Efficacy of prophylactic levetiracetam on functional outcomes in patients with acute intracerebral haemorrhage: a phase 3, randomised, double-blind, placebo-controlled trial

The primary objective is to evaluate whether prophylactic administration of an antiseizure drug improves functional outcome at 6 months in patients presenting with intracerebral haemorrhage. 5

Secondary objectives include the assessment of the following:

• The impact of prophylactic levetiracetam on the incidence of early and late clinical seizures, the evolution of neurologic deficit, quality of life, cognitive impairments, and functional outcome at 12 months.
• The effect on haematoma expansion and mass effect as observed on control brain imaging.
• The evaluation of safety markers, including the frequency of side effects, pneumonia, delirium, anxiety, depression, and mortality.

The sponsor did not provide the total number of participants for this study. The study population consists of patients, including both males and females, within the age ranges of 18-44 and 45-64 years. Eligible subjects must have experienced a spontaneous, non-traumatic supratentorial intracerebral haemorrhage confirmed by computed tomography or magnetic resonance imaging. Inclusion requires the onset of neurologic symptoms within 24 hours and an admission National Institutes of Health Stroke Scale score of 25 or less. Participants must be covered by a social insurance system or similar coverage.

This phase 3, randomised, double-blind, placebo-controlled trial evaluates the efficacy of prophylactic levetiracetam for improving functional outcomes in patients experiencing intracerebral haemorrhage. Following an initial screening to confirm eligibility based on spontaneous supratentorial haemorrhage diagnosis via CT or MRI, an NIHSS score ≤ 25, and symptom onset within 24 hours, participants are assigned to receive either the test product or a placebo. The primary endpoint is the functional status at 6 months, assessed using the modified Rankin Scale. Secondary outcomes include the frequency of clinical seizures, changes in stroke scale scores, cognitive impairment, quality of life, and all-cause mortality. Study visits include the inclusion phase, assessments at 72 hours, and follow-up evaluations at 1, 6, and 12 months to monitor clinical status and side effects. The total duration of participant involvement extends to 12 months, although the trial recruitment period is estimated to occur between 2026 and 2030.

The experimental treatment consists of levetiracetam administered in two pharmaceutical forms. The first form is film-coated tablets of 250 mg, which are intended for oral use at a dosage of 36 mg. The second form is a solution for infusion with a concentration of 100 mg/ml, administered via intravenous administration at a dosage of 100 mg/ml.

The control group receives a placebo to maintain the double-blind design of the study. The placebo administration includes a 125 mg formulation and a 100 mg/ml formulation to correspond with the experimental arms.

The primary efficacy endpoint is functional status, defined as death or dependency, assessed at 6 months. This will be measured using the modified Rankin Scale (mRS) via a standardized guided interview conducted by a certified stroke neurologist or a certified clinical research associate during a face-to-face or remote follow-up visit. Data analysis will utilize ordinal logistic regression, adjusted for the stratification criterion.

Secondary endpoints include the following parameters and assessments:

• The number of clinical seizures within 72 hours and at 1, 6, and 12 months.
• Changes in the National Institute of Health Stroke Scale (NIHSS) score between inclusion and 72 hours and 6 months.
• Cognitive impairment at 6 months as assessed by the Montreal Cognitive Assessment (MoCA) version 8.3.
• Cognitive complaint at 6 months evaluated using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) version 3.
• Quality of life at 6 and 12 months measured by the EuroQol - 5D-5L (EQ-5D-5L).
• The mRS score at 12 months.
• Changes in intracerebral haemorrhage volume and mass effect, defined as midline shift, via control brain imaging at 72 hours.
• Frequency of treatment-related side effects at 1 and 6 months.
• Frequency of pneumonia and delirium at 1 month.
• Anxiety and depression at 1 and 6 months evaluated with the Hospital Anxiety and Depression Scale (HADS).
• All-cause mortality at 1, 6, and 12 months.