Efficacy of Prophylactic Levetiracetam for Improving Functional Outcome in the Acute Phase of Intracerebral Haemorrhage: a Randomised, Double-blind, Placebo-controlled, Phase 3 Trial
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 580
- 试验地点
- 1
- 主要终点
- modified Rankin Scale (mRS) score to measure the functional status (death or dependency).
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
This is a double-blind trial. Patients and all those involved in patient management or clinical or imaging assessment of adverse events or outcomes will be masked to treatment allocation. The investigational drug will be distributed to participating centres in externally indistinguishable sealed treatment kits. Preparations of levetiracetam and placebo will be matched to ensure masking of participants and investigators, with vials, capsules, packaging, and labelling all identical in appearance.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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
研究组 & 干预措施
Intervention Group
290 patients will be recruited over 3 years in the intervention group.
In this group, Levetiracetam should be initiated within 24 hours of randomisation. Levetiracetam (500 mg every 12 hours) 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 (250 mg of levetiracetam every 12 hours for 7 days, followed by 250 mg of levetiracetam every 24 h for 7 days).
干预措施: Modified Rankin Scale (mRS) (Behavioral)
Intervention Group
290 patients will be recruited over 3 years in the intervention group.
In this group, Levetiracetam should be initiated within 24 hours of randomisation. Levetiracetam (500 mg every 12 hours) 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 (250 mg of levetiracetam every 12 hours for 7 days, followed by 250 mg of levetiracetam every 24 h for 7 days).
干预措施: Hospital Anxiety and Depression Scale (HADS) (Behavioral)
Control Group
290 patients will be recruited over 3 years in the control group.
In this group, the placebo (microcrystalline cellulose) should be initiated within 24 hours of randomisation. The placebo (500 mg every 12 hours) 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 (250 mg of placebo every 12 hours for 7 days, followed by 250 mg of placebo every 24 h for 7 days).
干预措施: Euroqol test (EQ-5D-5L) (Behavioral)
Intervention Group
290 patients will be recruited over 3 years in the intervention group.
In this group, Levetiracetam should be initiated within 24 hours of randomisation. Levetiracetam (500 mg every 12 hours) 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 (250 mg of levetiracetam every 12 hours for 7 days, followed by 250 mg of levetiracetam every 24 h for 7 days).
干预措施: Treatment administration (Levetiracetam or placebo) (Drug)
Intervention Group
290 patients will be recruited over 3 years in the intervention group.
In this group, Levetiracetam should be initiated within 24 hours of randomisation. Levetiracetam (500 mg every 12 hours) 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 (250 mg of levetiracetam every 12 hours for 7 days, followed by 250 mg of levetiracetam every 24 h for 7 days).
干预措施: National Institute of Health Stroke Scale (NIHSS) (Diagnostic Test)
Intervention Group
290 patients will be recruited over 3 years in the intervention group.
In this group, Levetiracetam should be initiated within 24 hours of randomisation. Levetiracetam (500 mg every 12 hours) 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 (250 mg of levetiracetam every 12 hours for 7 days, followed by 250 mg of levetiracetam every 24 h for 7 days).
干预措施: Euroqol test (EQ-5D-5L) (Behavioral)
Intervention Group
290 patients will be recruited over 3 years in the intervention group.
In this group, Levetiracetam should be initiated within 24 hours of randomisation. Levetiracetam (500 mg every 12 hours) 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 (250 mg of levetiracetam every 12 hours for 7 days, followed by 250 mg of levetiracetam every 24 h for 7 days).
干预措施: Montreal Cognitive Assessment (MoCA) (Behavioral)
Intervention Group
290 patients will be recruited over 3 years in the intervention group.
In this group, Levetiracetam should be initiated within 24 hours of randomisation. Levetiracetam (500 mg every 12 hours) 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 (250 mg of levetiracetam every 12 hours for 7 days, followed by 250 mg of levetiracetam every 24 h for 7 days).
干预措施: Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) (Behavioral)
Control Group
290 patients will be recruited over 3 years in the control group.
In this group, the placebo (microcrystalline cellulose) should be initiated within 24 hours of randomisation. The placebo (500 mg every 12 hours) 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 (250 mg of placebo every 12 hours for 7 days, followed by 250 mg of placebo every 24 h for 7 days).
干预措施: Treatment administration (Levetiracetam or placebo) (Drug)
Control Group
290 patients will be recruited over 3 years in the control group.
In this group, the placebo (microcrystalline cellulose) should be initiated within 24 hours of randomisation. The placebo (500 mg every 12 hours) 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 (250 mg of placebo every 12 hours for 7 days, followed by 250 mg of placebo every 24 h for 7 days).
干预措施: National Institute of Health Stroke Scale (NIHSS) (Diagnostic Test)
Control Group
290 patients will be recruited over 3 years in the control group.
In this group, the placebo (microcrystalline cellulose) should be initiated within 24 hours of randomisation. The placebo (500 mg every 12 hours) 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 (250 mg of placebo every 12 hours for 7 days, followed by 250 mg of placebo every 24 h for 7 days).
干预措施: Modified Rankin Scale (mRS) (Behavioral)
Control Group
290 patients will be recruited over 3 years in the control group.
In this group, the placebo (microcrystalline cellulose) should be initiated within 24 hours of randomisation. The placebo (500 mg every 12 hours) 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 (250 mg of placebo every 12 hours for 7 days, followed by 250 mg of placebo every 24 h for 7 days).
干预措施: Montreal Cognitive Assessment (MoCA) (Behavioral)
Control Group
290 patients will be recruited over 3 years in the control group.
In this group, the placebo (microcrystalline cellulose) should be initiated within 24 hours of randomisation. The placebo (500 mg every 12 hours) 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 (250 mg of placebo every 12 hours for 7 days, followed by 250 mg of placebo every 24 h for 7 days).
干预措施: Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) (Behavioral)
Control Group
290 patients will be recruited over 3 years in the control group.
In this group, the placebo (microcrystalline cellulose) should be initiated within 24 hours of randomisation. The placebo (500 mg every 12 hours) 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 (250 mg of placebo every 12 hours for 7 days, followed by 250 mg of placebo every 24 h for 7 days).
干预措施: Hospital Anxiety and Depression Scale (HADS) (Behavioral)
Intervention Group
290 patients will be recruited over 3 years in the intervention group.
In this group, Levetiracetam should be initiated within 24 hours of randomisation. Levetiracetam (500 mg every 12 hours) 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 (250 mg of levetiracetam every 12 hours for 7 days, followed by 250 mg of levetiracetam every 24 h for 7 days).
干预措施: Neuroimaging (Radiation)
Control Group
290 patients will be recruited over 3 years in the control group.
In this group, the placebo (microcrystalline cellulose) should be initiated within 24 hours of randomisation. The placebo (500 mg every 12 hours) 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 (250 mg of placebo every 12 hours for 7 days, followed by 250 mg of placebo every 24 h for 7 days).
干预措施: Neuroimaging (Radiation)
结局指标
主要结局
modified Rankin Scale (mRS) score to measure the functional status (death or dependency).
时间窗: 6 and 12 months after inclusion
The mRS score will be measured by a certified neurologist, blinded to the patient study group. It categorises disability with reference to pre-stroke activities. mRS is a single-item scale ranging from 0 (no disability) to 5 (severe disability) and 6 (death). Its analysis will be performed by an ordinal logistic regression model with proportional odds and mixed effects. The treatment arm will be introduced in the model as fixed effect and the NIHSS score (≤ 15 vs \>15) will be taken into account as a fixed effect. It will also take into account, as random effect, a random intercept by centre.
modified Rankin Scale (mRS) score to measure the functional status (death or dependency).
时间窗: 6 months after inclusion
The mRS score will be measured by a certified neurologist, blinded to the patient study group. It categorises disability with reference to pre-stroke activities. mRS is a single-item scale ranging from 0 (no disability) to 5 (severe disability) and 6 (death). Its analysis will be performed by an ordinal logistic regression model with proportional odds and mixed effects. The treatment arm will be introduced in the model as fixed effect and the NIHSS score (≤ 15 vs \>15) will be taken into account as a fixed effect. It will also take into account, as random effect, a random intercept by centre.
次要结局
- Change in intracerebral haemorrhage volume (ml)(72 hours after inclusion)
- Score at the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog)(At 1 month after inclusion)
- Frequency of irritability/aggressivity(At 6 months after inclusion)
- Frequency of irritability/aggressivity(At 1 months after inclusion)
- Number of clinical seizures(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.(At 6 months after inclusion)
- Change in modified Rankin Scale (mRS) score between inclusion and 6 months and 12 months(At 12 months after inclusion)
- Score at the Euroqol (EQ-5D-5L) to assess quality of life.(At 12 months after inclusion)
- Score at the Montreal Cognitive Assessment (MoCA) version 8.3 to assess cognitive impairment.(6 months after inclusion)
- Change in intracerebral haemorrhage volume (cc)(72 hours after inclusion)
- Frequency of pneumonia(1 month after inclusion)
- Frequency of side effects related to treatment(6 months after inclusion)
- Frequency of delirium(1 month after inclusion)
- Score at the Hospital Anxiety and Depression Scale (HADS) to assess anxiety and depression(At 6 months after inclusion)
- Death rate(At 12 months after inclusion)
- Score at the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog)(At 6 months after inclusion)
- Number of clinical seizures(within 72 hours after inclusion)
- Number of clinical seizures(at 1 month after inclusion)
- Number of clinical seizures(at 6 months after inclusion)
- Change in National Institute of Health Stroke Scale (NIHSS, 11 items version) score between inclusion and 72 h, and 6 months.(At inclusion)
- Change in National Institute of Health Stroke Scale (NIHSS, 11 items version) score between inclusion and 72 h, and 6 months.(At 72 hours)
- Change in modified Rankin Scale (mRS) score between inclusion and 6 months and 12 months(At inclusion)
- Change in modified Rankin Scale (mRS) score between inclusion and 6 months and 12 months(At 6 months after inclusion)
- Score at the Euroqol (EQ-5D-5L) to assess quality of life.(At 6 months)
- Frequency of side effects related to treatment(1 month after inclusion)
- Death rate(At 1 month after inclusion)
- Death rate(At 6 months after inclusion)