Event(Through study completion, an average of 1 year)
- Concentration of serum Human Chorionic Gonadotropin (HCG or ßhCG) ≥ 100 IU/l(14 days following follicular aspiration)
- Uterine volume change(after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group)
- First trimester miscarriage occurrence(Before 12 weeks of gestation)
- Occurrence of neonatal complications(Until 6 weeks post-partum)
- Number of Participants with clinical pregnancy with fetal heart beat(7 weeks after embryo transfer)
- Occurrence of menopause-like symptoms symptoms at the end of the GnRH agonist treatment(after 90 days desensitization in ultra-long protocol group and after 15 days desensitization in long protocol group)
- Occurrence of pregnancy and post-partum complications(Until 6 weeks post-partum)