Clinical trial NCT03940326
Conditions: Epilepsy, Idiopathic Generalized
Sponsor: Mazandaran University of Medical Sciences
Start date: 2018-04-01; Completion date: 2019-12-01
Enrollment: 103 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is an open-label, active-controlled,non-inferiority trial comparing efficacy and safety of levetiracetam versus valproate in idiopathic generalized tonic-clonic epilepsy.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Levetiracetam intervention 2: Valproate
Intervention descriptions: intervention 1: Levetiracetam with initial dose of 500 mg per 12 hours which will be increased 500 mg/week to target dose of 2000 mg/day and the dose could be increased to 3000 mg/day if seizures recurred intervention 2: Sodium valproate with initial dose of 500 mg/day which will be increased 500 mg/week to target dose of 1500 mg/day and the dose could be increased to 2000 mg/d if seizures recurred.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Levetiracetam Versus Valproate in Idiopathic 
Generalized Tonic-clonic Seizures 
 
ID: NCT03940326 
 
 
 
 
 
 
 
 
 
 
 
 
 
        8.11.2020


Study protocol 
This study was a non-randomized open label active-controlled clinical trial with a 
two-parallel-group design aimed to compare efficacy of levetiracetam (LEV) with 
valproate (VPA) for treatment of patients with idiopathic (genetic) generalized 
epilepsy. Patients aged ≥16 years with diagnosis of genetic generalized tonic-clonic 
seizures only (GTCS) or juvenile myoclonic epilepsy (JME) who were referred to 
our tertiary University hospital and epilepsy clinic were included. Normal brain 
magnetic resonance imaging (MRI), lack of focal epileptic discharges with or 
without generalized epileptiform discharges in electroencephalography (EEG) and 
seizure symptomatology in favor of GTCS or JME were mandatory. Patients with 
history of hepatic, renal and hematologic disorders, known psychosis, psychogenic 
non-epileptic seizure, status epilepticus and illegal drug abuse, patients who had 
been treated with LEV or VPA in the last 6 months and those with poor adherence 
to medications or plan for pregnancy were excluded. The study was approved by 
University ethics committee and performed in accordance with the International 
Conference on Harmonization Good Clinical Practice guidelines and the Declaration 
of Helsinki. All patients provided written informed consent before participation. 
Patients were treated by LEV or VPA. LEV was started with 500 mg/day (twice 
daily as equal doses) and the dose was increases by 500 mg/week to a total dose of 
2000 mg/day if needed. Starting dose for VPA was 500 mg/day with 500 mg/week 
increase to the maximum dose of 1500 mg/day in two divided doses based on 
clinician’s decision. Patients, who experienced adverse events (AEs) during titration 
which could be ameliorated by dose reduction, were reverted to previous acceptable 
dose. If one episode of seizure occurred, doses were increased to maximum 3000 
mg/ day for LEV and 2000 mg/day for VPA with the same titration protocol, 
according to clinician’s judgment. Evaluations have scheduled at weeks 4, 12 and 
26 after initiation of treatment. In each visit by neurologist, adherence to AED, 
seizure recurrence and AEs were assessed. The primary outcomes were time to first 
seizure and seizure freedom rate at 6 months after start of treatment. The secondary 
outcomes were defined as time to withdrawal and withdrawal rate at 6th month and 
also severity of adverse events. Withdrawal rate was calculated based on 
discontinuation of monotherapy with each medication due to AEs, lack of efficacy 
and need to drug switch or combination therapy. 
 
 


Statistical analysis 
SPSS version 19 software (SPSS Inc.) was used for statistical analysis. Chi‐square 
test or Fisher's exact test were used to compare categorical variables between groups. 
Numerical variables were analyzed with student’s t-test or Mann-Whitney test, 
according to distribution. Time to first seizure and time to withdrawal were analyzed 
using the Kaplan–Meier survival curves. For analysis of time to first seizure, patients 
who did not experience any seizure during the first 26 weeks of treatment were 
censored at the end of 26 weeks. For analysis of time to withdrawal, patients who 
discontinue medication before 26 weeks were considered to have the event. Cox’s 
regression model was used to investigate time to withdrawal and time to first seizure. 
A Hazard ratio (HR) of less than 1 was considered in favor of LEV. P-value of less 
than 0.05 was considered statistically significant.