Certolizumab in Recurrent Implantation Failure (RIF)

• Status: Recruiting
• Trial end date: 2029-04-01
• Target enrollment: 0
• Participant gender: Female

Summary

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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Assistance Publique - Hôpitaux de Paris
• Treatments: Certolizumab Pegol

Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

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.