Insulin for Hyperglycemia in Stroke Trial

METHODOLOGY:

Type of study: Single-center, open-label, randomized trial Place of Study: Department of Neurology, National Institute of Neurosciences \& Hospital, Dhaka.

Study Period: February to June, 2021 Study population: Patients admitted in the Department of Neurology with acute stroke and hyperglycemia

Sample Size:

Sample size was calculated according to following formula for non-inferiority trial (17):

Here, N= sample size per group α= 0.05 β= 0.20 δ0= a clinically acceptable margin (assumed as 3 mmol/L of blood glucose) S2= Pooled standard deviation of both comparison group= 8 So,

As a result, 50 patients will be randomly assigned to two treatment groups (50 human insulin regimen, 50 analog insulin regimen).

Study Procedure Patients will be randomly assigned to receive either a human insulin regimen (starting with regular insulin three times a day with NPH insulin twice a day) or analog insulin regimen (basal insulin glargine once daily and insulin aspart three times a day) following a computer-generated randomization table. All oral antidiabetic drugs will be discontinued on admission.

For a patient who is known to have diabetes but were not getting insulin previously (or previous insulin dosage is not known), insulin therapy will be started at a total daily dose of 0.3-0.4 units/kg/day for an admission BG between 10-15 mmol/L or 0.5-0.6 units/kg/day for a BG >15 mmol/L. In previously insulin treated patients, ongoing total daily dose of insulin will be started. If there is history of poor glycemic control with ongoing insulin dose, then 10-20% increase of daily dose of insulin will be considered.

For a patient who is not known to have diabetes, insulin therapy will be started if admission BG is >10 mmol/L in two or more occasions. A total daily dose of 0.3-0.4 units/kg/day will be started if admission BG is 10-15 mmol/L and 0.5-0.6 units/kg/day for a BG >15 mmol/L.

Patients treated with human insulin regimen will receive 50% of total daily dose as NPH insulin at around 6 am and 6 pm, while the rest 50% regular human insulin three times a day in 3 equally divided doses at around 6 am, 12 pm and 6 pm.

Patients treated with modern insulin regimen will receive 50% of total daily dose as basal insulin glargine at the same time of day and 50% as insulin aspart given in 3 equally divided doses at 6 am, 12 pm and 6 pm.

In both groups, insulin dosage will be adjusted daily to a target fasting and premeal BG 7.8-10.0 mmol/L in the absence of hypoglycemia. Insulin dosage will be adjusted daily according to BG values. If the fasting and/or premeal BG is 10-15 mmol/L in the absence of hypoglycemia, the total daily dose will be increased by 10% every day. If the fasting and/or premeal BG is >15 mmol/L, the insulin daily dose will be increased by 20% every day. If a patient develops hypoglycemia (BG <3.9 mmol/L), the insulin daily dose will be decreased by 20%. Supplemental regular insulin will be given in addition to scheduled mealtime insulin for BG >10 mmol/L using a supplemental insulin protocol.

BG will be measured before each bolus insulin injection (at 6 am, 12 pm and 6 pm). Glycated hemoglobin (HbA1c) will be measured after hospital admission if not done within last three months. Except anti-diabetic treatment, other treatments will be continued as per the decisions of the treating physicians. If NG feeding is discontinued and patient is kept NPO, conventional group will receive neutralizing insulin with any dextrose containing fluid along with low dose NPH insulin, if needed. Modern insulin group will receive neutralizing insulin with any dextrose containing fluid with glargine insulin as before.

After recruitment, each recruited patient will be visited daily (even in holidays according to a predefined schedule) by one of the investigators and insulin dose will be adjusted according to glucose profile of previous day. Insulin injection and capillary blood glucose monitoring by glucometer will be done by trained nurses as part of their routine patient care. Doctors and nurses on duty will be provided with cell number of the investigators who will receive call on 24/7 basis for any emergency or uncertainty regarding management of hyperglycemia.

Hypoglycemia is regarded as the only short-term adverse event of insulin. As both treatment arms will use established and recognized insulin regimen, no compensation will be provided to the patient or his/her attendants in case of any adverse event. As most of the hospitalized patients have severe stroke with case fatality rate around 20%, death will not be regarded as parameter of primary treatment outcome.

During discharge, last in-hospital insulin dose will be continued with education to the caregiver regarding insulin injection and glucose monitoring technique. No follow up visit is included in the study.

Protocol deviation and protocol violation:

Deviation to protocol will be recorded and reported to ethical committee as soon as possible. Failure to obtain informed written consent, use of incorrect insulin regimen, not fulfilling inclusion and exclusion criteria will be regarded as protocol violation and will be reported to ethical committee immediately. In case of protocol violation, the data of related participant will be discarded.