Isosorbide Mononitrate and Butylphthalide to Reduce the Risk of Disability in Patients With Acute Lacunar Stroke: a 2×2 Factorial Randomized Controlled Trial (IMPACT)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 3,156
- 主要终点
- Proportion of participants with post-stroke disability at 6 months
研究概览
简要总结
The goal of this multicenter, double-blind, 2×2 factorial randomized controlled trial is to evaluate the efficacy and safety of isosorbide mononitrate, butylphthalide, and their combination in reducing disability in patients with acute lacunar stroke.
详细描述
There is an urgent need for effective therapeutic strategies for acute ischemic cerebral small vessel disease (CSVD). Isosorbide mononitrate and butylphthalide may exert protective effects; however, large-scale randomized controlled trials are required to confirm their efficacy and safety and to guide clinical practice.
In this study, patients presenting with a clinical lacunar syndrome within 7 days of onset will be randomly assigned, in a 1:1:1:1 ratio, to one of four groups in addition to routine care: (1) isosorbide mononitrate plus butylphthalide, (2) isosorbide mononitrate plus butylphthalide placebo, (3) isosorbide mononitrate placebo plus butylphthalide, or (4) isosorbide mononitrate placebo plus butylphthalide placebo. The treatment period will last 6 months, with a total follow-up of 1 year, including assessments at 7 days, 1 month, 3 months, 6 months, and 1 year.
The primary efficacy outcome is post-stroke disability at 6 months. The primary safety outcome is moderate or more severe headache within 6 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 30 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 30 years;
- •Clinical lacunar syndrome within 7 days;
- •Brain CT/MRI after symptom onset:
- •a relevant (in time and location) acute lacunar infarct;
- •if no relevant lesion, symptom duration >24 hours, with no other suspected stroke etiologies (such as cerebral hemorrhage, cortical infarction, seizures, etc.)
- •MoCA score meeting the following criteria:
- •MoCA ≥ 13 if educated ≤ 6 years;
- •MoCA ≥ 15 if 7 ≤ educated ≤ 12 years;
- •MoCA ≥ 18 if educated ≥ 13 years；
- •mRS ≤ 1 prior to this episode;
- •Patient or a legally authorized representative signed informed consent.
排除标准
- •Ischemic stroke of large artery atherosclerosis, cardioembolism, or other etiologies (TOAST classification);
- •Diagnosed or suspected hereditary CSVD;
- •Intracerebral hemorrhage within the past 3 months including parenchymal, intraventricular, subarachnoid hemorrhage, subdural/epidural hematoma;
- •Neurodegenerative diseases or systemic diseases that may lead to cognitive impairment, such as Alzheimer's disease, mixed dementia, Parkinson's disease, systemic autoimmune diseases, hepatic encephalopathy, or uremic encephalopathy.
- •Previously diagnosed psychiatric disorders (DSM-5 criteria).
- •Other active neurological disorders (e.g., recurrent seizures, brain tumors, vascular malformations, untreated aneurysms >3 mm).
- •Hypotension (seated systolic blood pressure <100 mmHg), bradycardia (heart rate <60 bpm), sick sinus syndrome or severe cardiopulmonary disease.
- •History of congestive heart failure, acute myocardial infarction or other severe cardiac dysfunctions (NYHA Class III-IV).
- •Coagulation disorders, bleeding tendency or systemic bleeding, including but not limited to prothrombin time >3×upper limit of normal (ULN), platelet count <50×109/L, hemophilia, capillary fragility, gastrointestinal bleeding, urinary tract bleeding, hemoptysis, or vitreous hemorrhage, etc.
- •Severe hepatic or renal insufficiency (note: severe hepatic insufficiency is defined as ALT or AST > 3×ULN or acute hepatitis, chronic active hepatitis, cirrhosis; severe renal insufficiency is defined as eGFR < 45 ml/min/1.73m², creatinine clearance < 40 ml/min, or known chronic kidney disease of stage 3 or higher).
- •Head trauma, intracranial or spinal surgery, major surgical procedures or severe trauma within the past 4 weeks.
- •ISMN or NBP use within the past 3 days.
- •Have contraindications to ISMN or NBP, or allergy to their components.
- •Have to use the contraindicated drugs of this trial for a long time.
- •Pregnant, breastfeeding or planning to pregnant during this study.
- •Unable to tolerate MRI or with MRI contraindications.
- •Have severe diseases or expected survival <12 months.
- •Participate in other clinical trials within 30 days before this trial.
- •Unlikely to comply with study procedures and follow-up procedures for whatever reason in the opinion of the research physician.
研究组 & 干预措施
isosorbide mononitrate plus butylphthalide
干预措施: Isosorbide Mononitrate (Drug)
isosorbide mononitrate plus butylphthalide
干预措施: Butylphthalide (Drug)
isosorbide mononitrate plus butylphthalide placebo
干预措施: Isosorbide Mononitrate (Drug)
isosorbide mononitrate plus butylphthalide placebo
干预措施: Butylphthalide Placebo (Drug)
isosorbide mononitrate placebo plus butylphthalide
干预措施: Butylphthalide (Drug)
isosorbide mononitrate placebo plus butylphthalide
干预措施: Isosorbide Mononitrate Placebo (Drug)
isosorbide mononitrate placebo plus butylphthalide placebo
干预措施: Isosorbide Mononitrate Placebo (Drug)
isosorbide mononitrate placebo plus butylphthalide placebo
干预措施: Butylphthalide Placebo (Drug)
结局指标
主要结局
Proportion of participants with post-stroke disability at 6 months
时间窗: 6 months
A composite endpoint defined as the occurrence of any of the following: modified Rankin Scale (mRS) score ≥ 3, major adverse cardiovascular events (MACE), cognitive impairment, or all-cause mortality. The mRS measures post-stroke functional outcome on a scale from 0 (no symptoms) to 6 (death). MACE includes non-fatal stroke, non-fatal myocardial infarction (MI), and vascular death.The assessment of cognitive function involves three stages: a cognitive screening test, supplementary cognitive testing, and adjudication by an expert panel. The Beijing version of the Montreal Cognitive Assessment (MoCA) is used as the cognitive screening scale. Scores on the MoCA range from 0 to 30, with lower scores indicating greater cognitive impairment.The supplementary cognitive assessment includes the evaluation of several domains: executive function, attention and processing speed, language, and memory, as well as activities of daily living.
Incidence of moderate or more severe headache within 6 months
时间窗: 6 months
Headache severity is assessed using the Numerical Rating Scale (NRS), where: 0 indicates no pain; 1 represents a mild headache (including feelings of head pressure or throbbing that are not considered painful); a score of 4 or higher (≥4) represents a headache of at least moderate intensity; and 10 represents the worst headache imaginable to the subject.
次要结局
- Proportion of participants with post-stroke disability at 1 year(1 year)
- Proportion of participants with the modified Rankin Scale (mRS) score ≥ 3 at 6 months and 1 year(6 months and 1 year)
- Incidence of recurrent stroke within 6 months and 1 year(6 months and 1 year)
- Proportion of participants with dementia at 6 months and 1 year(6 months and 1 year)
- National Institutes of Health Stroke Scale (NIHSS) scores at 7 days, 6 months, and 1 year (including changes from baseline)(baseline, 7 days, 6 months, and 1 year)
- Incidence of hypotension within 6 months(6 months)
- Incidence of syncope within 6 months(6 months)
- Incidence of liver function impairment within 6 months(6 months)
- Incidence of any bleeding within 6 months(6 months)
- Incidence of symptomatic intracranial hemorrhage within 6 months(6 months)
研究者
yilong Wang
Professor
Beijing Tiantan Hospital