CTRI/2023/11/060062 [Registered on: 21/11/2023] Trial Registered Prospectively
Last Modified On:
03/08/2024
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 Study to assess the efficacy and safety of Dapagliflozin and Metoprolol Tablets in heart disease patients.
Scientific Title of Study
A Phase III, Randomized, Double Blind, Active Controlled, Prospective, Parallel Group, Comparative, Multicentric Clinical Study to Evaluate the Efficacy, Safety and Tolerability of Fixed Dose Combination of Dapagliflozin plus Metoprolol Succinate Extended Release Tablets Versus Metoprolol Succinate Extended Release Tablets in Patients with Heart Failure with Reduced Ejection Fraction (HFrEF).
Trial Acronym
NIL
Secondary IDs if Any
Secondary ID
Identifier
CT/2023/11, Version No.: 02 and Dated Aug 04, 2023
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Rajasekhara Reddy Tamma
Designation
Managing Director
Affiliation
CLINWAVE RESERCH PRIVATE LIMITED
Address
Clinwave Research Pvt. Ltd., LIG: B/466, H. No.: 1-16-10/466, Dr. A.S. Rao Nagar, Kapra,Medchal-Malkajgiri (Dist.).
Medchal TELANGANA 500062 India
Phone
7989233379
Fax
Email
dr.sekhar@clinwave.co.in
Details of Contact Person Scientific Query
Name
Dr Rajasekhara Reddy Tamma
Designation
Managing Director
Affiliation
CLINWAVE RESERCH PRIVATE LIMITED
Address
Clinwave Research Pvt. Ltd., LIG: B/466, H. No.: 1-16-10/466, Dr. A.S. Rao Nagar, Kapra,Medchal-Malkajgiri (Dist.).
TELANGANA 500062 India
Phone
7989233379
Fax
Email
dr.sekhar@clinwave.co.in
Details of Contact Person Public Query
Name
Dr Rajasekhara Reddy Tamma
Designation
Managing Director
Affiliation
CLINWAVE RESERCH PRIVATE LIMITED
Address
Clinwave Research Pvt. Ltd., LIG: B/466, H. No.: 1-16-10/466, Dr. A.S. Rao Nagar, Kapra,Medchal-Malkajgiri (Dist.).
TELANGANA 500062 India
Phone
7989233379
Fax
Email
dr.sekhar@clinwave.co.in
Source of Monetary or Material Support
Exemed Pharmaceuticals,
Plot No. 133/1 and 133/2, GIDC,
Selvas Road, Vapi-396195, Gujarat, India.
Primary Sponsor
Name
Exemed Pharmaceuticals
Address
Plot No. 133/1 and 133/2, GIDC, Selvas Road, Vapi-396195, Gujarat, India.
Patients will be advised to take one tablet once daily orally, swallowed with water around same time every day for 24 weeks (168 ±3 days).
Inclusion Criteria
Age From
18.00 Year(s)
Age To
80.00 Year(s)
Gender
Both
Details
1. Male or female patients aged >18 years at the time of screening visit.
2. Patients with diagnosis of heart failure with reduced ejection fraction (HFrEF) with EF ≤ 40% at the time of screening visit.
3. Patients with established documented diagnosis of symptomatic HFrEF (New York Heart Association (NYHA) functional class II-III) at the time of screening visit.
4. Patients should receive a background standard of care for HErEF and be treated according to locally recognized guidelines with both drug and devices, as appropriate. Guideline recommended pharmacological medications should be used at recommended doses unless contraindicated or not tolerated [“diuretic†and “ACE inhibitor†OR “ARB†and a “beta-blocker†and a “mineralocorticoid receptor antagonist (only if considered appropriate by the treating cardiologist)]. Therapy should have been individually optimized and stable for ≥4 weeks (this does not apply to diuretics).
Note:
 Patients who have not received beta-blockers prior to screening shall be initiated on low dose beta-blocker treatment followed by dose up titration (Metoprolol Succinate Extended Release Tablets 25 mg once daily for first 2 weeks followed by up-titration to Metoprolol Succinate Extended Release Tablets 50 mg once daily for next 2 weeks) in the screening phase (day -28 to day 0).
 The patient’s heart rate should be stable on Metoprolol Succinate Extended Release Tablets 50 mg.
 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.
5. Patients with elevated N-terminal pro-B type natriuretic peptide (NT-proBNP) levels at the time of screening visit.
6. Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study. WOCBP must have a negative urine pregnancy test at screening / baseline visit.
7. Patients with ability to understand and provide written, signed and dated informed consent form, which must have been obtained prior to screening.
8. Patients willing to comply with all the protocol related requirements.
ExclusionCriteria
Details
1. Patients with a history of type 1 diabetes mellitus or secondary diabetes mellitus or diabetes insipidus.
2. Patients with a history of metabolic acidosis or diabetic ketoacidosis.
3. Patients with history or present symptoms of bradycardia (pulse rate <60 bpm) and/or hypotension (systolic blood pressure <95 mmHg and diastolic blood pressure <70 mmHg) with or without treatment with beta-blockers at 2 out of 3 measurements either at screening or randomization.
4. Patients with symptoms recent worsening heart failure or other cardiovascular events or procedures (or planned procedures).
5. Patients with hypoxia, a room air saturation of less than 95%.
6. Patients with ongoing myocardial ischemia requiring revascularization.
7. Patients with present or history of hyperkalemia (serum potassium level of more than 5.5 mEq per litre).
8. Patients with type 2 diabetes mellitus whose diabetes has not been stable and controlled for the previous three months and with HbA1c value ≥ 8%.
9. Patients receiving treatment for type 2 diabetes mellitus with SGLT2 inhibitors within 8 weeks prior to screening visit.
10. Patients with history of angioedema and multi-organ dysfunction.
11. Patients with history of bronchial asthma and/or chronic obstructive pulmonary disease (COPD).
12. Patients with a history of genital mycotic infections.
13. Patients with history or present symptoms of recurrent urinary tract infections.
14. Patients with known case of congenital renal glucosuria, history of unstable or rapidly progressing renal disease.
15. Patients with intolerance, contraindication or potential allergy/hypersensitivity to SGLT-2 inhibitors.
16. Female patients who are pregnant or breast-feeding or expecting to conceive within the projected duration of the study.
17. Female patients who are of childbearing potential and who are neither surgically sterilized nor willing to use reliable contraceptive methods (like hormonal, barrier methods or intrauterine device).
18. Patients with clinically significant impaired hepatic function (SGOT & SGPT more than 3X the UNL and/or Total bilirubin more than 2X the UNL) at screening.
19. Patients with clinically significant renal disorders:
 Estimated glomerular filtration rate: <30 mL/min/1.73 m2.
 Serum creatinine and blood urea nitrogen (BUN) values ≥1.5 times the upper limit of normal.
20. Patients with current acute decompensated HF or hospitalization due to decompensated HF <4 weeks prior to enrolment.
21. Patients with MI, unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior to randomization.
22. Patients with Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valvular repair/replacement within 12 weeks prior to randomization or planned to undergo any of these operations after randomization.
23. Patients with implantation of a cardiac CRT within 12 weeks prior to enrolment or intent to implant a CRT device.
24. Patients with previous cardiac transplantation or implantation of a ventricular assistance device (VAD) or similar device, or implantation expected after randomization.
25. Patients with HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease.
26. Patients with symptomatic bradycardia or second or third degree heart block without a pacemaker.
27. Patients with any condition outside the CV and renal disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator´s clinical judgement.
28. Patients with an active or history of malignancy requiring treatment.
29. Patients with EF <25% as per Simpson’s method on 2D Echo.
30. Patients with known case of infection with hepatitis B, hepatitis C or HIV.
31. Patients with concurrent participation in another clinical trial or any investigational therapy within 90 days prior to signing informed consent.
32. Patients with a history of substance abuse or dependence that in the opinion of the Investigator is considered to interfere with the patient’s participation in the study.
33. Patients currently taking any of the prohibited medications(s) and inability/unwillingness to discontinue them for the entire study period.
34. Patients with suspected inability or unwillingness to comply with the study procedures.
35. Patient with any condition which, in the judgment of the Investigator, may render the patient unable to complete the study or which may pose a significant risk to the patient.
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
Mean improvement of ejection fraction (EF) from baseline to end of the study visit (Week 24).
At Screening / Baseline Visit (Visit 1),
Visit 5 - Follow up visit / Week 12 (Day 84±3) and
Visit 7 - End of the study visit / Week 24 (Day 168±3).
Secondary Outcome
Outcome
TimePoints
Mean improvement in NYHA functional class from baseline to end of the study visit (Week 24).
At Screening / Baseline Visit (Visit 1),
Visit 5 - Follow up visit / Week 12 (Day 84±3) and
Visit 7 - End of the study visit / Week 24 (Day 168±3).
Mean change in plasma NT-pro BNP levels from baseline to end of the study visit (Week 24).
At Screening / Baseline Visit (Visit 1),
Visit 5 - Follow up visit / Week 12 (Day 84±3) and
Visit 7 - End of the study visit / Week 24 (Day 168±3).
Mean changes in vital parameters (blood pressure and heart rate) from baseline to end of the study visit (Week 24).
At Screening / Baseline Visit (Visit 1),
Visit 3 - Follow up visit / Week 2 (Day 14±3),
Visit 4 - Follow up visit / Week 6 (Day 42±3),
Visit 5 - Follow up visit / Week 12 (Day 84±3),
Visit 6 - Follow up visit / Week 18 (Day 126±3) and
Visit 7 - End of the study visit / Week 24 (Day 168±3).
Mean change in the potassium levels from baseline to end of the study visit (Week 24).
At Screening / Baseline Visit (Visit 1),
Visit 4 - Follow up visit / Week 6 (Day 42±3),
Visit 5 - Follow up visit / Week 12 (Day 84±3),
Visit 6 - Follow up visit / Week 18 (Day 126±3) and
Visit 7 - End of the study visit / Week 24 (Day 168±3).
Worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) from baseline to end of the study visit (Week 24).
Throughout the study.
Adverse events & serious adverse events reported during the study.
Throughout the study.
Changes in clinical laboratory parameters from baseline to end of the study visit (Week 24).
At Screening / Baseline Visit (Visit 1),
Visit 4 - Follow up visit / Week 6 (Day 42±3),
Visit 5 - Follow up visit / Week 12 (Day 84±3),
Visit 6 - Follow up visit / Week 18 (Day 126±3) and
Visit 7 - End of the study visit / Week 24 (Day 168±3).
Target Sample Size
Total Sample Size="267" Sample Size from India="267" Final Enrollment numbers achieved (Total)= "267" Final Enrollment numbers achieved (India)="267"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This
trial is a phase III, randomized, double blind, active controlled, prospective,
parallel group, comparative, multicentric clinical study to evaluate the
efficacy, safety and tolerability of fixed dose combination of Dapagliflozin
plus Metoprolol Succinate Extended Release Tablets versus Metoprolol Succinate
Extended Release Tablets in patients with heart failure with reduced ejection
fraction (HFrEF).
Patients
who are willing and able to participate in the study will sign and date the
Informed Consent Form on the day of screening visit (Visit 1). During this
screening period, patients who are willing to give consent will be evaluated
for all the eligibility criteria. Eligible patients (male or female) aged
between 18 years and above meeting all the inclusion criteria and none of the
exclusion criteria prior to screening will be considered for the study.
After confirming the inclusion/exclusion criteria the
subject will be randomized and provided with study medication at randomization
visit. Subjects will be provided with patient diary at randomization visit,
which need to be brought along with in each subsequent visit till the last
visit. Follow up visits will be done on week 2/day 14(±3), week 6/day 42(±3), week
12/day 84(±3), week 18/day 126(±3) and week 24/day 168(±3) (final visit) of
treatment to assess efficacy, safety and tolerability.
Patients will be assigned to either of the three arms
i.e., Arm A or Arm B or Arm C consisting of FDC of Dapagliflozin 10 mg +
Metoprolol Succinate Extended Release 25 mg Tablets or FDC of Dapagliflozin 10
mg + Metoprolol Succinate Extended Release 50 mg Tablets or Metoprolol
Succinate Extended Release Tablets 50 mg. Patients will be advised to take one
tablet once daily orally, swallowed with water around same time every day for 24
weeks.