A randomised double blind study of prophylactic leviteracetam for the prevention of post stroke seizures

Stroke is a common cause of disability and death worldwide. Seizures following stroke is a major cause for hospitalisations, emergency care and morbidity and is estimated to occur in 10% of stroke patients. Several clinicians prescribe antiepileptics prophylactically in stroke patients in the hope of reducing incidence of post stroke seizures. However this practice is not backed by robust evidence. A recent Cochrane review on this issue concluded that there is insufficient evidence at present to recommend this practice. We aim to determine whether administration of prophylactic antiepileptics (Leviterecetam) in the immediate post stroke period would reduce the incidence of seizures. We propose to conduct a randomised double blind placebo controlled trial to address this question. Consecutive patients diagnosed with arterial or venous cortical stroke would be included in the study if they fulfil inclusion criteria (diagnosis supported by imaging and/or clinical evidence of cortical involvement). They will be randomized to receive tablet Leviterecetam or placebo for a period of 1 month using a computer-generated blocked randomization sequence with a block size of 4.  All participants in both groups will receive standard treatment. The first-time follow-up will be conducted at seven days post randomization, thereafter 3, 6 and 12 months. Occurrence of first late epileptic seizure, defined as an unprovoked epileptic seizure more than one week after arterial stroke or two weeks after ICVT will be the primary outcome. Time from stroke to occurrence  of a late epileptic seizure, occurrence of early epileptic seizures after stroke, seizure severity, neurological function, quality of life, midline shift, enlargement of hematoma, death (all cause), functional outcome assessed by Glasgow Outcome Scale and modified Rankin Scale and the occurrence of side effects of the trial medication would include secondary outcome measures. A subgroup of our stroke patients are likely to present with seizures.  This ‘presenting with seizure’ group will be randomized into two interventions – 1 week leviteracetam and 3 months leviteracetam. In this study, we also study the adverse effects that might include gastrointestinal disorder (nausea, abdominal pain, and diarrhea), hematological disorder (thrombocytopenia and bone marrow suppression), nervous system disorder (agitation,mood changes, confusion), and skin and subcutaneous tissue abnormalities (erythema multiforme, rash, toxic epidermal necrolysis, and Steven–Johnson syndrome). Severe adverse effect (SAE) is defined as death, stroke of all cause, and vegetative state. The primary analysis will be Leviteracetam for prevention of the primary end-point following the ‘intention to treat’ principle. Analyses of primary and secondary end-points, comparing time to event in the two arms, will be performed using the log rank method. Cox regression will also be carried out. All significance tests will be two sided. Preplanned sub-group analysis will be performed for the following sub-groups: with or without surgical treatment; location of the lesion (cortical or deep); age (≥70); severity of the disease (GCS); and hemorrhage etiology (hypertension, vascular malformations, coagulopathy, and other). Informed consent will be taken from all the participants. The pharmaceutical company providing the drug and placebo will have no role in data management.  The confidentiality will be strictly maintained. Data management and safety will be monitored by an independent board and findings of the study would be submitted to the Institute Ethics Committee; research would be disseminated through publication in a peer reviewed indexed journal.