Efficacy of Certolizumab in Women With Unexplained Recurrent Implantation Failure: a Double-blind Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 161
- 试验地点
- 1
- 主要终点
- Clinical pregnancy defined as the presence of cardiac activity on ultrasound scan
研究概览
简要总结
Recurrent implantation failure (RIF), defined as the absence of clinical pregnancy after the transfer of three good-quality embryos, concerns up to 40% of IVF couples and is associated with a low success rate. The causes remain unexplained in over 50% of cases.
Various dysimmune changes (related to immune T cells profiles, pro-inflammatory cytokines levels) have been described in unexplained RIF as compared to fertile controls, and it has been estimated that such dysimmunity may occur in 50% of unexplained RIFs. Previous data on a benefit of general immune modulation by steroids or immunoglobulins are heterogenous and failed to demonstrate clinically significant benefit. The proinflammatory cytokine Tumor Necrosis Factor (TNF) α participates in the regulation of the immune balance of the endometrium, its peripheral blood and endometrial concentrations are increased in RIF patients as compared to fertile controls. In 2009, a pilot placebo controlled study showed that TNF-α antagonist treatment allowed a 56% live birth rate (versus 13% in controls) in 13 women with unexplained RIF. Due to the lack of maternal and fetal tolerance data, TNF-α antagonists were not further evaluated. Today, safety data issued from 1200 pregnancies are reassuring allowing the use of TNF-α antagonists during pregnancy (www.lecrat.org). In addition the TNF-α antagonist certolizumab does not cross the placental barrier.
We hypothesize that certolizumab may improve clinical pregnancy rates in women with unexplained RIF with a good safety profile.
详细描述
The European Society of Human Reproduction and Embryology (ESHRE) consortium has proposed to define recurrent implantation failure (RIF) as the failure to obtain a clinical pregnancy after the transfer of three good-quality embryos according to the Istanbul consensus 2011. Although its prevalence is difficult to estimate, RIF could concern up to 40% of couples undergoing assisted reproductive technology (ART) treatments. More than 50% of RIF cases remain unexplained after extensive exploration and clinical pregnancy rate in this population is particularly low, estimated at about 15%.
Endometrial environment plays a crucial role in embryo implantation and early placental development. In normal pregnancy, the survival of the semi-allogeneic fetus is dependent on the induction of maternal immune tolerance, with regulatory T cells and Th-2 anti-inflammatory profile. Several studies show a misbalance of immune cells and cytokines expression in women with implantation failure. Most studies analyze immune cells and cytokines profile in peripheral blood, with few data on cells and cytokines profiles in endometrial tissues during the periimplantation period. However, the immune endometrial balance could be disturbed in up to 80% of RIF cases.
Tumor Necrosis Factor (TNF) α, together with other pro-inflammatory cytokines, participates in the regulation of the immune balance of the endometrium. TNF-α and TNF-α / interleukin (IL)-10 ratio are increased in the endometrium of RIF patients, which suggests they could be involved in physiopathology of RIF.
To date there is no effective treatment to improve the low clinical pregnancy rate in unexplained RIF. The repeated failure of embryo transfers and the lack of efficient treatment are associated with psychological distress in infertile couples and raises economic problems because of the important cost of in vitro fertilisation (IVF).
Some treatments with immunomodulatory effect, such as steroids, were previously evaluated. However, studies were small and included heterogeneous populations, resulting in inconclusive results.
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
- Double (Participant, Investigator)
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
- •Women aged 18-40 years
- •Idiopathic, male or tubal factor infertility
- •Unexplained recurrent implantation failure defined as consecutive failure to obtain clinical pregnancy after at least transfers of 3 good-quality embryos (Istanbul criteria)
- •Affiliation to a French social security system (beneficiary or legal)
- •Informed and signed consent
排除标准
- •Known cause of RIF among the following:
- •Genetic parental anomalies
- •Non-gestational diabetes mellitus of type I and II,
- •Infectious disease
- •Antiphospholipid syndrome
- •Sickle cell disease
- •Diffuse adenomyosis
- •No contraindication to Freeze-thaw embryo transfer (FET) treatment
- •Linked to certolizumab:
- •Hypersensitivity to the active substances or to any of the excipients
- •Primary or secondary immunodeficiency (history of or currently active)
- •Active uncontrolled infection
- •Active tuberculosis
- •Cardiac insufficiency (moderate to severe, New York Heart Association (NYHA) III/IV classes)
- •Any malignant neoplasm except adequately treated basal or squamous cell carcinoma of the skin
- •Immunization with a live/ attenuated vaccine within 4 weeks prior to baseline or simultaneously with treatment
- •Cytopenia as defined by platelet count < 100 × 109/L (100,000/mm3), hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L), absolute neutrophil count < 2.0 × 109/L (2000/mm3), lymphocyte count < 0.5 × 109/L (500/mm3)
- •Liver cytolysis (AST / ALT > 5 N)
- •Insufficient kidney function, as defined by a serum creatinine of more than 3 mg/dL or creatinine clearance of 20 ml/min or less
- •Demyelinating neurological disease
- •Linked to rifampicin and isoniazid (RIFINAH®)
- •Hypersensitivity to the active substances or to any of the excipients
- •Porphyria
- •Decreased blood-clotting from low vitamin K
- •Liver cytolysis (AST / ALT >5 N)
- •Combination with bictegravir, cobicistat, daclatasvir, dasabuvir, delamanid, grazoprevir / elbasvir, protease inhibitors boosted by ritonavir, isavuconazole, ledipasvir, lurasidone, midostaurine, ombitasvir / paritaprévir, praziquantel, rilpivirine, sofosbuvir, velpatasvir, voriconazole, voxilaprevir
- •Acute hepatitis, hepatic failure or chronic hepatic disease
- •Acute nephropathy
- •Contraindication to anti-pneumococcal vaccination (Pneumovax®)
- •Hypersensitivity to the active substances or to any of the excipients
- •Other criteria:
- •Absence of health insurance (include AME)
- •Subject under guardianship or curatorship
- •Subject deprived of their liberty by a judicial or administrative decision
- •Participation in another interventional study or being in the exclusion period at the end of a previous study.
研究组 & 干预措施
1
Certolizumab (CIMZIA® ; TNF-α antagonist )
干预措施: Certolizumab (CIMZIA® ; TNF-α antagonist) (Drug)
2
Placebo (NaCl 0.9 % solution)
干预措施: Placebo (NaCl 0.9 % solution) (Drug)
结局指标
主要结局
Clinical pregnancy defined as the presence of cardiac activity on ultrasound scan
时间窗: 5 weeks +/- 6 days of gestation
Presence of cardiac activity on ultrasound scan at 5 weeks +/- 6 days of gestation
次要结局
- Live birth(22 to 40 weeks of gestation)
- Miscarriage(Before 12 weeks of gestation)
- All adverse events distinguishing serious adverse events(Through study completion, a maximum of 64 months and 3 weeks)