A multi-country cohort database study to assess pregnancy and infant outcomes after potential maternal or paternal exposure to cladribine tablets in the treatment of multiple sclerosis: the CLEAR study methods and status update

Abstract

Background: Cladribine tablets are contraindicated during pregnancy; therefore, safety data on pregnancies exposed to this treatment are limited. CLEAR collects and describes pregnancy outcomes in this understudied population.

Objectives: To describe the main features of the CLEAR study design, including the data sources and the methodological approach, and provide a status update.

Design: CLEAR is a non-interventional, multi-database, comparative cohort study. Four cohorts are included: pregnancies of women with multiple sclerosis (MS) exposed to cladribine tablets (maternal cohort exposed); pregnancies of women with MS unexposed to any disease-modifying therapy (DMT; maternal cohort unexposed); pregnancies fathered by men with MS exposed to cladribine tablets; and pregnancies fathered by men with MS unexposed to any DMT.

Methods: A staggered methodological approach, using data from Denmark, Finland, France, Germany, Norway, Scotland, and Sweden, will be applied to analyze the occurrence of major congenital anomalies (primary outcome) and selected pregnancy outcomes. The first interim analysis (performed using German pregnancy cohorts) was conducted when ⩾75 pregnant women (including 25 women from the maternal cohort exposed) were cumulatively reached across all participating countries. The end of the study period will be established once pregnancy counts reach 149 in the maternal cohort exposed and 298 in the maternal cohort unexposed in all countries combined, or 5 years after pregnancy counts are first assessed (whichever occurs first).

Results: As of January 2024, data on pregnancies of women exposed to cladribine tablets (n = 28-36 (numbers are approximate due to masking of some counts)), and pregnancies of women unexposed to cladribine tablets (n = 2834) were available from Denmark, Finland, Germany, Scotland, and Sweden.

Conclusion: The CLEAR study, using a staggered methodological approach, aims to provide further insight into the safety outcome data for cladribine tablets in pregnant women, as a regulatory commitment with the European Medicines Agency.

Trial registration: EU PAS Register number, EUPAS25027.

Keywords: cladribine tablets; multiple sclerosis; pregnancy outcomes; safety; staggered methodological approach.

Figure 1.

Illustration of the timeframe for the CLEAR study. ^aThe first interim analysis (performed using the German data) was conducted when at least 75 pregnant women (25 pregnant women with MS exposed to cladribine tablets and 50 women with MS unexposed to any DMT) were cumulatively reached across all participating countries. Additional interim analyses will be conducted each time 25 additional pregnant women with MS exposed to cladribine tablets and 50 pregnant women with MS unexposed to any DMT have been cumulatively reached across all participating countries. ^bStart and end of the observation period will vary by country, depending on the launch date of cladribine tablets and the data source-specific data lags. ^cThe target study size is 134 live births from 149 pregnant women with MS exposed to cladribine tablets and 268 live births from 298 pregnant women with MS unexposed to any DMT in all countries combined. If target study size is not met, the end of the study period will be 5 years after pregnancy counts are first assessed. DMT, disease-modifying therapy; MS, multiple sclerosis.

Figure 2.

Summary of the primary, secondary, and exploratory outcomes of the CLEAR study. *Only for pregnancies in female patients with MS. EUROCAT, European Surveillance of Congenital Anomalies; MS, multiple sclerosis; TOPFA, termination of pregnancy due to fetal anomaly; TOPMR, termination of pregnancy due to maternal risk.

Figure 3.

Study design and definition of exposed and unexposed study cohorts. (a) Pregnant women with MS are included in CLEAR if they have been: (i) Exposed to cladribine tablets during pregnancy, or within 6 months before the LMP. (ii) Unexposed to any DMT within the DMT-specific exposure windows. (b) Pregnancies with an exposed father with MS are included in CLEAR if the father has been: (i) Exposed to cladribine tablets within 6 months before the LMP. (ii) Unexposed to any DMT within the DMT-specific exposure windows. DMT, disease-modifying therapy; LMP, last menstrual period; MS, multiple sclerosis; 1T, first trimester; 2T, second trimester; 3T, third trimester.