Study type

Study topic

Human medicinal product

Study type

Non-interventional study

Scope of the study

Drug utilisation

Data collection methods

Secondary use of data
Non-interventional study

Non-interventional study design

Cohort
Study drug and medical condition

Name of medicine

AAVELI

Name of medicine, other

Methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin, paramethadione, trimethadione, ethadione, phensuximide, mesuximide, ethosuximide, combinations, clonazepam, carbamazepine, oxcarbazepine, rufinamide, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, sultiame, phenacemide, lamotrigine, felbamate, topiramate, pheneturide, levetiracetam, zonisamide, stiripentol, lacosamide, carisbamate, retigabine, perampanel, brivaracetam, cenobamate, fenfluramine, ganaxolone, beclamide, gabapentin, pregabalin, mirogabalin, eslicarbazepine, diazepam, lorazepam, clobazam, midazolam.

Study drug International non-proprietary name (INN) or common name

BRIVARACETAM
CARBAMAZEPINE
CENOBAMATE
FENFLURAMINE HYDROCHLORIDE
GABAPENTIN
LACOSAMIDE
LAMOTRIGINE
LEVETIRACETAM
PERAMPANEL
PHENOBARBITAL
PREGABALIN
RETIGABINE
RUFINAMIDE
STIRIPENTOL
TOPIRAMATE
VALPROIC ACID
VALPROMIDE
VIGABATRIN
ZONISAMIDE

Anatomical Therapeutic Chemical (ATC) code

(A08AA02) fenfluramine
fenfluramine
(N02BF) Gabapentinoids
Gabapentinoids
(N02BF01) gabapentin
gabapentin
(N02BF02) pregabalin
pregabalin
(N02BF03) mirogabalin
mirogabalin
(N03A) ANTIEPILEPTICS
ANTIEPILEPTICS
(N03AA01) methylphenobarbital
methylphenobarbital
(N03AA02) phenobarbital
phenobarbital
(N03AA03) primidone
primidone
(N03AA04) barbexaclone
barbexaclone
(N03AA30) metharbital
metharbital
(N03AB01) ethotoin
ethotoin
(N03AB02) phenytoin
phenytoin
(N03AB03) amino(diphenylhydantoin) valeric acid
amino(diphenylhydantoin) valeric acid
(N03AB04) mephenytoin
mephenytoin
(N03AB05) fosphenytoin
fosphenytoin
(N03AC01) paramethadione
paramethadione
(N03AC02) trimethadione
trimethadione
(N03AC03) ethadione
ethadione
(N03AD01) ethosuximide
ethosuximide
(N03AD02) phensuximide
phensuximide
(N03AD03) mesuximide
mesuximide
(N03AD51) ethosuximide, combinations
ethosuximide, combinations
(N03AE01) clonazepam
clonazepam
(N03AF01) carbamazepine
carbamazepine
(N03AF02) oxcarbazepine
oxcarbazepine
(N03AF03) rufinamide
rufinamide
(N03AG01) valproic acid
valproic acid
(N03AG02) valpromide
valpromide
(N03AG03) aminobutyric acid
aminobutyric acid
(N03AG04) vigabatrin
vigabatrin
(N03AG05) progabide
progabide
(N03AX03) sultiame
sultiame
(N03AX07) phenacemide
phenacemide
(N03AX09) lamotrigine
lamotrigine
(N03AX10) felbamate
felbamate
(N03AX11) topiramate
topiramate
(N03AX13) pheneturide
pheneturide
(N03AX14) levetiracetam
levetiracetam
(N03AX15) zonisamide
zonisamide
(N03AX17) stiripentol
stiripentol
(N03AX18) lacosamide
lacosamide
(N03AX19) carisbamate
carisbamate
(N03AX21) retigabine
retigabine
(N03AX22) perampanel
perampanel
(N03AX23) brivaracetam
brivaracetam
(N03AX25) cenobamate
cenobamate
(N03AX26) fenfluramine
fenfluramine
(N03AX27) ganaxolone
ganaxolone
(N03AX30) beclamide
beclamide
(N03AF04) eslicarbazepine
eslicarbazepine
(N05BA01) diazepam
diazepam
(N05BA06) lorazepam
lorazepam
(N05BA09) clobazam
clobazam
(N05CD08) midazolam
midazolam
Population studied

Short description of the study population

The source population comprises all persons from the 9 included data sources, BIFAP (ES), SIDIAP (ES), VID (ES), CPRD (UK), Finish registries (FI), EFEMERIS (FR), Norwegian registries (NO), PHARMO (NL), and Val Padana LHU (IT) between 01/01/2000 and latest availability. From the source population, we will select a study cohort for each of the different study sub-objectives, as below:
For the denominators of rates in sub-objective 1, we use a ‘base population cohort’ of all individuals of childbearing age from the included data sources. Here individuals must be at least 12 years old and have one year of available data (run-in period) in the data source. They will be followed up until the earliest of 56 years (for women only), death, moving out of database, last data available or last data extraction from data source.
For for numerators of rates in sub-objective 1, and the rest of outcome measures in sub-objective 2, we build an ‘ASM (new) user cohort’, which will be a sub-cohort from the base population cohort and comprises individuals therefrom who receive a new ASM prescription/dispensing. Patients will be followed from the start of an ASM prescription/dispensing, until the end of follow-up.
To address sub-objectives 3, 4 & 5, we will construct two cohorts. First, a ‘pregnancy cohort regardless of ASM’ will be built from the base population cohort by calculating start and end dates of pregnancies using the ConcePTION pregnancy algorithm.
Follow-up ends at the end date of the pregnancy, or the end of follow-up (as specified above), whichever is earliest.
Second, a 'pregnancy with ASM cohort' will be constructed from the pregnancies cohort with additional inclusion criteria of an ASM prescription/dispensing in 12 months prior to (3 months for THL and 2.5 months for EFEMERIS), or during pregnancy.
Follow-up starts here with the ASM prescription date, and ends at the end date of pregnancy, or end of follow-up (as specified above), whichever is earliest.
For the sub-objective 5, we use the same ‘pregnancy with ASM cohort' with additional inclusion criterion of availability of information on prescribed daily dose in the data sources.

Age groups

Adolescents (12 to < 18 years)
Adult and elderly population (≥18 years)
Adults (18 to < 65 years)
Adults (18 to < 46 years)
Adults (46 to < 65 years)
Elderly (≥ 65 years)
Adults (65 to < 75 years)
Adults (75 to < 85 years)
Adults (85 years and over)

Special population of interest

Pregnant women

Estimated number of subjects

63000000
Study design details

Study design

This will be a retrospective population-based cohort study.

Main study objective

The main objective of this study is to describe the utilisation of antiseizure medications and related drugs (i.e., antiepileptics (ATC codes N03A), gabapentinoids (N02BF), and all benzodiazepines with antiepileptic properties) in pregnant women, other women of childbearing potential (12-55 years of age), and men (12 years and older).

Setting

This study will be conducted using electronic health record data from 9 data sources in 7 countries in Europe comprising a total active population of 63 million persons.
This includes BIFAP (ES), SIDIAP (ES), VID (ES), CPRD (UK), Finish registries (FI), EFEMERIS (FR), Norwegian registries (NO), PHARMO (NL), and Val Padana LHU (IT).
The source population comprises all women of childbearing potential (12-55 years old) and men (≥12 years old). Data sources vary in the type of data banks that can be accessed.
Participation per sub-objective differs based on data availability for the specific objectives and the finite resources/timelines. Some Data Access Partners (DAPs) will re-use the data instance they use for ConcePTION (UiO, CHUT), whereas other DAPs re-extract and use the requested populations (THL, AEMPS, SIDIAP, FISABIO, UU, PHARMO, INSPIRE).
More than 5 countries (i.e., 7) can participate in each sub-objective and more than 2 DAPs (i.e., 6 as UU, THL, CHUT, UiO, PHARMO, INSPIRE) have data completeness for 15 years.

Comparators

NA

Outcomes

The drug utilisation outcome measures that are covered here are: incidence and prevalence of ASM use among in women of childbearing potential and in men; treatment duration, discontinuation, and treatment switches to other ASMs or alternative medications and polytherapy in women of childbearing potential and men; pre-pregnancy ASM use, and initiation and continuous use of ASMs during pregnancy period; pre-pregnancy, early and late discontinuation of ASMs, treatment switches to other ASMs or alternative medications and polytherapy among pregnant women; and dose changes of ASMs in women prior to and during pregnancy.

Data analysis plan

In sub-objective 1, the annual incidence and prevalence rates of ASM use will be calculated in the total population among both women and men of childbearing age overall (N03A), by subgroup, and by individual generic substance, for each DAP, and stratified by sex, age group, calendar year.
In sub-objective 2, the duration of ASM use in the ASM user’s cohort, annual discontinuation rates of ASMs, use of alternative medications in prevalent users of ASMs, and annual incidence of treatment switches from an ASMs to another ASM or to an alternative medication will be estimated, for each DAP, and stratified by sex, age group, indication, comorbidities, and calendar year.
In sub-objective 3, the annual rates of pre-pregnancy ASM use, initiation of ASMs during pregnancy, and continuous use of ASMs during pregnancy for individual drugs, subgroups, and overall group, will be assessed among pregnant women.
In sub-objective 4, the annual rates of pre-pregnancy discontinuation of ASMs, early and late discontinuation during pregnancy, polytherapy, and switching from an ASM to another ASM or to an alternative medication will be estimated among pregnant women in all data sources, and stratified by indication.
In sub-objective 5, to report dosage change patterns before and during pregnancy in those pregnant women who use ASMs around pregnancy (including continuous ASM users, and late discontinuers of ASMs), we will calculate the mean weighted daily doses of ASMs, stratified as low (<0.5 DDD), mid (0.5-1.49 DDD), and high (>1.5 DDD) for each individual, and then will investigate descriptively and visualise (in bar chart, or Sankey diagram) the proportion of each stratum of the mean weighted daily doses of ASMs around pregnancy (i.e., from 3-months before the pregnancy to first, second and third trimesters), per each data source.