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

Обзор

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, 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.

Вмешательства

• Препарат Treatment administration (Levetiracetam or placebo)
  Treatment should be initiated within 24 hours of randomisation. It will be administered intravenously for at least 48 hours and then the route of administration will be changed to oral administration at the same dosage after assessment of swallowing function. The treatment period will be 30 days at full dose, followed by a gradual tapering over 2 weeks.
• Лучевая терапия Neuroimaging
  Neuroimaging (brain CT or MRI) will be performed 72h post inclusion
• Диагностический тест National Institute of Health Stroke Scale (NIHSS)
  NIHSS, a clinician -reported 11-items stroke-specific severity scale, will be administered by a neurologist during all patients' study visits except at visits 1 month and 12 months.
• Поведенческое Modified Rankin Scale (mRS)
  This questionnaire will be administered 3 time, at inclusion, 6 months and 12 months to measure post-stroke functional status and disability
• Поведенческое Euroqol test (EQ-5D-5L)
  This self-reported questionnaire will be completed by patients at 6 and 12 months, to assess the multidimensional chronic consequences of stroke on their daily lives
• Поведенческое Montreal Cognitive Assessment (MoCA)
  This test will be administered by a neurologist at 6 months to assess patients' cognitive impairment
• Поведенческое Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)
  This self-reported questionnaire will be completed by patients at 6 months, to assess patient's cognitive function (memory, attention, concentration, language, and thinking abilities)
• Поведенческое Hospital Anxiety and Depression Scale (HADS)
  This questionnaire will be administered at 6 months to evaluate patients' anxiety and depression

Первичные конечные точки

• modified Rankin Scale (mRS) score to measure the functional status (death or dependency). [Срок оценки: 6 months after inclusion]

Вторичные конечные точки (12)

• Number of clinical seizures [Срок оценки: within 72 hours after inclusion]
• Number of clinical seizures [Срок оценки: at 1 month after inclusion]
• Number of clinical seizures [Срок оценки: at 6 months after inclusion]
• Number of clinical seizures [Срок оценки: at 12 months after inclusion]
• Change in National Institute of Health Stroke Scale (NIHSS, 11 items version) score between inclusion and 72 h, and 6 months. [Срок оценки: At inclusion]
• Change in National Institute of Health Stroke Scale (NIHSS, 11 items version) score between inclusion and 72 h, and 6 months. [Срок оценки: At 72 hours]
• Change in National Institute of Health Stroke Scale (NIHSS, 11 items version) score between inclusion and 72 h, and 6 months. [Срок оценки: At 6 months after inclusion]
• Change in modified Rankin Scale (mRS) score between inclusion and 6 months and 12 months [Срок оценки: At inclusion]
• Change in modified Rankin Scale (mRS) score between inclusion and 6 months and 12 months [Срок оценки: At 6 months after inclusion]
• Change in modified Rankin Scale (mRS) score between inclusion and 6 months and 12 months [Срок оценки: At 12 months after inclusion]
• Score at the Euroqol (EQ-5D-5L) to assess quality of life. [Срок оценки: At 6 months]
• Score at the Euroqol (EQ-5D-5L) to assess quality of life. [Срок оценки: At 12 months after inclusion]

Критерии участия

Критерии включения

• 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 legal representative
• Patients benefiting from a social insurance system or a similar system

Критерии исключения

• 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
• Severe renal insufficiency (creatinine clearance < 30 ml/min)
• Pregnancy or breastfeeding
• Previous history of severe depression or psychotic disorder
• Known terminal illness
• Known allergy or hypersensitivity to levetiracetam
• Known allergy or hypersensitivity to microcrystalline cellulose or lactose
• Being under legal protection

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• Hospices Civils de Lyon — Bron

Идентификаторы

NCT: NCT07336992 · 69HCL23_0934

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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