Status: Planned First registered on: 19/03/2020
Last updated on: 24/06/2020
1. Study identification
EU PAS Register NumberEUPAS34201
Official titleA post-authorization safety study (PASS) to evaluate the paternal exposure to valproate and the risk of neurodevelopmental disorders including autism spectrum disorders as well as congenital abnormalities in offspring - a population-based retrospective study
Study title acronym
Study typeObservational study
Brief description of the studyThis population-based retrospective cohort study using secondary data from national registries within Norway, Denmark and Sweden aims to examine the association between paternal exposure to valproate at conception and the risk of Neurodevelopmental disorders (NDD), including Autism spectrum disorder (ASD), as well as Congenital Malformations (CM) in offspring. The primary objective is to investigate the risk of NDD, including ASD, in offspring paternally exposed to valproate (monotherapy), compared to lamotrigine or levetiracetam (composite monotherapy) treatment at the time of conception. Secondary objectives are to 1) investige the risk of CM in live and non-live offspring paternally exposed to valproate (monotherapy), compared to lamotrigine or levetiracetam (composite monotherapy) treatment at the time of conception, in Norway and Denmark; 2) describe the anti-epileptic drug (AED) exposure (posology and duration) data and health characteristics of male patients prescribed AEDs (including valproate and lamotrigine/levetiracetam) in treatment of epilepsy and other indications at the time of conception of their offspring, both for NDD and CM cohort; and 3) identify potentially important risk factors for outcomes of interest, in offspring paternally exposed to valproate (monotherapy) or lamotrigine or levetiracetam (composite monotherapy) at the time of conception, by examining AED exposure and health characteristics of the offspring and their mothers. Additional exploratory and sensitivity analyses apply (such as narrow case definition for primary outcome with a focus on ASD). Separate cohorts for analysis will be created where medical record linkage between offspring (<12 years), mother and father is available; the NDD cohort will consist of live births and the CM cohort will consist of live births, stillbirths and spontaneous abortions during gestation (2nd or 3rd trimester) for Norway and Denmark, and live births only for Sweden.
Was this study requested by a regulator?Yes: EMA
Is the study required by a Risk Management Plan (RMP)? EU RMP category 1 (imposed as condition of marketing authorisation)
Regulatory procedure number (RMP Category 1 and 2 studies only)EMEA/H/A-31/1454
Other study registration identification numbers and URLs as applicable
2. Research centres and Investigator details
Coordinating study entity
Centre to which the investigator belongsIQVIA
Department/Research groupEMEA Data Science Hub
Organisation/affiliationIQVIA
Website/Homepagehttps://www.iqvia.com/
Details of (Primary) lead investigator
Title Professor
Last name Layton
First name Deborah
Is this study being carried out with the collaboration of a research network?
No
Other centres where this study is being conducted
Not applicable (single centre)

Countries in which this study is being conducted
International study

Denmark
Norway
Sweden
3. Study timelines: initial administrative steps, progress reports and final report
PlannedActual
Date when funding contract was signed09/10/2018
Start date of data collection01/09/2020
Start date of data analysis
Date of interim report, if expected13/08/2021
Date of final study report13/08/2022
4. Sources of funding
Please provide estimates of the percentage of funding by source for this study
Names(s)Approximate % funding
Pharmaceutical companiesA Consortium of Marketing Authorization Holders for valproate and related substances100
Charities
Government body
Research councils
EU funding scheme
5. Contact details for enquiries
Scientific Enquiries
Title Professor
Last name Layton
First name Deborah
Address line 1210 Pentonville Road
Address line 2 
Address line 3 
CityLondon 
PostcodeN1 9JY 
CountryUnited Kingdom
Phone number (incl. country code)44-07825844639 
Alternative phone number 
Fax number (incl. country code) 
Email address DLayton@uk.imshealth.com
Public Enquiries
Title Professor 
Last name Layton 
First name Deborah 
Address line 1210 Pentonville Road 
Address line 2 
Address line 3 
CityLondon 
PostcodeN1 9JY 
CountryUnited Kingdom 
Phone number (incl. country code)44-07825844639 
Alternative phone number 
Fax number (incl. country code) 
Email address DLayton@uk.imshealth.com 
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