CTRI Number	CTRI/2021/04/032858 [Registered on: 15/04/2021] Trial Registered Prospectively
Last Modified On:	23/03/2023
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study	Drug
Study Design	Randomized, Parallel Group, Placebo Controlled Trial
Public Title of Study Modification(s)	A thorough scientific evaluation of effect of the drug Digoxin in patients having rheumatic heart disease
Scientific Title of Study	Digoxin in patients with rheumatic heart disease - a randomised placebo-controlled trial
Secondary IDs if Any Modification(s)
Details of Principal Investigator or overall Trial Coordinator (multi-center study)	Name  Ganesan Karthikeyan  Address  Room No. 24, Department of Cardiology, 7th Floor, Cardio-thoracic Sciences Centre, AIIMS, Ansari Nagar, Delhi South DELHI 110029 India  Phone  01126594464   Fax     Email  karthik2010@gmail.com
Details Contact Person Scientific Query	Name  Ganesan Karthikeyan  Address  Room No. 24, Department of Cardiology, 7th Floor, Cardio-thoracic Sciences Centre, AIIMS, Ansari Nagar, Delhi South DELHI 110029 India  Phone  01126594464   Fax     Email  karthik2010@gmail.com
Details Contact Person Public Query	Name  Ganesan Karthikeyan  Address  Room No. 24, Department of Cardiology, 7th Floor, Cardio-thoracic Sciences Centre, AIIMS, Ansari Nagar, Delhi South DELHI 110029 India  Phone  01126594464   Fax     Email  karthik2010@gmail.com
Source of Monetary or Material Support Modification(s)	Indian Council of Medical Research V. Ramalingaswami Bhawan, P.O. Box No. 4911 Ansari Nagar, New Delhi - 110029, India
Primary Sponsor Modification(s)	Name  All India Institute of Medical Sciences  Address  Ansari Nagar East, New Delhi - 110029, India  Type of Sponsor  Research institution and hospital
Details of Secondary Sponsor	Name  Address  NIL  NIL
Countries of Recruitment	India
Sites of Study Modification(s)	No of Sites = 12   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr G Karthikeyan  All India Institute of Medical Sciences  Room No. 24 7th Floor Cardio-Thoracic Sciences Centre AIIMS Ansari Nagar South   01126594464 gkarthik2010@gmail.com  Dr Mohit Gupta  Govind Ballabh Pant Hospital   Department of Cardiology New Delhi   011232342425124 drmohitgupta@yahoo.com  Dr Sanjeev Astora  IG Medical College Shimla  Department of Cardiology IG Medical College Shimla Shimla   9418080804 dr.sanjeev00@gmail.com  Dr Santosh Satheesh  Jawahar lal Institute of PostGraduate Medical Education & Research, Puducherry  Depoartment of Cardiology Jawahar lal Institute of PostGraduate Medical Education & Research, Puducherry Pondicherry   9443426244 drsanthoshsatheesh@gmail.com  Dr Rishi Sethi  King George Medical College  Department of Cardiology Lucknow   9305887032 drrishisethi1@gmail.com  Dr Sudeep Kumar  Sanjay Gandhi Post Graduate Institute of Medical Sciences  Department of Cardoilogy Sanjay Gandhi Post Graduate Institute of Medical Sciences Lucknow Lucknow   9415016197 sudeepkum@yahoo.com  Dr Chandrabhan Meena  Sawai Man Singh Medical College  New SMS Campus Rd, Gangawal Park, Adarsh Nagar Jaipur   9414250934 drcbhan@gmail.com  Dr Arun Gopala Krishnan  Sree Chitra Tirunal Institute for Medical Sciences and Technology Trivandrum  Department of Cardiology Sree Chitra Tirunal Institute for Medical Sciences and Technology Trivandrum Thiruvananthapuram   8547609631 arungopalakrishnan99@gmail.com  Dr Ravi S Math  Sri Jayadeva Institute of Cardiovascular Sciences and Research Bangalore  Department of Cardiology Sri Jayadeva Institute of Cardiovascular Sciences and Research Bangalore Bangalore   9535108410 ravismath@rediffmail.com  Dr SN Boopathy  Sri Ramachandra Medical Center Chennai  Department of Cardiology Sri Ramachandra institute of Higher Education and Research Chennai Chennai   9789836339 drsnboopathy@gmail.com  Dr Prayag Kinni  Sri Sathya Sai Institute of Higher Medical Sciences  EPIP Zone, Whitefield, Bangalore   9900084979 imeprayaag@gmail.com  Dr Sandeep Bansal  Vardhman Mahavir Medical College & Safdarjung Hospital  Room No. 725, 7 th Floor , SSB building South   9810543368 drsbansal2000@yahoo.com
Details of Ethics Committee Modification(s)	No of Ethics Committees= 12   Name of Committee  Approval Status  Ethics Committee, S.M.S Medical college  Approved  Institute Ethics Committee All India Institute of Medical Sciences New Delhi  Approved  Institute Ethics Committee VMMC and Safdarjung Hospital  Submittted/Under Review  Institutional Ethics Committee Indira Gandhi Medical College Shimla  Approved  Institutional Ethics Committee Sree Chitra Tirunal Institute for Medical Sciences and Technology Trivandrum  Approved  Institutional Ethics Committee Sri Ramachandra institute of Higher Education and Research Chennai  Approved  Institutional Ethics Committee, Jawaharlal Institute of Post Graduate Medical Education & Research, Puducherry  Approved  Institutional Ethics Committee, King Georges Medical University UP  Approved  Institutional Ethics Committee, Maulana Azad Medical College and Associated Hospital, New Delhi  Approved  Institutional Ethics Committee, Sanjay Gandhi Post Graduation Institute of Medical Sciences, Lucknow  Approved  Sri Jayadeva Ethics Committee Sri Jayadeva Institute of Cardiovascular Sciences and Research Bangalore   Approved  Srisatya Sai Institute of higher learning institutional Ethics Committee  Approved
Regulatory Clearance Status from DCGI	Status  Not Applicable
Health Condition / Problems Studied	Health Type  Condition  Patients  Rheumatic heart disease, unspecified
Intervention / Comparator Agent Modification(s)	Type  Name  Details  Intervention  Digoxin  In order to preserve the pragmatic nature of the trial, no specific dosing regimen will be mandated for trial participants. Physicians will be allowed to follow other accepted dosing schedules at their discretion. However, the most commonly used regimen in India consists of a fixed oral dose of 0.25 mg (or 0.125 mg) once daily with 2 “digoxin-free” days per week. Therapy will be given throughout the period of follow-up i.e. 2 years  Comparator Agent  Placebo  Placebo for oral administration in identical packaging will be given once daily, throughout the period of follow-up i.e. 2 years
Inclusion Criteria	Age From  18.00 Year(s) Age To  80.00 Year(s) Gender  Both  Details  1. Age ≥ 18 years 2. RHD documented by echocardiography 3. Already on treatment with digoxin as advised by their treating doctors 4. Not already on digoxin, but haveeither of the following conditions: i. Heart failure - diagnosed in the presence of current or past clinical symptoms (limitation of activity, fatigue, and dyspnea, orthopnea or paroxysmal nocturnal dyspnea), signs (edema, elevated jugular venous pressure, or rales), or radiologic evidence of pulmonary congestion ii. Atrial fibrillation or flutter -documented on a 12-lead ECG
ExclusionCriteria	Details  1. Significant renal insufficiency (serum creatinine >2 mg/dL) 2. Uncorrected hypokalemia (<3.2 mmol/L) or hyperkalemia (>5.5 mmol/L) 3. Presence of sinus bradycardia (HR <50/min), II or III degree AV block, sick sinus syndrome or pre-excitation 4. Physician does not wish to start digoxin 5. Coexisting coronary artery disease or other cardiac conditions (hypertrophic, dilated or restrictive cardiomyopathies) 6. Patients with mechanical heart valves (however, patients who undergo mechanical valve replacement surgery during the course of the study will be continued on study drug) 7. Pregnant women 8. Presence of severe comorbid conditions which may limit life expectancy to <2 years
Method of Generating Random Sequence	Computer generated randomization
Method of Concealment	On-site computer system
Blinding/Masking	Participant and Investigator Blinded
Primary Outcome Modification(s)	Outcome  TimePoints  A composite of all-cause death and new or worsening heart failure  every three months till minimum 18 months and maximum 36 months
Secondary Outcome Modification(s)	Outcome  TimePoints  Death due to HF  every three months till minimum 18 months and maximum 36 months   All-cause death   every three months till minimum 18 months and maximum 36 months  Composite of HF-related death or hospitalisation for HF  every three months till minimum 18 months and maximum 36 months  Composite of HF-related death, new-onset or worsening heart failure  every three months till minimum 18 months and maximum 36 months  Hospitalisation for HF  every three months till minimum 18 months and maximum 36 months  New-onset or worsening heart failure  every three months till minimum 18 months and maximum 36 months  Quality of life (EQ-5D-5L)  At baseline, 12 months, 18 months and 24 months  Sudden death  every three months till minimum 18 months and maximum 36 months
Target Sample Size	Total Sample Size="1800" Sample Size from India="1800"
Phase of Trial	Phase 4
Date of First Enrollment (India) Modification(s)	25/02/2022
Date of First Enrollment (Global)	No Date Specified
Estimated Duration of Trial	Years="4" Months="0" Days="0"
Recruitment Status of Trial (Global) Modification(s)	Not Applicable
Recruitment Status of Trial (India)	Open to Recruitment
Publication Details Modification(s)	Nil
Brief Summary	Acute rheumatic fever and rheumatic heart disease (RHD) remain a significant public health problem in less developed countries resulting in high mortality and morbidity.1-5 Recent data from a worldwide RHD registry (Rheumatic Heart Disease Global Registry, REMEDY) suggest that about a fourth of patients have atrial fibrillation, and a third have either heart failure (HF) or poor functional class at presentation.3 Patients with RHD presenting to hospital have a high mortality and a significant risk of worsening HF or developing new onset HF.4   Digoxin is widely used in the medical management of patients with rheumatic heart disease (RHD). In the REMEDY study, over a third of patients (with and without AF) were receiving treatment with digoxin at the time of enrolment.3 As in patients without valve disease, clinicians use digoxin in patients with RHD, for rate control in those with AF, and for treatment of heart failure. However, these practices are based almost entirely on anecdotal data. There are no large studies which have evaluated the efficacy and safety of digoxin in this population. In an open-label, cross-over trial, Ahuja et al randomized 10 patients with AF to receive digoxin, verapamil or metoprolol and compared the efficacy of these agents in improving symptoms and exercise capacity.6 Of the three drugs, digoxin produced the least improvement in subjective symptoms and peak treadmill exercise capacity. In the Control of Rate versus Rhythm in Rheumatic Atrial Fibrillation Trial (CRRAFT), although rate control regimens were not systematically evaluated, digoxin was used as add-on therapy to diltiazem in 15% of patients in the rate control arm to optimize treatment.7 Neither of these studies was designed to evaluate cardiovascular outcomes in relation to digoxin use. More recently, we performed a retrospective analysis of the association of digoxin use with clinical outcomes in the REMEDY study.8 In line with expectation, digoxin was used at baseline more often among patients who had AF, were in HF or were in poor functional class. While digoxin use was associated with a higher risk of mortality at two years in unadjusted analyses, the magnitude of this association diminished markedly and progressively with multivariable and propensity weight adjustment.8 This highlights the substantial influence of prescription bias and the need for randomized trials to assess the true utility of digoxin in this population.8 These findings are mirrored by the data on digoxin use in patients with non-valvular AF.9 Adverse outcomes with digoxin may be plausible among patients with non-valvular AF, due to their older age and higher prevalence of hypertension, diabetes and atherosclerotic cardiovascular disease.10 However, patients with RHD are younger, without associated comorbidity, and it is unclear if digoxin will have similar adverse effects in these patients. Extrapolating the results of studies in patients without valve disease, to patients with RHD may result in underuse of an inexpensive treatment which has proven benefit in reducing hospitalization for worsening HF. There is therefore a clear need for an adequately powered randomized controlled trial to evaluate the efficacy and safety of digoxin in patients with RHD.