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CTRI Number  CTRI/2023/06/053569 [Registered on: 05/06/2023] Trial Registered Prospectively
Last Modified On: 20/07/2023
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Active Controlled Trial 
Public Title of Study   A clinical study to evaluate the efficacy, safety and tolerability of Fixed Dose Combination of Dapagliflozin 10 mg and metoprolol 50 mg XR versus metoprolol 50 mg XR in patients with heart failure.  
Scientific Title of Study   A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, COMPARATIVE, ACTIVE-CONTROLLED, PHASE III CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY AND TOLERABILITY OF FIXED-DOSE COMBINATION OF DAPAGLIFLOZIN 10 MG AND METOPROLOL 50 MG XR VERSUS ONLY METOPROLOL 50 MG XR IN PATIENTS WITH HEART FAILURE POST ACUTE MYOCARDIAL INFARCTION 
Trial Acronym  NA 
Secondary IDs if Any  
Secondary ID  Identifier 
ICS/ERI/2022-010 Version 2.0, dated 15 DEC 2022   Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr R M Chhabra  
Designation  Trial Coordinator 
Affiliation  Insignia Clinical Services Pvt. Ltd. 
Address  Insignia Clinical Services Pvt Ltd. #512, Clinical Trial Division, Clinical Operations Department, Best Sky Tower Netaji Subhash Place , Pitampura

North West
DELHI
110034
India 
Phone  011-49049115   
Fax    
Email  Chhabradrrm@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Kartik Sahni 
Designation  Director 
Affiliation  Insignia Clinical Services Pvt Ltd. 
Address  Insignia Clinical Services Pvt Ltd. #512, Clinical Trial Division, Clinical Operations Department, Best Sky Tower Netaji Subhash Place , Pitampura

North West
DELHI
110034
India 
Phone  011-49049115  
Fax    
Email  kartik.sahni@insigniacs.com  
 
Details of Contact Person
Public Query  
Name  Kartik Sahni 
Designation  Director 
Affiliation  Insignia Clinical Services Pvt Ltd. 
Address  Insignia Clinical Services Pvt Ltd. #512, Clinical Trial Division, Clinical Operations Department, Best Sky Tower Netaji Subhash Place , Pitampura

North West
DELHI
110034
India 
Phone  011-49049115  
Fax    
Email  kartik.sahni@insigniacs.com  
 
Source of Monetary or Material Support  
ERIS LIFESCIENCES LIMITED, Opp. Swati Bunglow, Shivarth Ambit, Ramdas Road, Thaltej, Ahmedabad, Gujarat, 380059.  
 
Primary Sponsor  
Name  ERIS LIFESCIENCES LIMITED 
Address  Plot No. 30-31, Brahmaputra Industrial Park, Village-Silla Amingaon, North Guwahati Assam- 781031  
Type of Sponsor  Pharmaceutical industry-Indian 
 
Details of Secondary Sponsor  
Name  Address 
ERIS LIFESCIENCES LIMITED  Opp. Swati Bunglow, Shivarth Ambit, Ramdas Road, Thaltej, Ahmedabad, Gujarat, 380059.  
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 12  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr K Sunil Naik  Government Medical College and Government General Hospital  Clinical Research Wing Second Floor, Government Medical College and Government General Hospital, Srikakulam 532001
Srikakulam
ANDHRA PRADESH 		 9912320517

muralidhargudla@yahoo.com 
Dr Amit Kumar  KCare Hospital   Department of Cardiology, Room 01 Ground Floor 16, 111, Mall Road Civil Lines Kanpur, Uttar Pradesh 208001 India
Kanpur Nagar
UTTAR PRADESH 		 9828321416

dramitdmkhms@gmail.com 
Dr Awadhesh Kumar Sharma   LPS Institute of Cardiology, GSVM Medical College   Swaroop Nagar, Kanpur 208002
Kanpur Nagar
UTTAR PRADESH 		 9501958808

awakush@gmail.com 
Dr Nirav Bhalalni  Rhythm Heart Institute   Shop No. 429, Vardhan complex, VIP Road, Karelibaug, Vadodara- 390018 Gujarat
Vadodara
GUJARAT 		 8128995863

trial@rhythmheart.com 
Dr Tanmoy Majee  Ruby General Hospital Ltd  Department of Cardiology, 1st Floor 576 Anandpur EM Bypass Kasba, Kolkata West Bengal 700107
Kolkata
WEST BENGAL 		 9339127440

drtanmoymajee@gmail.com 
Dr Ashutosh Angrish   Santosh Medical College and Hospital   Department of Cardiology, First Floor Santosh Medical College and Hospital Ambedkar Road Opp. Old Bus Stand
Ghaziabad
UTTAR PRADESH 		 9643111673

smchgzb@gmail.com 
Dr Ganesh Manudhane   Seven Hills Hospital  Department of Cardiology, Block 12, 4th Floor 3506 Type 3 Building Campus Andheri East Marol Naka Mumbai 400059 , Maharashtra
Mumbai
MAHARASHTRA 		 7276705766

drganeshmanudhane@gmail.com 
Dr Prashant Pawar  Signus Hospital  Research Department, Room No 4, 5th Floor Atlanta Shoppers, Signus Hospital Pathardi Phata, Nashik 422010
Nashik
MAHARASHTRA 		 9623195719

prashantpawar125@gmail.com 
Dr Satish Suryavanshi  SMCH Heart and IVF Research Center   Department of Cardiology Room No 01 Ground Floor Infront of BSNL Office Vidhan Sabha Road Khamardih Raipur Chhattisgarh 492007, India
Raipur
CHHATTISGARH 		 6263014909

drsatish_suryavanshi@yahoo.co.in 
Dr Dhananjay Sigh Shekhawat   SMS Medical College and Attached Hospital  Department of Cardiology JLN Marg 302004 Jaipur
Jaipur
RAJASTHAN 		 9828350188

drdhananjayshekawat@gmail.com 
Dr Amit Varshney  Sri Ram Murti Smarak Institute of Medical Sciences  Department of Medicine, OPD No 09, First Floor Branch office Bareilly, Nainital Road, Bhojipura, Bareilly Uttar Pradesh-247775 , India
Bareilly
UTTAR PRADESH 		 7055778855

varshneyamit25@gmail.com 
Dr Sagar S Garud  Vighnaharta Multi Specialty Hospital  Department of General Medicine, OPD 2, First Floor, Pachora Central, APMC Compound Maharashtra 424201
Jalgaon
MAHARASHTRA 		 9881491555

sagarsgarud@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 12  
Name of Committee  Approval Status 
Ethics Committee Brij Medical Centre   Approved 
ETHICS COMMITTEE GSVM MEDICAL COLLEGE KANPUR GSVM MEDICAL COLLEGE  Approved 
Ethics Committee S.M.S. Medical College and Attached Hospitals  Approved 
Ethics Committee Vighnaharta Multispeciality Hospital  Approved 
Institutional Ethics Committee Govt. Medical College Govt.General Hospital   Approved 
Institutional Ethics Committee Ruby General Hospital   Approved 
Institutional Ethics Committee, SRMSIMS   Approved 
Medical Ethics Committee Seven Hills  Approved 
Rhythm Heart Institute Ethics Committee  Approved 
SASTRA Ethics Committee   Approved 
Signus Hospital Ethics Committee  Approved 
SMC Heart Institute Institutional Ethics Committee   Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: I219||Acute myocardial infarction, unspecified,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Fixed-Dose Combination of Dapagliflozin 10 mg and Metoprolol 50 mg XR tablets   One tablet daily in morning two to three (2-3) hours after breakfast daily for 180 days 
Comparator Agent  Metoprolol 50 mg XR tablets   One tablet daily in morning two to three (2-3) hours after breakfast daily for 180 days 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  1. Subjects of either sex having age >18years at the time of screening.

2. Adult subjects who are capable of understanding and giving written informed consent and willing to comply with the study protocol.

3. Subjects diagnosed established documented diagnosis of symptomatic HF [New York Heart Association (NYHA) functional class II-III] with recent history of (<2months) post-acute myocardial infarction (MI) followed by PCI carried out within 24 hours of occurrence of acute MI with estimated survival time >1 year.

4. Should have been under treatment with optimized standard doses of guideline directed medical therapy which may contain combination of drugs from medication classes suggested in standard guidelines for treatment of HF [“diuretic” and “ACE inhibitor” OR “ARB” and a “beta-blocker” and a “mineralocorticoid receptor antagonist (only if considered appropriate by the treating physician)”]. Therapy should have been individually optimized and stable for ≥4 weeks (this does not apply to diuretics).
NB:
-Patients who have not received beta-blockers prior to Screening shall be initiated on low dose beta-blocker treatment followed by dose up titration during Screening Phase (Day -28 to Day 0).
-Patients should demonstrate stable heart rate on Metoprolol 50mg daily dose at the time of randomization in 2 out of 3 measurements.
-Most patients with heart failure require treatment with a diuretic to control sodium and water retention leading to volume overload. It is recognized that diuretic dosing may be titrated to symptoms, signs, weight and other information and may thus vary. Each patient should, however, be treated with a diuretic regimen aimed at achieving optimal fluid/volume status for that individual.
-Patients in whom any additional pharmacological or device therapy is contemplated or should be considered, must not be enrolled until therapy has been optimized and is stable for ≥4 weeks
-Guideline-recommended medications should be used at recommended doses unless contraindicated or not tolerated

5. Increased N-terminal pro-B- levels at the time of screening.

6. Mildly reduced or reduced ejection fraction <50% on clinical imaging at the time of screening:
-If there is more than one assessment of LVEF the value from the most recent measurement should be used in assessing eligibility.
-2D-ECHO reports from within last 8 weeks are acceptable. In case imaging reports are older, 2D-ECHO to be repeated locally at the time of screening to establish baseline.

7. Females of non-child bearing potential (surgically sterile or menopausal) OR females of child bearing potential using effective birth control measures and non-pregnant & non-lactating females.
 
 
ExclusionCriteria 
Details  1. Subjects previously sensitive to any of the ingredients of the fixed-dose combination under study or beta-blockers or SGLT2 Inhibitors

2. Subjects with past history or present symptoms of Bradycardia [Pulse rate <60bpm] and/or Hypotension [SBP <110 mmHg and DBP <70mmHg] with or without treatment with beta-blockers at 2 out of 3 measurements either at Screening or Randomization.

3. Subjects with history of Bronchial Asthma & COPD.

4. Subjects with history or present symptoms of recurrent UTI infections.

5.Subjects receiving treatment with SGLT2 inhibitors within 8 weeks prior to enrolment.

6. Stroke or transient ischemic attack within 12 weeks prior to enrollment

7. Type-1 Diabetes Mellitus patients

8. Type-2 Diabetes Mellitus patients with frequent episodes of hypoglycemia [Patients with type 2 diabetes mellitus continue to take their glucose lowering therapy but doses could be adjusted as required. Specifically the doses of insulin and sulfonylureas could be reduced to minimize the risk of hypoglycemia]

9. Current acute decompensated HF or hospitalization due to decompensated HF <8 weeks prior to enrolment.

10. Cardiac CRT implantation within 12 weeks or intended to implant prior to enrollment

11. Previous cardiac transplantation or implantation of a ventricular assisted device (VAD) or similar device, or implantation expected after randomization.

12. Symptomatic bradycardia or second- or third-degree heart block without a pacemaker.

13. Active malignancy requiring treatment at the time of visit 1 (with the exception of successfully treated basal cell or treated squamous cell carcinoma) or any history of malignancy

14. Subjects with clinically significant renal disorders:
-Estimated glomerular filtration rate: <30 mL/min/1.73 m2)
-Subjects with S. Creatinine values and S.BUN values ≥ 1.5 times the upper limit of normal.

15. Subjects with hepatocellular insufficiency and in subjects with hepatic failure or active liver disease [abnormal Liver Function Test with values more than 3 times the upper limit of normal].

16. Subjects with EF <25% as per Simpson’s method on 2D Echo.

17. Any known cardiac disease/disorder in which any of the study medication is contra-indicated (e.g. severe bradycardia, heart block greater than a first degree or significant first-degree block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome without pacemaker etc.).

18. Subjects with known significant respiratory/ liver/ kidney/ neurological diseases/ uncontrolled diabetes.

19. Pregnant and lactating women or the women of child bearing age who are not practicing the effective means of contraception.

20. Subjects otherwise judged to be inappropriate for inclusion in the study by the investigator’s judgment.

21.Subjects who will receive some other drug during the study besides that in the protocol that could alter the pharmacokinetic/ pharmacodynamic profile of the study drug.

22.Subjects with known alcohol or drug abuse.

23.Chronic use of Non-steroidal anti-inflammatory drugs (NSAIDS) as they cause fluid retention

24.Subjects with known History or active HIV, Hepatitis B and Hepatitis C, HbsAg infection.

25.Hemodynamically unstable subjects
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Pre-numbered or coded identical Containers 
Blinding/Masking   Participant and Investigator Blinded 
Primary Outcome  
Outcome  TimePoints 
Proportion of subjects achieving at one class symptomatic improvement from baseline in New York Heart Association (NYHA) functional classification for Heart Failure

Proportion of patients showing improvement in LVEF 		 180 days

Baseline, 180 day  
 
Secondary Outcome  
Outcome  TimePoints 
Mean reduction in NT-pro BNP levels from baseline   Baseline, day 90 and day 180
 
Alteration in quality of life using Kansas City Cardiomyopathy questionnaire  Till 180 days  
6-min walk test  Till 180 days 
Worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure or death from cardiovascular causes)  Till 180 days 
 
Target Sample Size   Total Sample Size="236"
Sample Size from India="236" 
Final Enrollment numbers achieved (Total)= "0"
Final Enrollment numbers achieved (India)="0" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   15/06/2023 
Date of Study Completion (India) Date Missing 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="0"
Months="9"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details   NIL 
Individual Participant Data (IPD) Sharing Statement

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

Response - NO
Brief Summary   Heart failure is a progressive and debilitating disease associated with increased risk of hospitalization and poor quality of life. Heart failure is major health issue with an estimated worldwide prevalence of >37.7 million out of which India accountability for heart failure is 1.3 millon to 4.6 millon. The overall incidence is likely to increase in future, hence need to improve quality of life in heart failure patient becomes necessary. Use of angiotensin-receptor neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonist (MRA), SGLT-2 inhibitor, beta blockers has been identified as the standard for care for patient with heart failure by American Heart Association (AHA).

Dapagliflozin is a SGLT2 inhibitor, various studies states that along with hypoglycemic effect, it lowers the blood pressure, inhibits myocardial fibrosis and improves myocardial homeostatsis. Metoprolol is a selective beta blocker, prevents the adrenergic receptor activation induced myocardial inflammation and reduces preload on heart and improves the ventricular loading condition. The proposed study aims to evaluate the efficacy, safety and tolerability of similar fixed dose combination of Dapagliflozin and Metoprolol in heart failure post-acute myocardial infarction with PCI in Indian patients. 



 
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