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CLINICAL EFFICACY OF DAPAGLIFLOZIN IN ASSOCIATION WITH GENETIC POLYMORPHISM AND ITS PLASMA LEVELS IN CHRONIC HEART FAILURE PATIENTS

Protocol summary

Study aim
To evaluate clinical efficacy of Dapagliflozin in association with genetic polymorphism and its plasma levels in patients with CHFrEF in Pakistani population
Design
Randomized Controlled Trial
Settings and conduct
Department of Pharmacology & Therapeutics, Army Medical College, National University of Medical Sciences (NUMS), Rawalpindi
Participants/Inclusion and exclusion criteria
1) INCLUSION CRITERIA Pakistani patients of 18 years and above, males and females Diagnosed symptomatic heart failure (NYHA class 1–IV) Ejection fraction (EF) ≤ 40% on imaging study within last 12 months prior to enrolment Patient on stable GDMT of heart failure for ≥4 weeks Both diabetic and non-diabetic patients 2) EXCLUSION CRITERIA Type-1 diabetics or patients having any history of DKA Patients having eGFR ≤ 25 ml/ min/ 1.73 m2 as per (CKD-EPI formula), systolic blood pressure (SBP) < 95 mmHg Patients having MI, unstable angina, stroke, acute heart failure (HF) or any hospitalization due to acute HF <4 weeks preceding enrolment Patients undergoing PCI /CABG or valvular replacement, any previous transplantation of heart or infixing of ventricular assistance device (VAD), implantation of Cardiac resynchronization therapy (CRT) within 3 months preceding enrolment or any plan to undergo after randomization
Intervention groups
Include Dapagliflozin in addition to GDMT.
Main outcome variables
BIOCHEMICAL TESTS: Serum uric acid and creatinine,Urine R/E and P/C ratio,HbA1c at day 0 and after intervention at 12th week. Echocardiography & eGFR will be calculated at day 0 and 12th week. Plasma levels of Dapagliflozin will be determined by High Performance Liquid Chromatography (HPLC) Improvement in symptoms and QoL will be ascertained by KCCQ questionnaire & NYHA classification.

General information

Reason for update
Acronym
IRCT registration information
IRCT registration number: IRCT20230331057788N1
Registration date: 2023-04-04, 1402/01/15
Registration timing: prospective

Last update: 2023-04-04, 1402/01/15
Update count: 0
Registration date
2023-04-04, 1402/01/15
Registrant information
Name
Saima Rafique
Name of organization / entity
National University of Medical Sciences
Country
Pakistan
Phone
+92 300 8546013
Email address
saimarafiqu34@gmail.com
Recruitment status
Recruitment complete
Funding source
Expected recruitment start date
2023-04-10, 1402/01/21
Expected recruitment end date
2024-04-10, 1403/01/22
Actual recruitment start date
empty
Actual recruitment end date
empty
Trial completion date
empty
Scientific title
CLINICAL EFFICACY OF DAPAGLIFLOZIN IN ASSOCIATION WITH GENETIC POLYMORPHISM AND ITS PLASMA LEVELS IN CHRONIC HEART FAILURE PATIENTS
Public title
Dapagliflozin in Chronic Heart failure patient
Purpose
Treatment
Inclusion/Exclusion criteria
Inclusion criteria:
Pakistani patients of 18 years and above, males and females Diagnosed symptomatic heart failure (NYHA class 1–IV) Ejection fraction (EF) ≤ 40% on imaging study within last 12 months prior to enrolment Patient on stable GDMT of heart failure for ≥4 weeks Both diabetic and non-diabetic patients
Exclusion criteria:
Type-1 diabetics or patients having any history of DKA Patients having eGFR ≤ 25 ml/ min/ 1.73 m2 as per (CKD-EPI formula), systolic blood pressure (SBP) < 95 mmHg Patients having MI, unstable angina, stroke, acute heart failure (HF) or any hospitalization due to acute HF <4 weeks preceding enrolment Patients undergoing PCI /CABG or valvular replacement, any previous transplantation of heart or infixing of ventricular assistance device (VAD), implantation of Cardiac resynchronization therapy (CRT) within 3 months preceding enrolment or any plan to undergo after randomization Patients having active myocarditis, uncorrected primary valvular disease, restrictive or hypertrophic (obstructive) cardiomyopathy; bradycardia, 2nd or 3rd degree heart block without having any pacemaker Patients received any SGLT2i within 12 weeks preceding screening visit or hypersensitivity to Dapagliflozin Pregnant ladies and nursing mothers, severe COPD leading to dyspnea, any malignancy or hepatic impairment
Age
No age limit
Gender
Both
Phase
4
Groups that have been masked
No information
Sample size
Target sample size: 170
Randomization (investigator's opinion)
Randomized
Randomization description
Patients will be randomized on basis of computer- generated random numbers. Each patient will be given a particular code number.
Blinding (investigator's opinion)
Not blinded
Blinding description
Placebo
Not used
Assignment
Parallel
Other design features

Secondary Ids

empty

Ethics committees

1

Ethics committee
Name of ethics committee
Ethical Review Committee
Street address
Army Medical College, Abid Majeed Road, Rawalpindi Cantt
City
Rawalpindi
Postal code
46000
Approval date
2023-01-06, 1401/10/16
Ethics committee reference number
ERC/ID/254

Health conditions studied

1

Description of health condition studied
Chronic Heart Failure
ICD-10 code
I50.42
ICD-10 code description
Chronic combined systolic (congestive) and diastolic (congestive) heart failure

Primary outcomes

1

Description
Primary outcome will include exploration of clinical efficacy of Dapagliflozin in CHF patients
Timepoint
At day 0 and after 12 weeks
Method of measurement
By biochemical parameters including (BNP/ NT-pro BNP, serum uric acid, creatinine, HbA1c, urine R/E, spot urine P/C ratio, echocardiography), improvement in quality of life by KCCQ questionnaire, NYHA functional class. SAFETY ANALYSIS OF DAPAGLIFLOZIN will be analyzed by observing number of events of major hypoglycemia, hypotension urogenital infection, fournier’s gangrene, DKA and any amputation before and after intervention. MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) including heart failure hopsitalisations, urgent heart failure visits, stroke, arrhythmia, MI, acute kidney injury and cardiogenic death will be observed for a number of episodes before and after intervention with Dapagliflozin.

Secondary outcomes

1

Description
1)To determine the prevalence of Dapagliflozin transporter genes SLC5A2 for its single nucleotide polymorphism (SNPs) of SLC5A2 (rs3813008 G>A ,rs9934336 G > A and rs3116150 G>A) encoding SGLT2 transporter in Pakistani CHF population. 2)To estimate steady state plasma drug levels of Dapagliflozin and evaluate association of (SNPs) of Dapagliflozin transporter genes on steady state concentration in Pakistani CHF patients.3)To evaluate association of SNPs and plasma levels of Dapagliflozin with clinical efficacy in Pakistani CHF patients.
Timepoint
After intervention of 12 weeks with Dapagliflozin
Method of measurement
Polymerase Chain Reaction (PCR) will be performed for genetic analysis of SNPs of SLC5A2 (rs3813008 G>A and rs3116150 G>A) followed by Restriction Fragment Length Polymorphism (RFLP). Allele Specific- Polymerase Chain Reaction (AS-PCR) will be performed for genotyping of variant allele (rs9934336 G>A) of SLC5A2. Drug levels will be estimated by HPLC.

Intervention groups

1

Description
Experimental Group: (n=85), This group will receive intervention of drug Dapagliflozin (10mg) daily orally in addition to guideline directed medical therapy (GDMT) in Chronic heart failure patients
Category
Treatment - Drugs

2

Description
Control group: This group will receive only guideline directed medical therapy GDMT in chronic heart failure patients
Category
Treatment - Drugs

Recruitment centers

1

Recruitment center
Name of recruitment center
Army Medical College, Pak Emirates Military Hospital
Full name of responsible person
Dr. Saima Rafique
Street address
Army Medical College, Abid Majeed Road, Rawalpindi, Wah Cantt
City
Rawalpindi
Postal code
46000
Phone
+92 300 8546013
Email
saimarafiqu34@gmail.com

Sponsors / Funding sources

1

Sponsor
Name of organization / entity
National University of Medical Sciences
Full name of responsible person
Dr. Dilshad Khan
Street address
Army Medical College, Abid Majeed Road, Rawalpindi Cantt
City
Rawalpindi
Postal code
46000
Phone
+92 300 8546013
Email
saimarafiqu34@gmail.com
Grant name
PhD grant
Grant code / Reference number
Is the source of funding the same sponsor organization/entity?
Yes
Title of funding source
National University of Medical Sciences
Proportion provided by this source
10
Public or private sector
Public
Domestic or foreign origin
Domestic
Category of foreign source of funding
empty
Country of origin
Type of organization providing the funding
Academic

Person responsible for general inquiries

Contact
Name of organization / entity
Army Medical College, National University of Medical Sciences
Full name of responsible person
Dr. Saima Rafique
Position
Assistant Professor
Latest degree
Master
Other areas of specialty/work
Cardiology
Street address
Army Medical College, Abid Majeed Road, Rawalpindi Cantt
City
Rawalpindi
Province
Punjab
Postal code
46000
Phone
+92 51 5516755
Email
saimarafiqu34@gmail.com

Person responsible for scientific inquiries

Contact
Name of organization / entity
Army Medical College, National University of Medical Sciences, Pakistan
Full name of responsible person
Saima Rafique
Position
Assistant Professor
Latest degree
Master
Other areas of specialty/work
Cardiology
Street address
Army Medical College, Abid Majeed Road, Rawalpindi Cantt
City
Rawalpindi
Province
Punjab
Postal code
74600
Phone
+92 51 5516755
Email
saimarafiqu34@gmail.com

Person responsible for updating data

Contact
Name of organization / entity
Army Medical College, National University of Medical Sciences
Full name of responsible person
Saima Rafique
Position
Assistant Professor
Latest degree
Master
Other areas of specialty/work
Cardiology
Street address
Army Medical College, Abid Majeed Road, Rawalpindi Cantt
City
Rawalpindi
Province
Punjab
Postal code
74600
Phone
+92 51 5516755
Email
saimarafiqu34@gmail.com

Sharing plan

Deidentified Individual Participant Data Set (IPD)
No - There is not a plan to make this available
Justification/reason for indecision/not sharing IPD
Data of Army Personnel can not be shared due to security reasons.
Study Protocol
No - There is not a plan to make this available
Statistical Analysis Plan
No - There is not a plan to make this available
Informed Consent Form
No - There is not a plan to make this available
Clinical Study Report
No - There is not a plan to make this available
Analytic Code
No - There is not a plan to make this available
Data Dictionary
No - There is not a plan to make this available
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