Isosorbide Mononitrate and Butylphthalide to Reduce the Risk of Disability in Patients With Acute Lacunar Stroke (IMPACT)

Official title

Isosorbide Mononitrate and Butylphthalide to Reduce the Risk of Disability in Patients With Acute Lacunar Stroke: a 2×2 Factorial Randomized Controlled Trial (IMPACT)

Overview

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.

Detailed description

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.

Interventions

• Drug Isosorbide Mononitrate
  Days 1-7: Isosorbide mononitrate injection, 20 mg once daily by intravenous infusion. Days 8-6 months: Isosorbide mononitrate sustained-release tablets, 40 mg once daily orally (dose reduced to 20 mg once daily during the final week).
• Drug Butylphthalide
  Days 1-7: Butylphthalide injection, 25 mg twice daily by intravenous infusion. Days 8-6 months: Butylphthalide soft capsules, 200 mg three times daily orally.
• Drug Isosorbide Mononitrate Placebo
  Days 1-7: Isosorbide mononitrate injection placebo, once daily by intravenous infusion. Days 8-6 months: Isosorbide mononitrate sustained-release tablet placebo, once daily orally (dose reduced to half a tablet once daily during the final week).
• Drug Butylphthalide Placebo
  Days 1-7: Butylphthalide injection placebo, twice daily by intravenous infusion. Days 8-6 months: Butylphthalide soft capsule placebo, 2 capsules three times daily orally.

Primary outcome measures

• Proportion of participants with post-stroke disability at 6 months [Time frame: 6 months]
• Incidence of moderate or more severe headache within 6 months [Time frame: 6 months]

Secondary outcome measures (10)

• Proportion of participants with post-stroke disability at 1 year [Time frame: 1 year]
• Proportion of participants with the modified Rankin Scale (mRS) score ≥ 3 at 6 months and 1 year [Time frame: 6 months and 1 year]
• Incidence of recurrent stroke within 6 months and 1 year [Time frame: 6 months and 1 year]
• Proportion of participants with dementia at 6 months and 1 year [Time frame: 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) [Time frame: baseline, 7 days, 6 months, and 1 year]
• Incidence of hypotension within 6 months [Time frame: 6 months]
• Incidence of syncope within 6 months [Time frame: 6 months]
• Incidence of liver function impairment within 6 months [Time frame: 6 months]
• Incidence of any bleeding within 6 months [Time frame: 6 months]
• Incidence of symptomatic intracranial hemorrhage within 6 months [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07252544 · 2023ZD0504802

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗