Efficacy of Prophylactic Levetiracetam for Improving Functional Outcome in the Acute Phase of Intracerebral Haemorrhage: a Randomised, Double-blind, Placebo-controlled, Phase 3 Trial

Efficacy of Prophylactic Levetiracetam for Improving Functional Outcome in the Acute Phase of Intracerebral Haemorrhage: a Randomised, Double-blind, Placebo-controlled, Phase 3 Trial

Epileptic seizures are a common complication at the acute phase of intracerebral haemorrhage (ICH). The incidence of seizures occurring within 7 days reaches 40% when subclinical seizures are diagnosed by continuous electroencephalogram (EEG).

Some studies have suggested that early seizures are associated with haematoma expansion (Vespa., Neurology 2003), worse neurological outcomes (Gilmore., Stroke 2016) or increased mortality. By contrast, other studies have shown no association of acute seizures with long-term mortality and outcome. However, the interpretation of these works is subject to bias because almost all studies were based on clinical detection of seizures only, while it has been shown that most early seizures after ICH are clinically unrecognised and can only be diagnosed with EEG monitoring.

The PEACH trial, a double-blind, randomised, placebo-controlled, showed that clinical and/or electrographic seizures occur in more than 40% of patients with ICH and that Levetiracetam (LVT) is safe and effective in preventing these seizures. However, it remains unclear whether preventing acute seizures might lead to improved functional outcomes after ICH. An adequately powered randomised controlled trial is needed to answer whether primary seizure prophylaxis improves functional outcome in this setting. Answering this question would result in an important change in ICH acute care guidelines, which currently do not recommend primary prophylactic antiseizure treatment. As compared to research in acute ischemic stroke management, fewer clinical trials have been conducted in acute ICH and no effective medical treatments are available in this subset of patients.

The main objective of PEACH 2 is to establish if prophylactic antiseizure therapy with LVT improves functional outcome in adults with acute spontaneous ICH. Functional outcome assessed by the modified Rankin score (mRS score) six months after acute ICH will be compared between patients receiving prophylactic antiseizure therapy with levetiracetam and patients receiving placebo.

The secondary objectives are to examine the effect of prophylactic antiseizure therapy with levetiracetam versus placebo on:

• the number of early and late clinical seizures, on the short term and long term evolution of the neurologic deficit as assessed by the NIHSS, on long term functional outcome (12 months) as assessed by the mRS, on quality of life and cognitive impairment, and on haematoma expansion and mass effect on control brain imaging

• the frequency of side effects at 1 and 6 months, pneumonia at 1 month, delirium at 1 month, irritability/aggressivity, anxiety and depression at 1 and 6 months, and all-cause mortality at 1, 6 and 12 months.

  580 patients will be recruited over 3 years.

Inclusion Criteria:

• Age ≥ 18 years
• Spontaneous (non-traumatic) supratentorial intracerebral haemorrhage diagnosed by brain CT or MRI
• Onset of neurologic symptoms within 24 hours
• NIHSS score on admission ≤ 25
• Informed consent given by the patient or his/her impartial witness
• Patients benefiting from a social insurance system or a similar system
• For women of childbearing age, use of highly effective contraceptive method, which will be continued until the end of relevant systemic exposure of the treatment (i.e 56 hours after end of treatment).

Exclusion Criteria:

• Intracerebral haemorrhage known or suspected by study investigator to be secondary to trauma, vascular malformation, haemorrhagic transformation of ischaemic stroke, or tumour
• Current use of antiseizure drugs or history of epilepsy
• Patients with inaugural seizures at the onset of symptoms associated with intracerebral hemorrhage
• Patients with QTc prolongation
• Patients who have been part of a clinical study involving another investigational product in the previous 30 days or within 5 half-lives of the other investigational product prior to Screening, whichever is longer, or participant is currently receiving an investigational product
• Severe renal insufficiency (creatinine clearance < 30 ml/min)
• Pregnancy or breastfeeding
• Previous history of severe depression or psychotic disorder or suicidal attempt
• Known terminal illness
• Known allergy or hypersensitivity to levetiracetam or other pyrrolidone derivatives, or any of the excipients
• Known allergy or hypersensitivity to microcrystalline cellulose or lactose
• Patients taking probenecid, methotrexate or macrogol
• Being under legal protection
• Patients with seizures occurring between the inclusion of the patient and the start of the treatment
• Positive pregnancy test at inclusion for women of childbearing age