Insulin for Hyperglycemia in Stroke Trial
Condition: Hyperglycemia; Stroke, Acute
MeSH terms: Stroke; Hyperglycemia
Study type: Interventional
Phase: Phase 4

Summary: 
      Introduction: Glycemic control in acutely ill stroke patients with hyperglycemia is vital.
      Although insulin is the choice of anti-diabetic agent during acute stage, it is not clear
      which insulin regimen is better in terms of glycemic control and prevention of hypoglycemia
      in hospitalized acute stroke patients who are usually on small frequent nasogastric tube
      feeding. The present study aims to evaluate the efficacy and safety of human insulin (regular
      insulin and neutral protamine hagedorn, NPH insulin) to analog insulin (basal insulin
      glargine and rapid acting insulin aspart) in hospitalized acute stroke patients with
      hyperglycemia.

      Justification: Analog insulins are developed by minor alteration of the amino acid chain
      which alters their pharmacokinetics and make them more physiological. However, these insulins
      are costly and are not widely available. Conventional human insulins are more commonly used
      in our country. Comparison of these two regimen is necessary in our own setting to optimize
      optimal glycemic management of hospitalized acute stroke patients.

      Methodology: In this single-center, open-label, randomized trial, 100 patients with acute
      stroke and hyperglycemia (capillary blood glucose ≥10 mmol/L on 2 or more occasions) or
      history of type 2 DM admitted in the in-patient Department of Neurology, National Institute
      of Neurosciences (NINS) & Hospital will be randomly assigned to receive human insulin or
      modern insulin therapy in 1:1 ratio. The study will be carried out from February to June
      2021. Blood glucose (BG) will be monitored by standardized glucometer thrice a day and
      insulin dose will be adjusted daily. The primary outcome of the study will be the differences
      in glycemic control between groups, as measured by mean daily BG concentration during the
      hospital stay. Secondary outcomes include differences between treatment groups in any of the
      following measures: number of hypoglycemic events (BG <3.9 mmol/L), total daily dose of
      insulin, length of hospital stay, hospital complications and mortality.
    

Detailed description: 
      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.
    

Intervention name(s): Analog Insulin; Human insulin
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Insulin Aspart and Insulin Glargine; Regular insulin and NPH insulin
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Aspart
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hyperglycemia; Stroke; Human insulin; Analog insulin