Clinical trial NCT04834362
Conditions: Hyperglycemia Stroke, Acute
Keywords: Hyperglycemia Stroke Human insulin Analog insulin
Sponsor: National Institute of Neurosciences and Hospital, Dhaka
Start date: 2021-04-05; Completion date: 2021-06-25
Enrollment: 452 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: Patients treated with insulin analog 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. arm 2: 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
Interventions: intervention 1: Analog Insulin intervention 2: Human insulin
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
Project Title: 
 
Efficacy and safety of human insulin versus analog insulin in 
hospitalized acute stroke patients with hyperglycemia:  
a randomized, open-label, single center trial  
 
 
NCT ID: NCT04834362 
 
 
 
Date: 01/Nov/2021 
 
 
 
 
 
 
 


Project Title: 
 
Efficacy and safety of human insulin versus analog insulin in 
hospitalized acute stroke patients with hyperglycemia:  
a randomized, open-label, single center trial  
 
Primary Investigator 
 
 
Dr. Mashfiqul Hasan 
Assistant Professor of Endocrinology, NINS 
 
Co-Investigators 
 
Dr. Mohammad Atiqur Rahman,  
Assistant Professor of Endocrinology, NINS 
Dr. Sharmin Chowdhury 
Medical Officer, Neurology, NINS 
 
Advisor/Guide 
Dr. Mohammad Selim Shahi  
Associate Professor of Neurology, NINS 
 
 
 
 
 
 
 
 
Diabetes & Endocrinology team 
National institute of Neurosciences & Hospital 
Dhaka, Bangladesh 


3 
 
Section - A 
 
 
1. Project Title:  Efficacy and safety of human insulin versus analog insulin in 
hospitalized acute stroke patients with hyperglycemia: a randomized, open-label, 
single center trial  
 
2. Principal Investigator  
 
SI 
Name and designation 
Research position 
 
Dr. Mashfiqul Hasan 
Assistant Professor (Endocrinology) 
National Institute of Neurosciences & Hospital 
Principal Investigator  
 
3. Co-investigators:  
SI 
Name and designation 
Research position 
1 
Dr. Mohammad Atiqur Rahman 
Assistant Professor (Endocrinology) 
National Institute of Neurosciences & Hospital 
Co-Principal Investigator (1) 
2 
Dr. Sharmin Chowdhury 
Medical Officer (Neurology) 
National Institute of Neurosciences & Hospital 
Co-Principal Investigator (2) 
3 
Dr. Mohammad Selim Shahi 
Associate Professor (Neurology) 
National Institute of Neurosciences & Hospital 
Co-Principal Investigator/ 
Guide & supervisor 
 
4. Place of the study/Institution: National Institute of Neurosciences & Hospital, Sher-E-
Bnagla Nagar, Dhaka-1207. 
5. Sponsoring/Collaborating Agencies: PMR Operational Plan, DGHS 
6. Duration: 05 Month 
7. Date of Commencement :01/02/2021 
8. Date of Completion: 30/06/2021 
9. Total Cost: 2,00,000/-(BDT) 
10. Other Support for Proposed Research: Not required  
11. Date of Submission: 18/02/2021 
 
 
 
 
12. Signature of Principal Investigator: 
 
 
 
13. Signature of Co-investigators: 
 
 
 
 
 


3 
 
 
 
14. Approval of the Head of the Institute /Principal 
 
 
 
 
 
 
 
 
Name and Signature 
 
Designation  
 
Official Seal 


4 
 
Sections - B 
Title: Efficacy and safety of human insulin versus analog insulin in hospitalized acute stroke 
patients with hyperglycemia: a randomized, open-label, single center trial 
EXECUTIVE 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. 
Expected outcome/ result: The result will clearly show the efficacy and safety of newer insulins in 
comparison to conventional human insulin. 
Recommendation: The study may help generating recommendations about insulin use in 
hospitalized acute stroke patients. 


Section-C  
 
 
INTRODUCTION: 
 
It is well known that good clinical outcome in hospitalized patients with hyperglycemia cannot be 
expected unless target blood glucose is promptly achieved and maintained (1-3). This is also true for 
acute stroke patients. Hyperglycemia may affect the outcome of both ischemic and hemorrhagic 
stroke (4-6). Pro-oxidative and proinflammatory state imposed by hyperglycemia can cause direct 
neuronal toxicity. An increase of cerebral edema may be caused by hyperglycemia-mediated increase 
in matrix metalloproteinase-9 causing neuronal damage. Moreover, hyperglycemia may be 
responsible for a procoagulant state that can further compromise blood supply to the penumbral areas 
in acute ischemic stroke (7).  
Management of hyperglycemia in acute stroke patients is particularly challenging because many of 
the patients cannot take their usual food and need feeding by nasogastric (NG) tube. Common practice 
is to feed 200 ml of liquid food (soup or milk) 2 hourly starting at morning and continue up to night 
(10 feeds/day). As such, insulin regimen used to control hyperglycemia in patients taking three major 
meals may not be appropriate in this setting.   Moreover, many acute stroke patients receive 
corticosteroid therapy, which further deteriorates glycemic status. Dislodgement of NG tube may 
result in interruption of interruption of feeding, predisposing to hypoglycemia. All these challenges 
need to be kept in mind while choosing appropriate insulin regimen.  
Hyperglycemia in hospitalized patients is defined as blood glucose levels >7.8 mmol/L. Insulin 
therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold ≥10.0 
mmol/L. Once insulin therapy is started, a target glucose range of 7.8–10.0 mmol/L is recommended 
for the majority of critically and non-critically ill patients (8). More stringent goals, such as <7.8 
mmol/L may be appropriate for selected patients, as long as this can be achieved without significant 
hypoglycemia.  
In most instances in the hospital setting, insulin is the preferred treatment for hyperglycemia (8). 
Human insulin in the form of regular insulin and intermediate acting insulin (neutral protamine 
hagedorn; NPH) are the most common insulin used for glycemic control in people with diabetes. 
However, they may not mimic the physiological insulin secretion pattern properly. As a result, tight 
glycemic control often leads to hypoglycemia. To improve the pharmacokinetics of the insulin, minor 
structural alterations are made to produce analogs insulin that have similar pharmacodynamics 
properties. These include long acting basal insulin like insulin detemir, glargine and degludec and 
rapid acting prandial insulin like insulin lispro, aspart or glulisine. These modern insulins are costlier 
and availability is often limited.  
An insulin regimen with basal, prandial, and correction components is the preferred treatment for non-
critically ill hospitalized patients with good nutritional intake (9). Clinical guidelines from 


6 
 
professional organizations recommend the use of subcutaneous insulin in the form of basal-bolus 
regimen as the preferred therapy for glycemic control in hospitalized medical and surgical patients 
with type 2 diabetes mellitus (T2DM) (8,10,11). Sliding scale regular human insulin regimen or 
premixed insulin in acute setting is strongly discouraged by current recommendations (12). These 
recommendations are mainly based on studies done on patients taking three major meals. 
Use of regular insulin thrice a day is a common practice in our setting mainly due to its simplicity and 
relevance to feeding practice in acute stroke patients. Nevertheless, this regimen is associated with 
limited therapeutic success because of the lack of basal insulin coverage. Adding a long acting basal 
insulin in the form of NPH or basal insulin analogs are often not introduced in-hospital settings due to 
fear of hypoglycemia (9). Modern basal insulin analogs may be superior in this respect as they have 
more physiological pharmacokinetic properties (13).  
In different countries, basal-bolus therapies with insulin analogs are being used more commonly. But 
intermediate-acting and regular human insulin are also observed to have almost similar efficacy and 
safety (12,14). No inpatient trials have been conducted in our region to determine optimal treatment 
regimens for hospitalized patients with T2DM in special situation like acute stroke. As there are 
significant differences in patient demographics, admission cause, feeding practice and availability of 
hospital resources between patients of developed and developing countries, the choice of agents may 
not be similar (15,16). In this background, the present study aims to compare the efficacy and safety 
of conventional human insulin (regular insulin and intermediate acting NPH insulin) to newer analog 
insulin (basal insulin glargine with rapid acting insulin aspart) in acute stroke patients with 
hyperglycemia admitted in a referral tertiary neuroscience institute of Dhaka.  
 
 
 


7 
 
RATIONALE: 
 
One in five patients hospitalized for acute stroke has hyperglycemia. For optimum outcome 
of these patients, proper glycemic control is essential. Acute stroke patients, who need 
hospitalization, are usually unable to take food normally and they are fed through nasogastric 
tube with small frequent feeding (200 ml, 2-hourly, 10 feed/day). It is not clear which insulin 
regimen will suit better to these type of feeding practice. Moreover, corticosteroids 
(dexamethasone) are often used in these patients as treatment adjunct which further 
challenges glucose homeostasis. Different insulin regimens are used in such patients but none 
is validated in clinical trials. Episodes of hypoglycemia may cause further neurological 
deterioration in acute stroke patients. So regimen with less chance of hypoglycemia needs to 
be identified. Although analog insulins are observed to have less chance of hypoglycemia, 
they are costly and had not been well studied in our setting. It is essential for us to know the 
efficacy and safety of analog insulin regimen in comparison to human insulin, so that 
appropriate management decision can be made 


8 
 
OBJECTIVES: 
 
General objective:  
 
To compare the efficacy and safety of human insulin (regular insulin and intermediate acting 
NPH insulin) to analog insulin (basal insulin glargine and rapid acting insulin aspart) in 
hospitalized acute stroke patients with hyperglycemia 
 
Specific objectives:  
 
In hospitalized acute stroke patients with hyperglycemia -  
 
To evaluate the efficacy and safety of human insulin (regular insulin and intermediate acting 
NPH insulin) 
 
To assess the efficacy and safety of insulin analog (basal insulin glargine and rapid acting 
insulin aspart) 
 
To compare the efficacy and safety of two insulin regimen  
 
To evaluate the socio-demographic and clinical characteristics of the patients included in two 
treatment arms 
 
 
.   
 
 


9 
 
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). 
Inclusion criteria 
 
Patients admitted to adult neurology ward with acute stroke with  
 
Patients having hyperglycemia (capillary blood glucose ≥10 mmol/L in 2 or more occasions or 
having history of treatment for DM) 
 
Patients with age of 18-80 years of both sexes 
 
Patients or their attendants giving consent to take part in the study 


10 
 
Exclusion Criteria 
 
Patients with hyperglycemic emergencies (hyperglycemic hyperosmolar state or  
diabetic 
ketoacidosis) 
 
Pregnant patients  
 
Those not giving consent to participate in the study 
 
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. 


11 
 
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. 
 
Outcome variables  
The primary efficacy outcome of the study will be the differences in glycemic control between 
groups, as measured by mean daily BG concentration during the hospital stay. 
The primary safety outcome will be the frequency of hypoglycemic events (BG <3.9 mmol/L). 
Secondary outcomes include differences between treatment groups in any of the following measures: 
total daily dose of insulin, length of hospital stay, hospital complications, and mortality. 
Data collection technique  
Data will be collected in a predesigned questionnaire by the research team. The researchers will 
recheck randomly and blindly to verify the collected data. 


12 
 
Data management  
All data will be compiled and edited meticulously by thorough checking and rechecking. All 
omissions and inconsistencies will be corrected and will be removed methodically. 
Statistical analysis 
Computer based statistical analysis will be carried out with appropriate techniques and systems by 
SPSS 22.0. Quantitative data will be expressed as mean and standard deviation or median and inter-
quartile range; and qualitative data will be expressed as frequency and percentage. Continuous 
variables, analysis will be made by the Students T-test or Mann-Whitney U test. Categorical variables 
will be analyzed by the χ2 test. All probabilities will be 2-tailed. Statistical significance will be 
accepted at p≤0.05.  
 
Utilization of results 
The result of study will be helpful for the physicians to choose appropriate insulin regimen in patients 
hospitalized with acute stroke having hyperglycemia. It will also help the policy makers in ensuring 
adequate supply of appropriate insulin that may help improve the outcome of patients.  
 
FLOW CHART  
 
Sl. No. 
Job Title 
Feb’21 
Mar’21 
Apr’21 
May’21 
Jun’21 
1.  
Questionnaire Validation 
√ 
 
 
 
 
2.  
Data Collection  
√ 
√ 
√ 
 
 
3.  
Data Analysis 
 
  
 
√ 
  
4.  
Report writing and Printing 
  
  
 
√ 
√ 
5.  
Submission 
 
 
 
 
√ 
 
 
 
 
 
 


13 
 
ETHICAL IMPLICATIONS: 
Prior to the commencement of this study, approval of the institutional review board (IRB) of National 
Institute of Neurosciences & Hospital, Dhaka will be sought. The aims and objectives of the study 
along with its procedure, risks and benefits of this study will be explained to the patients or attendants 
of the patients in easily understandable local language and then written consent will be taken from 
each. It will be assured that all information and records would be kept confidential. 
 
   
Role of funding agency 
The funding agency will have no role in protocol development, data collection, analysis, interpretation 
or writing the report. The authors will have full access to all study data and will have the final 
responsibility for the decision to submit for publication.  


14 
 
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3. 
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Glargine in Type 1 Diabetes. Diabetes care. 2000 May 1;23(5):639-43. 
14.  
Umpierrez GE, Hor T, Smiley D, Temponi A, Umpierrez D, Ceron M, Munoz C, Newton C, 
Peng L, Baldwin D. Comparison of inpatient insulin regimens with detemir plus aspart versus 
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15. 
Leite SA, Locatelli SB, Niece SP, Oliveira AR, Tockus D, Tosin T. Impact of hyperglycemia 
on morbidity and mortality, length of hospitalization and rates of re-hospitalization in a 
general hospital setting in Brazil. Diabetol Metab Syndr. 2010;2:49. 
16.  
Torres-Torres N, Maldonado-Rodríguez MA, Pérez-López S, Sierra-Martínez K, García AJ. 
Glycemic control and the outcomes of Hispanic patients with diabetes admitted to the general 
ward of a community hospital in Puerto Rico. P R Health Sci J. 2011;30:43-50. 
17. 
Zhong B. How to calculate sample size in randomized controlled trial?. Journal of thoracic 
disease. 2009 Dec;1(1):51. 
 
\ 


16 
 
Section - D 
 
 
 
BUDGET 
 
 
Total Budget: 2,00,000/- (BDT) 
 
Detailed Budget: 
 
1. Personnel Cost: 40,000/-(BDT) 
 
Time spent by the persons 
Sl. No 
Category of the Persons 
Percentage of time spent 
1 
Professional Scientific Staff 
70% 
2 
Technical 
20% 
3 
Other Staff 
10% 
 
2. Field Expenses/Laboratory Cost: 25,000/-(BDT) 
3. Supplies and Materials (Ten glucometers with strips):25,000/-(BDT) 
4. Patient Cost: Not Applicable 
5. Travel Cost (Internal travel cost only): 15,000/-(BDT) 
6. Transportation of Goods: 10,000/-(BDT) 
7. Office Stationery (Items & quantity to be specified):10,000/-(BDT) 
8. Data Processing/Computer Charges (If applicable):30,000/-(BDT) 
9. Printing and Reproduction:25,000/-(BDT) 
10. Contractual Services (Other than manpower): Not Applicable 
11. Administrative Overhead /Dissemination:20,000/- 
12. Miscellaneous 5,000/-  


17 
 
Section - E 
 
 
Directorate General of Health Services 
Planning, Monitoring and Research 
Mohakhali, Dhaka-1212 
pmr@ld.dghs.gov.bd 
www.dqhs.gov.bd 
 
 
Application for Ethical Clearance 
 
 
Principal Investigator:  
Dr. Mashfiqul Hasan, Assistant Professor of Endocrinology, National Institute of Neurosciences 
and Hospital, Sher-e-Bangla Nagar, Dhaka 
 
 
Co-investigators: 
Dr. Mohammad Atiqur Rahman, Assistant Professor of Endocrinology, National Institute of 
Neurosciences and Hospital, Sher-e-Bangla Nagar, Dhaka 
Dr. Sharmin Chowdhury, Medical Officer, National Institute of Neurosciences and Hospital, Sher-
e-Bangla Nagar, Dhaka 
 
Guide/Supervisor: 
Dr. Mohammad Selim Shahi, Associate Professor of Neurology, National Institute of 
Neurosciences and Hospital, Sher-e-Bangla Nagar, Dhaka 
 
 
Place of the Study/institution: National Institute of Neurosciences & Hospital, Sher-E-Bangla 
Nagar, Dhaka-1207 
 
 
 
 
Title of Study: Efficacy and safety of human insulin versus analog insulin in hospitalized 
acute stroke patients with hyperglycemia: a randomized, open-label, single center trial 
 
 
 
Type of Study: Clinical trial 
 
 
 
Duration: 5 months 
 
 
Total Cost: 2,00,000/- 
 
 


18 
 
Funding Agency: DGHS 


19 
 
Circle the appropriate answer to each of the following 
(If not Applicable wife NA) 
 
(a) 
Nature and 
Yes 
No 
(b) 
Non* lll Subjects 
Yes 
No 
purposes of study 
(c) 
Minors or persons 
Yes 
No 
(b) 
Procedures to be 
Yes 
No 
             under guardianship 
followed including 
alternatives used 
2. Does the study involve: 
(c) 
Physical risks 
Yes 
No 
(a) 
Physical risks 
Yes 
No 
             to the subjects 
(d) 
Private questions 
(b) 
Social Risks 
Yes 
No 
(e) 
Invasion of the Body 
Yes 
No 
(C) 
Psychological risks to        
                subjects 
Yes 
No 
(|) 
Benefits to be derived 
Yes 
No 
 
Right to refuse 
Yes 
No 
(d) 
Discomfort to subjects 
Yes 
No 
to participate or 
to withdraw from study 
(e) 
invasion of the body 
Yes 
No 
(h) 
Confidential 
Yes 
No 
(fl 
Invasion of Privacy 
Yes 
No 
handling of data 
(g) 
Disclosure of 
Yes 
No 
(i) 
Compensation 
Yes 
No 
Information damaging 
where there are risks or 
to subject or others 
loss of workng time or 
privacy is involved in 
any particular procedure 
 
3. Does the study involve: 
 
Use of records. (Hospital, 
medical, death, birth or other) 
 
Use of fetal tissue 
or abort us 
 
Use of organs or 
Body fluids 
Yes 
No 
5. 
 
 
 
Yes 
No 
 
 
Yes 
No 
Will signed consent 
form/verbal consent be 
required 
 
From Subjects 
 
From parent or guardian (if 
subjects are minors) 
 
 
 
Yes 
No 
 
Yes 
No 
 
 
4. Are subjects clearly informed about  
6. Will precautions 
be taken to 
protect anonymity 
of subject 
Yes 
No 


10 
 
Section -F 
 
Abstract for IRB/Ethical Committee:  
 
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. 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. Computer based statistical analysis will be carried out by SPSS 22.0. 
Quantitative data will be expressed as mean and standard deviation or median and inter-quartile range; and 
qualitative data will be expressed as frequency and percentage. Continuous variables will be compared by 
the Students T-test or Mann-Whitney U test. Categorical variables will be analyzed by the χ2 test. All 
probabilities will be 2-tailed. Statistical significance will be accepted at P≤0.05. Prior to the 
commencement of this study, approval of the institutional review board (IRB) of NINS will be sought. The 
aims and objectives of the study along with its procedure, risks and benefits of this study will be explained 
to the patients or attendants of the patients in easily understandable local language and then written consent 
will be taken from each. The result of the study may help us to choose appropriate insulin regimen for 
hospitalized acute stroke patients in our setting. 
 
 
 
 
 
 


11 
 
Case record form – insulin trial 
Reg. No. 
 
Ward 
 
Bed 
 
Name 
 
Age (yr) 
 
Gender 
M/F 
Address 
 
Phone 
(1) 01__________________________ 
(2) 01__________________________ 
Date and time of admission 
______/_______/____________, ___________ am/pm 
Date and time of stroke event 
______/_______/____________, ___________ am/pm 
Assigned group 
 
Presenting features on admission (Circle or underline the appropriate options) 
Chief complaints 
Unconsciousness, Hemiparesis Rt/Lf, Headache, Vomiting, Seizure 
Duration of symptoms 
___________ days, ____________ hours 
Past history 
HTN, DM, IHD, CKD, Stroke, Others: 
Drug history 
 
Family history 
 
Smoking 
Never/ Ex / Current smoker 
GCS  
E_____V_____M_____ 
NIHSS score 
 
Pulse (beats/min) 
_______, regular/irregular 
BP (mm of Hg) 
________/________ 
Any remarkable findings 
 
 
Investigation Profile 
 
CT 
findings 
Hemorrhage 
Site: 
 GT/Lobar/Brain stem/Cerebellar/SAH/IVH 
 
 
Volume:_____________ml 
Ventricular Extension: Present/Absent 
Infarct 
Large vessel infarct/Perforator infarct;  
Anterior circulation/Posterior circulation/Water shade zone infarct 
MRI/MRV/MRA/CTA 
 
CBG on admission 
 
Chest X-ray 
 
Creatinine (mg/dL) 
 
ECG 
 
Sodium (mmol/L) 
 
Echo 
 
Potassium (mmol/L) 
 
Hemoglobin (g/dL) 
 
Total Cholesterol 
 
Cloride (mmol/L) 
 
ESR (mm) 
 
HDL 
 
Troponin-I 
 
WBC (109/L) 
 
LDL 
 
HbA1c (%) 
 
DC of WBC (N,L%) 
 
TG 
 
RBS 
 
Platelet (109/L) 
 
 
 
SGPT (U/L) 
 
 
 
 
 
Urine R/E 
 
 
 
 
 
 
In-hospital events/diagnosis  
Pneumonia 
Yes, No 
Treatment needed for hypertension 
Yes, No 


12 
 
Pressure sore  
Yes, No 
Treatment needed for hyperglycemia 
Yes, No 
UTI 
Yes, No 
≥2 blood glucose >10 mmol/L 
Yes, No 
Thrombolytic therapy 
Yes, No 
Cardiac event 
Yes, No 
Neurosurgical procedure (specify) 
 
Yes, No 
Electrolyte imbalance (Specify) 
Yes, No 
Any other event/diagnosis:  
Outcome 
Hospital outcome 
Discharged to home/ Referred to other hospital/ Death 
Date of outcome  
 
mRS at discharge 
 
 
 
For hyperglycemic patients  
Date 
7 am 
1 pm 
7pm 
 
 
Insulin 
Feeding 
Steroid 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


13 
 
Section - H 
 
 
PRINCIPAL INVESTIGATOR INFORMATION SHEET 
 
1. (i) 
Name  
: Dr. Mashfiqul Hasan 
(i) 
Designation 
: Assistant Professor (Endocrinology) 
(ii) 
Official Address with telephone: National Institute of Neurosciences & Hospital, Sher-E-Bangla 
Nagar, Dhaka-1207. Telephone: +88029137305 
(iii) 
Present Residential Address with telephone: Kha-42/1, Shahjadpur, Gulshan, Dhaka-1212. 
 
Academic Qualification 
 
Degree 
 
Institute/University 
 
Field of study 
Year 
 
Postgraduate: 
MD 
 
 
Bangabandhu Sheikh Mujib  
Endocrinology  
Jan 2016 
 
 
 
Medical University (BSMMU)  
MCPS  
 
Bangladesh College of 
 
Medicine 
 
Jul   2009 
 
 
 
Physicians and Surgeons (BCPS) 
 
Ggraduate: 
MBBS  
 
Dhaka Medical College 
 
Medical Sciences 
May 2005 
  
 
 
(University of Dhaka)   
 
Undergraduate: 
HSC   
 
Dhaka College, Dhaka Board  
 
 
 
1999 
SSC   
 
Banani Bidya Niketon, Dhaka Board  
 
 
1997 
 
 
(a) Research Experience: 10 years 
 
(b) Other Experience :  
Teaching: 4 Years 
 
Administration 
 
Others : 
 
 
Percentage of time to be devoted to this Project :  50% 
 
Number of Scientific Publications: 27