Study identification

EU PAS number

EUPAS1000000707

Study ID

1000000707

Official title and acronym

PaTernal exposure to vAlproate, further iNvestiGation on the risk of NeuroDevelopmental Disorders (NDD) and Major Congenital Malformation (MCM) in Offspring: A Non-Interventional Post-Authorization Safety Study (TANGO)

DARWIN EU® study

No

Study countries

Denmark
Finland
Germany
Norway
Sweden

Study description

As part of the 2018 EU-referral, a previous PASS(EUPAS34201) was conducted to evaluate the association between paternal exposure to valproate and the risk of neurodevelopmental disorders (NDD), as well as congenital malformation (CM) in offspring.
Regarding NDD, the results suggested a possible increased risk in children born to fathers taking valproate in the 3 months prior to conception (spermatogenic window) in comparison to lamotrigine or levetiracetam (in monotherapy). The risk in children born to fathers exposed outside of the spermatogenic window wasn’t investigated. Regarding CM, this study did not identify a higher risk in offspring.
That first study had limitations, including differences between the groups in the conditions for which the medicines were used and in follow-up times. PRAC could therefore not establish whether the increased occurrence of these disorders was due to valproate use. In addition, the study was not large enough to assess the NDD subtypes.
On January 2024, PRAC requested to conduct a new PASS to further investigate the association between paternal exposure to valproate and the risk of NDD, as well as CM in offspring, and provided methodological recommendations to control biases and limitations.
The TANGO study has been set up to further investigate the association between paternal exposure to valproate and (1)the risk of NDD in offspring and (2)the risk of major CM in live and non-live born offspring, considering different paternal exposure windows and other relevant factors such as valproate indication, type of epilepsy, characteristics of the follow-up and outcome occurrence.
This study will be a multi-country, real-world, population-based cohort study using routinely collected data from registries and databases in where the family linkage (father-mother-child) is available: Denmark, Finland, Germany, Norway and Sweden, and will use all the data available to date in each country, allowing at least 1 year pre-inclusion period.

Study status

Planned
Research institutions and networks

Institutions

Sanofi
First published:
01/02/2024
Institution

Networks

The SIGMA Consortium (SIGMA)
Denmark
European Union
France
Germany
Italy
Netherlands
Norway
Spain
Sweden
United Kingdom
First published:
16/12/2024
Network
ENCePP partner

Contact details

Laure Carcaillon-Bentata 0000-0003-1556-8590

Primary lead investigator
ORCID number:
0000-0003-1556-8590

Study timelines

Date when funding contract was signed

Planned:

Study start date

Planned:

Data analysis start date

Planned:

Date of final study report

Planned:
Sources of funding
Pharmaceutical company and other private sector 

More details on funding

A Consortium of Marketing Authorization Holders for valproate and related substances
Regulatory

Was the study required by a regulatory body?

Yes

Is the study required by a Risk Management Plan (RMP)?

EU RMP category 1 (imposed as condition of marketing authorisation)

Regulatory procedure number

EMEA/H/N/PSP/J/0108