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

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.

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.

The difinition of post-stroke disability is the same as the primary outcome measure.

The modified Rankin Scale (mRS) is used to measure the degree of disability and dependence after a stroke. The scale ranges from 0 to 6. A score of 0 represents no symptoms, 1 represents no significant disability, 2 represents slight disability, 3 represents moderate disability, 4 represents moderately severe disability, 5 represents severe disability, and 6 represents death.

Dementia (all of the following criteria must be met):

A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:1.Concern from the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function. 2.A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

B. The cognitive deficits interfere with independence in everyday activities (i.e., at a minimum, requiring assistance with complex instrumental activities of daily living, such as paying bills or managing medications).

C. The cognitive deficits do not occur exclusively in the context of a delirium.

D. The cognitive deficits are not better explained by another mental disorder.

The National Institutes of Health Stroke Scale (NIHSS) is a standardized tool used to objectively measure the severity of a stroke by quantifying a patient's neurological deficits. Its primary purposes are to evaluate the acuity of a stroke, guide treatment decisions, and predict patient outcomes. The scale's total score ranges from 0 to 42, with higher scores representing more severe neurological impairment.

Hypotension is defined as a systolic blood pressure (SBP) of less than 100 mmHg or a 30% decrease from baseline.

Syncope is a transient loss of consciousness caused by transient global cerebral hypoperfusion, characterized by a rapid onset, short duration, and spontaneous, complete recovery.

The diagnosis requires the following conditions to be met:

• A transient loss of consciousness with a rapid onset (from a few seconds to 1 minute);
• A short duration (from a few seconds to a few minutes);
• Spontaneous and complete recovery;
• Absence of focal neurological signs;
• Exclusion of head trauma and epileptic seizures.

Liver function impairment may be diagnosed if at least one of the following criteria is met:

• Serum AST or ALT > 5 × the upper limit of normal (ULN), or ALP > 2 × ULN (or from an abnormal baseline value);
• Serum total bilirubin (TBil) > 2.5 mg/dL (42.75 μmol/L) accompanied by any elevation in serum AST, ALT, or ALP levels.

Bleeding events are evaluated using the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) classification and categorized as severe, moderate, or mild.

According to the Heidelberg Bleeding Classification established at the 12th Thrombolytic Therapy in Acute Ischemic Stroke workshop in Germany in 2015, symptomatic intracerebral hemorrhage (sICH) is defined as meeting all of the following conditions:

• Any form of intracranial hemorrhage (including types 1a, 1b, 1c, 2, 3a, 3b, 3c, and 3d of the Heidelberg classification) that is detected by imaging (head CT or MRI) and confirmed by a radiologist;
• The patient experiences clinical deterioration, defined as: an increase in the NIHSS score of ≥ 4 points from the last score prior to deterioration, OR an increase of ≥ 2 points on any single item of the NIHSS, OR an outcome leading to tracheal intubation, decompressive craniectomy, ventricular drainage, or other major medical/surgical intervention;
• The clinical deterioration cannot be explained by any cause other than the intracranial hemorrhage.

Changes in the levels of neuroinflammation indicators, thormbotic inflammation indicators and novel blood-based biomarkers [e.g. phosphodiesterase 3A(PDE3A), transgelin 2(TAGLN2), integrin subunit alpha M(ITGAM), protein phosphatase, Mg2+/Mn2+ dependent 1D(PPM1D)] associated with the prognosis of CSVD compared with baseline levels at 6 months and 1 year.

Assessed using Diffusion Tensor Imaging (DTI) with fiber tractography to evaluate the structural integrity of white matter fibre tract.

Assessed using resting-state functional MRI (rs-fMRI) to measure the temporal correlation and connectivity between brain regions within a specific network.

Assessed by combining Arterial Spin Labeling (ASL) and Blood-Oxygen-Level-Dependent (BOLD) fMRI to measure the hemodynamic response following neural activity in specific regions.

Assessed using two complementary methods: the Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) index, which serves as an imaging proxy for glymphatic system activity, and the quantification of Basal Ganglia Enlarged Perivascular Spaces (BG-EPVS) volume from high-resolution 3D T2-weighted images.

Assessed using multi-compartment Diffusion Tensor Imaging (DTI) models to quantify the fraction of extracellular free water, considered a marker for neuroinflammation and edema.

Assessed via analysis of Electrocardiogram (ECG) recordings to evaluate the balance of the autonomic nervous system.

Assessed via orthostatic testing to measure the cardiovascular system's response to postural changes.

Assessed using Transcranial Doppler (TCD) ultrasonography to measure the brain's ability to maintain stable cerebral blood flow despite changes in blood pressure.

Assessed using Transcranial Doppler (TCD) ultrasonography to measure the dilatory capacity of cerebral blood vessels in response to a vasodilatory stimulus (e.g., CO₂).

Assessed using task-state Transcranial Doppler (TCD) ultrasonography to measure the relationship between transient neural activity and the subsequent cerebral blood flow response.

Assessment of neuroelectrical signals by quantifying the dispersion and variability of oscillatory activity within different EEG frequency bands (e.g., Delta, Theta, Alpha, Beta).

Assessed using the Rey Auditory Verbal Learning Test (RAVLT) to measure memory and learning ability. Performance is scored by the number of words correctly recalled, with scores for a single trial ranging from a minimum of 0 to a maximum of 15. A higher score indicates better performance.

Assessed using the Color Trails Test (CTT) to measure sustained attention and processing speed. Performance is scored by the time required to complete the task. While the theoretical minimum is greater than 0 seconds, the test is typically discontinued if not completed within a maximum cutoff time of 240 seconds. A lower score (faster time) indicates better performance.

Assessed using the Stroop Color and Word Test (SCWT) to measure executive function. Performance is scored by the time to completion and the number of errors. The minimum score is 0 seconds and 0 errors. There is no theoretical maximum time, but the maximum number of errors is limited by the total number of items on the test card (e.g., 100 errors on a 100-item card). Lower times and fewer errors indicate better performance.

Assessed using the Verbal Fluency Test (VFT) to measure language production and executive control. Performance is scored by the total number of correct words generated in a set time. The minimum score is 0, but there is no defined maximum score. A higher score indicates better performance.