Efficacy of Certolizumab Pegol in Adult Women with Unexplained Recurrent Implantation Failure: A Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of certolizumab compared to placebo on the clinical pregnancy rate in women with unexplained recurrent implantation failure. This is clinically relevant as recurrent implantation failure (RIF) poses a significant challenge in reproductive medicine, and identifying effective treatments could improve pregnancy outcomes for affected women.

Secondary objectives include:

• Evaluating the efficacy of certolizumab compared to placebo in terms of live-birth rate and miscarriage rate.
• Assessing the safety of certolizumab in this patient population.

The clinical trial involves **adult women** aged 18 to 40 years who are experiencing **recurrent implantation failures** (RIF). The study population is exclusively female, with no male participants included. Participants are selected based on specific criteria, including idiopathic, male, or tubal factor infertility, and unexplained recurrent implantation failure as defined by the Istanbul criteria. All participants must be affiliated with the French social security system and have provided informed and signed consent. The trial does not include any vulnerable populations. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** of **certolizumab pegol** compared to a placebo in women with unexplained recurrent implantation failure. This study is a **double-blind**, **randomized**, and **controlled** trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, thus minimizing bias. The trial is expected to run from November 2023 to April 2029, with a maximum treatment period of 140 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, infertility factors, and previous implantation failures. Following successful screening, participants will be randomized to receive either the active treatment or placebo via **subcutaneous injection**. The study will include regular follow-up visits to monitor the participants' health, assess the primary endpoint of clinical pregnancy, and evaluate secondary endpoints such as live birth rates and adverse events. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

The expected length of participant involvement is approximately 140 days, with conditions for early termination including withdrawal of consent, adverse events, or protocol non-compliance. The trial aims to provide valuable insights into the treatment of recurrent implantation failure, with the primary endpoint being the presence of cardiac activity on an ultrasound scan at 5 weeks of gestation. Secondary endpoints will include live birth rates, miscarriage rates, and the occurrence of adverse events such as multiple pregnancies and fetal abnormalities.

The clinical trial involves the administration of two treatments: **Cimzia** and **Sodium Chloride**. **Cimzia**, with the active substance **certolizumab pegol**, is provided as a **solution for injection in a pre-filled syringe**. It is administered via **subcutaneous injection**. The maximum daily dose is 400 mg, with a total maximum dose of 3200 mg over a treatment period of 140 days. The pharmaceutical form is a solution for injection, and it is not a pediatric formulation. The product is authorized under the marketing authorization number EU/1/09/544/001 and is manufactured by UCB PHARMA S.A. (ANDERL BE). The active substance, **certolizumab pegol**, is a protein of other origin, classified under the ATC code L04AB05.

The comparator treatment in this trial is **Sodium Chloride**, which serves as a placebo. It is provided as a **solution for infusion** and is also administered via **subcutaneous injection**. The maximum daily dose is 2 ml, with a total maximum dose of 16 ml over the same treatment period of 140 days. This product is not a pediatric formulation and does not have a specific marketing authorization number. The active substance, **sodium chloride**, is of chemical origin. The use of **Sodium Chloride** as a placebo is intended to provide a control for evaluating the efficacy of **Cimzia** in the study population.

The efficacy of certolizumab in the clinical trial will be assessed by evaluating its impact on the **clinical pregnancy rate** in women with unexplained recurrent implantation failure. The primary endpoint is defined as the presence of cardiac activity on an ultrasound scan at 5 weeks ± 6 days of gestation, post-implantation. Secondary endpoints include live-birth rates, miscarriage rates defined as spontaneous abortion or pregnancy cessation before 12 weeks of gestation, and the occurrence of adverse events, with particular attention to multiple pregnancies, ectopic pregnancy, fetal abnormalities, small for gestational age, intrauterine growth restriction, and preeclampsia.

The trial is designed as a double-blind randomized controlled study, comparing certolizumab to a placebo. Efficacy parameters will be collected and analyzed at specified timepoints, with the primary endpoint being assessed at approximately 5 weeks of gestation. The trial will utilize validated ultrasound techniques to confirm clinical pregnancy and monitor for cardiac activity. The study is expected to conclude by April 2029, with recruitment starting in November 2023.