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CTRI Number  CTRI/2024/02/062375 [Registered on: 07/02/2024] Trial Registered Prospectively
Last Modified On: 29/01/2025
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Multiple Arm Trial 
Public Title of Study   A research study to see how well the new weekly medicine IcoSema, which is a combination of insulin icodec and semaglutide, controls blood sugar level in people with type 2 diabetes, compared to daily insulin glargine (COMBINE 4) 
Scientific Title of Study   A 40-week study comparing the efficacy and safety of once weekly IcoSema and daily insulin glargine 100 units/mL in participants with type 2 diabetes inadequately controlled on oral anti-diabetic drugs.  
Trial Acronym  COMBINE 4 
Secondary IDs if Any  
Secondary ID  Identifier 
022-502484-38-00  EudraCT 
NN1535-4988 Version 1, 12-Apr-2023  Protocol Number 
U1111-1283-8648  UTN 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query  
Name  Dr Maya Sharma 
Designation  Vice President - Clinical, Medical, Regulatory and Pharmacovigilance 
Affiliation  Novo Nordisk India Private Ltd 
Address  Novo Nordisk India Private Limited, Nxt Tower - 2, Floor 1 and 2 - Embassy Manyata Business Park, Nagavara Village, Kasaba Hobli, Bangalore - 560045. India

Bangalore
KARNATAKA
560045
India 
Phone  91-9911497869  
Fax  80-41123518  
Email  yrms@novonordisk.com  
 
Details of Contact Person
Public Query  
Name  Dr Maya Sharma 
Designation  Vice President - Clinical, Medical, Regulatory and Pharmacovigilance 
Affiliation  Novo Nordisk India Private Ltd 
Address  Novo Nordisk India Private Limited, Nxt Tower - 2, Floor 1 and 2 - Embassy Manyata Business Park, Nagavara Village, Kasaba Hobli, Bangalore - 560045. India

Bangalore
KARNATAKA
560045
India 
Phone  91-9911497869  
Fax  80-41123518  
Email  yrms@novonordisk.com  
 
Source of Monetary or Material Support
Modification(s)  
Novo Nordisk AS Novo Allé, 2880 Bagsvaerd Denmark 
 
Primary Sponsor
Modification(s)  
Name  Novo Nordisk India Private Limited 
Address  Nxt Tower-2, Floor 1 & 2 Embassy Manyata Business Park, Nagavara Village, Kasaba Hobli, Bangalore - 560045. India  
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     China
Greece
India
Japan
Poland
South Africa
Turkey
United States of America
Italy  
Sites of Study
Modification(s)  
No of Sites = 12  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Manoj Chawla  B.S.E.S Municipal General Hospital  Clinical Research Office, 7th floor, Inside waiting area, SV Road, Opp railway station, Andheri (W)
Mumbai
MAHARASHTRA 		 9820002333

drmanojchawla@yahoo.com 
Dr Nikhil Bhagwat  BYL Nair Hospital and T N Medical College  Department of endocrinology, College building, 4th floor, room no. 19, Dr A L Nair Road, 400008
Mumbai
MAHARASHTRA 		 9820238399

bhagwatnik@yahoo.co.in 
Dr Unnikrishnan AG  Chellaram Diabetes Institute, Chellaram Hospital  1st floor, Lalani Quantum, Pune-Bangalore NH4, Bavdhan(Budruk), Pune-411021, Maharashtra, India
Pune
MAHARASHTRA 		 9689287337

uagcdi@cdi.org.in 
Dr Surendra Kumar Sharma  Diabetes, Thyroid and Endocrine Centre  Jaipur, A-1, Madrampura, Near 4 no. ESI Hospital, Ajmer Road, Jaipur – 302006, India.
Jaipur
RAJASTHAN 		 9829010233

sksharmacr@gmail.com 
Dr Sujoy Ghosh  IPGME & R/SSKM Hospital  SSKM Hospital Rd, 244 AJC Base Rd, Bhowanipore
Kolkata
WEST BENGAL 		 9674625823

drsujoyghosh2000@gmail.com 
Dr Pramila Kalra  M S Ramaiah Memorial Hospital  Clinical Research Centre, First Floor Advance Learning Centre, Jyanagangothri Campus, New BEL Road, MSRIT Post, 560054
Bangalore
KARNATAKA 		 9243257161

kalrapramila@gmail.com 
Dr Mohan V  Madras Diabetes Research Foundation  Clinical trials Department 1st floor, 4, Conran Smith Road, Gopalapuram
Chennai
TAMIL NADU 		 9840134505

drmohans@diabetes.ind.in 
Dr Sumaiya Anjum  Mysore Medical College and Research Institute  Dept. of Medicine, K.R. Hospital, 570001
Mysore
KARNATAKA 		 7760218464

sumi_anjum262@yahoo.com 
Dr Sanjay Bhadada  Post Graduate Institute Of Medical Education & Research  Post Graduate Institute of Medical Education & Research, Madhya Marg, Sector 12, 160012
Chandigarh
CHANDIGARH 		 9876602448

bhadadask@rediffmail.com 
Dr Sandeep Kumar Mathur  S M S Medical College, Jaipur   Jawahar Lal Nehru Marg, Gangawal Park, Adarsh Nagar, Jaipur, Rajasthan 302004
Jaipur
RAJASTHAN 		 9414048666

drsandeepmathur@rediffmail.com 
Dr Tushar R Bandgar  Seth GS Medical College & KEM Hospital  KEM Hospital, Acharya Donde Marg, Parel
Mumbai
MAHARASHTRA 		 9820025037

drtusharb@gmail.com 
Dr Mukulesh Gupta  UDYAN HEALTH CARE Pvt Ltd  730 Udyan-1 Eldeco, opp. AWHO, Near Bangla Bazar, Lucknow, Uttar Pradesh – 226002, India
Lucknow
UTTAR PRADESH 		 9336046146

drmukulesh@yahoo.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 12  
Name of Committee  Approval Status 
BSES Municipal General Hospital Ethics Committee  Approved 
Chellaram Diabetes Institute-Institutional Ethics Committee  Approved 
Diabetes, Thyroid and Endocrine Centre  Approved 
ETHICS COMMITTEE   Approved 
Ethics Committee, S.M.S. Medical College and Attached Hospitals  Approved 
Institutional Ethics Committee  Approved 
Institutional Ethics committee -   Approved 
Institutional Ethics Committee - I  Approved 
Institutional Ethics Committee of Madras Diabetes Research Foundation  Approved 
Institutional Ethics Committee-Mysore Medical College and Research Institute and Associated Hospitals  Approved 
Institutional Human Ethics Committee, Udyaan Health Care  Approved 
IPGME and R Resaerch Oversight Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: E11||Type 2 diabetes mellitus,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  IcoSema  IcoSema. Solution for injection, Subcutaneous (into the thigh, upper arm or abdomen), 700 units/mL + 2 mg/mL,Administer IcoSema once weekly, on the same day each week, at any time of the day.Manufactured and supplied by Novo Nordisk A/S. 
Comparator Agent  Insulin glargine  Insulin glargine 100 units/mL. Solution for injection, Subcutaneous (into the thigh, upperarm or abdomen). Administer insulin glargine once daily, at any time of the day but at the same time every day throughout the study.Insulin glargine is manufactured by Sanofi-Aventis, but supplied by Novo Nordisk A/S. 
 
Inclusion Criteria
Modification(s)  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  1.Male or female and age above or equal to 18 years at the time of signing the informed consent.
2. Diagnosed with T2D greater than or equal to 180 days before screening.
3. HbA1c greater than or equal to 8.0% (greater than or equal to 64.0 mmol/mol) as assessed by central laboratory on the day of screening.
4. Insulin naïve. Short term insulin treatment for a maximum of 14 consecutive days before screening is allowed, as is prior insulin treatment for gestational diabetes.
5. Currently treated with 1-3 OADs with stable daily doses greater than or equal to 90 days before screening comprising any of the following anti-diabetic drug(s) at effective or maximum tolerated dose: Metformin, Sulfonylureas, Meglitinides (glinides), DPP-4 inhibitors, Sodium-glucose co-transporter 2 inhibitors, Alpha-glucosidase-inhibitors, Thiazolidinediones, marketed oral combination products only including the products listed above.
6. Body mass index (BMI) less than or equal to 40.0 kg/m2. 
 
ExclusionCriteria 
Details  1. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using highly effective contraceptive method.
2. Anticipated initiation or change in concomitant medication (for more than 14 consecutive days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or systemic corticosteroids).
3. Any episodesa of diabetic ketoacidosis or treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within 90 days before screening.
4. Presence or history of pancreatitis (acute or chronic) within 180 days before screening.b
5. Any of the following: Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days before screening.
6. Chronic heart failure classified as being in New York Heart Association Class IV at screening.
7. Recurrent severe hypoglycaemic episodes within the last year (12 months) as judged by the investigator.
8. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days before screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination
aas declared by the participant or in the medical records, bFor Turkey, stricter exclusion criteria applies “Presence or history of pancreatitis (acute or chronic)”
For Italy, an additional exclusion criteria “known severe diabetic autonomic neuropathy as judged by the investigator” is applicable.
Data monitoring committee: No
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
Change in HbA1c %  from baseline week 0 (V2) to week 40 (V42). 
 
Secondary Outcome  
Outcome  TimePoints 
Change in body weight Kg  From baseline week 0 (V2) to week 40 (V42 
Time in range 3.9-10.0 mmol/L (70-180 mg/dL) Using study provisioned continuous glucose monitoring (CGM) system, Dexcom G6  From week 36 (V38) to week 40 (V42) 
Time spent 3.0 mmol/L (54 mg/dL) aUsing study provisioned continuous glucose monitoring (CGM) system, Dexcom G6  From week 36 (V38) to week 40 (V42) 
Time spent 10.0 mmol/L (180 mg/dL) Using study provisioned continuous glucose monitoring (CGM) system, Dexcom G6  From week 36 (V38) to week 40 (V42) 
Weekly basal insulin dose  From week 38 (V40) to week 40 (V42) 
Change in fasting plasma glucose (FPG) mmol/L  From baseline week 0 (V2) to week 40 (V42) 
Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in total treatment satisfaction- Score 0-36 bHigher the score the greater the satisfaction with medication  From baseline week 0 (V2) to week 40 (V42) 
Number of clinically significant hypoglycaemic episodes (level 2) (3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3)  From baseline week 0 (V2) to week 45 (V44) 
Number of clinically significant hypoglycaemic episodes (level 2) (3.0 mmol/L (54 mg/dL), confirmed by BG meter)  From baseline week 0 (V2) to week 45 (V44) 
Number of severe hypoglycaemic episodes (level 3)  From baseline week 0 (V2) to week 45 (V44) 
 
Target Sample Size   Total Sample Size="474"
Sample Size from India="100" 
Final Enrollment numbers achieved (Total)= "0"
Final Enrollment numbers achieved (India)="0" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)
Modification(s)  		 23/02/2024 
Date of Study Completion (India) Date Missing 
Date of First Enrollment (Global)  15/02/2024 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial
Modification(s)  		 Years="1"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Completed 
Recruitment Status of Trial (India)  Completed 
Publication Details   N/A 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary
Modification(s)  
This study is designed to investigate the efficacy and safety of once weekly IcoSema and daily insulin glargine 100 units/mL in type 2 diabetes (T2D) participants inadequately controlled on oral anti-diabetic drugs (OADs).IcoSema could be a more convenient injectable option compared to daily basal insulin in people with T2D who are inadequately controlled on OADs. Once weekly IcoSema has been developed  with the intent to provide a more convenient and simple treatment regimen with significantly fewer injections, all in one pen, and thereby improve the treatment adherence. Further, IcoSema is expected to minimise the risk of hypoglycaemia and to provide a weight benefit compared to daily basal insulin treatment. As per latest ADA/EASD recommendations, a fixed ratio combination of insulin and GLP-1 RA can be considered for people with T2D who are inadequately controlled on OADs especially in people with T2D who are in need of higher efficacy. Overall, the results of the present study will be important for evaluating the efficacy and safety of IcoSema in participants with T2D inadequately controlled on OADs.
 
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