Metformin in Acute Ischemic Stroke

Study design: Multicentric placebo controlled randomised controlled study. Study Area or Settings: Hospital based

Inclusion criteria:

All the following:

1. Adults aged ≥18 years.
2. Patient or Legally Acceptable Representative (LAR) willing to give informed consent before study procedure.
3. Acute stroke is ischemic in origin and radiologically confirmed by Computed Tomography (CT) scan prior to enrolment.
4. Pre-stroke mRS score of 0 or 1 and first ever episode of stroke.
5. National Institute Health Stroke Scale (NIHSS) of >5 (NIHSS Level of Consciousness (1A) score must be <2).
6. Patients undergoing intravenous thrombolysis will be included.

Exclusion criteria:

Any of the following:

1. Patients receiving endovascular therapy or are candidates for any surgical intervention for treatment of stroke.
2. Prior history of stroke of any type (ischemic/hemorrhagic/ subarachnoid hemmorhage)
3. Patients classified as comatose (NIHSS Level of Consciousness (1A) score ≥ 2).
4. Evidence of intracranial hemorrhage in the baseline CT.
5. Pregnancy and lactation.
6. Patients with co-morbid illnesses like chronic liver disease/chronic kidney disease/malignancy limiting their life expectancy.
7. Concurrent participation in any other therapeutic clinical trial/ rehabilitation trial.
8. Patients are already on metformin treatment. • A non-interventional arm of patients who fulfill the eligibility criteria and are already on metformin before the stroke will also be recruited for the purpose of prospective follow-up to assess the outcome at 90 days.

Patients without diabetes will not be excluded from the study, as the doses of metformin to be used in our study have been amply used in other studies in non-diabetes conditions for indications like cancer, dementia, polycystic ovarian disease, obesity. A pre-hoc subgroup analysis will be done to look at differences in outcome in diabetic versus non-diabetic patients Interventions Patients randomised to the intervention arm will be given incremental doses of metformin as described in the detailed study protocol and the target dose will be based on the tolerability of the patient. The treatment will be given till the follow-up period of the patient (total duration of treatment will be 90 days).

Regular monitoring of renal and liver function tests will be done (every 48-72 hours during hospital stay, and 2 weekly after discharge).

Comparison Matching placebo tablets. The placebo tablets will ensure optimum blinding as well as treatment bias associated with open labelled studies

Primary outcome:

1. Proportion of patients with mRS 0-1 at 90 days

Secondary outcome:

1. Proportion of patients with mRS 0-1 at 30 days
2. Mortality at 30 days and 90 days
3. BI at 30 days and 90 days
4. Patients with early neurological improvement (ENI) (improvement of >=4 points in NIHSS) and early neurological deterioration (END) (deterioration of >=2 points NIHSS) at 7 days (±2 days).
5. Levels of hsCRP, Vitamin B12, Holotranscobalamin at 30 days (±7 days) and 90 days (±7 days).

Sample size estimation and sampling strategy The effect size has been taken from the recent study by Jian et al.14, using the superiority hypothesis, the proportion of patients with mRS 0-1 in the intervention arm as 74.9% and 61.5% in the control arm, a sample size of 372 patients will be required to have a 80% chance of detecting, at a significant at the 5% level. Assuming a 15% loss to follow up, the revised sample size will be 220 per group (total sample size of 440).

Data Collection methods, instruments used, measurements

Data collection:

All the data will be collected in central Redcap server, which will also be used for randomisation.