Status: Planned
First registered on:
30/07/2018
Last updated on:
29/07/2020
1. Study identification
EU PAS Register NumberEUPAS25027
Official titlePregnancy outcomes in women exposed to oral cladribine: a multi-country cohort database study
Study title acronymCLEAR
Study typeObservational study
Brief description of the studyThe design of this pregnancy PASS is a cohort study based on secondary use of data from various automated healthcare databases (AHDB) and registers in 7 European countries: Denmark, Finland, France, Germany, Norway, Sweden, and Scotland (United Kingdom). Women with Multiple Sclerosis (MS) who were exposed to oral cladribine during pregnancy and/or within 6 months before their last menstrual period (LMP) (i.e. exposure period, which correspond to the at-risk period for pregnancy outcomes, major congenital anomalies (MCA) in infants or alternations in growth and development in infants), or pregnancies fathered by men with MS treated with oral cladribine within 6 months before their LMP, will be identified in the selected databases/registers. Data will be retrieved on pregnancies and their outcomes, and infants for MCA, growth and development. Comparison of pregnancy outcomes will be conducted in pregnant women with MS between the exposed cohort (exposure to oral cladribine within the at-risk period) and the unexposed cohort (unexposed to any Disease-modifying drug [DMD] during the at-risk period, which can vary from 3 to 12 months according to the DMD) and in pregnant women whose pregnancy is fathered by men with MS between the exposed cohort (pregnancy fathered by men with MS exposed to oral cladribine within the at-risk period) and the unexposed cohort (pregnancy fathered by men with MS unexposed to any DMD during the at-risk period, which can vary from 3 to 6 months according to the DMD). In the selected data sources, pregnancies will be followed until the outcome of the pregnancy is known, and live births resulting from an identified pregnancy will be followed for up to one year of age.
Was this study requested by a regulator?Yes: Denmark, Finland, France, Germany, Norway, Sweden, United Kingdom
Is the study required by a Risk Management Plan (RMP)?
EU RMP category 3 (required)
Regulatory procedure number (RMP Category 1 and 2 studies only)
Other study registration identification numbers and URLs as applicable
2. Research centres and Investigator details
Coordinating study entity
Centre to which the investigator belongsRTI-HS
Department/Research groupPharmacoepidemiology & Risk Management
Organisation/affiliationRTI Health Solutions
Details of (Primary) lead investigator
Title Dr
Last name Alejandro
First name Arana
Is this study being carried out with the collaboration of a research network?
No
Other centres where this study is being conducted
Multiple centres
In total how many centres are involved in this Study?7
Danish Multiple Sclerosis Registry, Denmark
Observatoire français de la sclérose en plaques (OFSEP), France
German MS Pregnancy Registry, Germany
Norwegian MS-registry and biobank, Norway
Countries in which this study is being conducted
International study
Denmark
Finland
France
Germany
Norway
Sweden
United Kingdom
3. Study timelines: initial administrative steps, progress reports and final report
PlannedActual
Date when funding contract was signed20/12/201809/09/2019
Start date of data collection31/12/2020
Start date of data analysis31/12/2027
Date of interim report, if expected30/12/2023
Date of final study report28/07/2028
4. Sources of funding
Please provide estimates of the percentage of funding by source for this study
Names(s)Approximate % funding
Pharmaceutical companiesMerck Healthcare KGaA100
Charities
Government body
Research councils
EU funding scheme
5. Contact details for enquiries
Scientific Enquiries
Title Dr
Last name Merck Healthcare KGaA
First name Communication Center
Address line 1Frankfurter Str. 250
Address line 2
Address line 3
CityDarmstadt
Postcode64293
CountryGermany
Phone number (incl. country code)49-6151-725200
Alternative phone number
Fax number (incl. country code)
Public Enquiries
Title Dr
Last name Merck Healthcare KGaA
First name Communication Center
Address line 1Frankfurter Str. 250
Address line 2
Address line 3
CityDarmstadt
Postcode64293
CountryGermany
Phone number (incl. country code)49-6151-725200
Alternative phone number
Fax number (incl. country code)
6. Study drug(s) information
Product NameMavenclad®
CountryUnited Kingdom
Substance INN(s)CLADRIBINE
7. Medical conditions to be studied
Medical condition(s)Yes
Multiple sclerosis
8. Population under study
Age
Adults (18 - 44 years)
Adults (45 - 64 years)
Sex
Female
Other population
Pregnant women
9. Number of subjects
Estimated total number of subjects447
Additional information
This study will enroll participants in a ratio of 1:2 between the cohort of pregnant women with Multiple Sclerosis (MS) exposed to oral cladribine to the cohort of pregnant women with MS unexposed to any DMD. Thus, aim is to enroll a total of 447 pregnant woman with 149 pregnant women with MS exposed to oral cladribine and 298 pregnant women with MS unexposed to any DMD.
10. Source of data
Is this study being carried out with an established data source?Yes
Data sources not registered with ENCePP
Nordic health registers, Norway
the MEMO database in Scotland, United Kingdom
German MS pregnancy registry, Germany
OFSEP data source, France
Sources of data
Prospective study based on secondary use of data from various automated healthcare databases (AHDB) and registers
11. Scope of the study
What is the scope of the study?
Risk assessment
Primary scope : Risk assessment
12. Main objective(s)
What is the main objective of the study?
To estimate prevalence of MCA among infants of women with MS exposed to oral cladribine during and/or 6 months prior to pregnancy, and compare with prevalence in infants of pregnant women with MS unexposed to any disease-modifying drug (DMD) during pregnancy or 3 months prior to pregnancy (exceptions:12 months for rituximab, 6 months for methotrexate and mitoxantrone, and 4 months for alemtuzumab)
Are there primary outcomes?Yes
Occurrence of MCA (any and by type)
Are there secondary outcomes?Yes
Occurrence of pregnancy outcomes(any)including spontaneous abortions; ectopic pregnancies;TOPFA; TOPMR*;stillbirths;neonatal death;post-neonatal infant death;and maternal death*
Occurrence of alterations in growth evident in foetuses at end of pregnancy/delivery(eg,low birth weight [LBW],intrauterine growth restriction,small for gestational age [SGA])
*only for pregnancies in female MS patients
13. Study design
What is the design of the study?
Cohort study
14. Follow-up of patients
Will patients be followed up?Yes
Please describe duration of follow up
In the selected data sources, pregnancies will be followed until the
outcome of the pregnancy is known, and live births resulting from an
identified pregnancy will be followed for up to one year of age.
15. Data analysis plan
Please provide a brief summary of the analysis method
For each country, study variables will be described by study cohort. These variables will be used as potential confounders (if relevant) when comparing pregnancy outcomes between study cohorts. Descriptive statistics including number of outcomes (n) and prevalence (%, with corresponding 95% confidence interval [CI]) will be presented for each pregnancy outcome in each study cohort separately. In each country, prevalence of pregnancy outcomes will be further compared between study cohorts using log-binomial regression with adjustments for potential confounders. Relative risk (RR) estimates with 95% CI will be reported for these comparisons. Impact of exposure on each outcome will be assessed by stratification on timing of exposure (exposure will be categorized into Trimesters based on cladribine start and stop dates): before conception,1st, 2nd,or 3rd trimester, unknown, and age at LMP. Meta-analysis using aggregated results from each country database analysis will be performed.
16. ENCePP seal
Are you requesting the ENCePP seal for this study?
No
17. Full protocol
Available when the study ends
18. Study Results
Not submitted
Please list the 5 most relevant publications using data from your study
ReferenceLink to web-publication
None
19. Other relevant documents
Conflict(s) of interest of
investigator(s)Not submitted
Composition of Steering Group and
ObserversNot submitted
Other documentsNot
submitted
Signed Code of
Conduct Checklist
Not submitted
Signed Code of Conduct Declaration
Not submitted
Signed Checklist for Study
Protocols
Not submitted
