Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial

NCT05129722 | Terminated Phase 4 DMC

• 1 other identifier: 2021/PID02198
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 2

Brief Summary

Heart Failure (HF) in Australia affects 1-2% of the population. Heart failure with preserved ejection fraction (HFpEF) refers to a syndrome of clinical heart failure without impairment of systolic cardiac function. HFpEF has few therapeutic agents that are proven to improve outcomes and it was only recently, the published EMPEROR-Preserved trial demonstrated that empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) reduced composite outcome of heart failure hospitalisation and cardiovascular death by 21% among patients with HFpEF.\[1\] HFpEF therapies have traditionally aimed at providing symptomatic relief and treating coexisting illnesses. This multi-centre randomised clinical trial aims to establish the feasibility of a fixed low dose combination polypill consisting of bumetanide 0.5 mg, eplerenone 25 mg, and empagliflozin 10 mg in patients with HFpEF compared against empagliflozin 10 mg monotherapy in patients with HFpEF. Fixed dose combination low dose diuretics of this nature have not been rigorously studied in patients with HFpEF, and this study aims to help improve the treatment paradigm for this patient population.

Conditions

Heart Failure With Preserved Ejection Fraction

Keywords

Heart Failure with Preserved Ejection Fraction; HFpEF; Clinical Trial; SGLT2i; Sodium glucose co-transporter 2 inhibitor

Outcome Measures

Primary Outcomes (1)

• Feasibility of recruitment and compliance with study protocol (30 participants and 80% participant completion of study protocol)

  Recruitment of 30 participants, with completion of study related procedures (screening, randomisation, study drug allocation, follow-up procedures, and retention over 4 weeks) in ≥ 80% of participants.

  6 months

Secondary Outcomes (11)

• NT-proBNP

  4 weeks

• NYHA Class

  4 weeks

• 6-minute Walk Test (6MWT) distance

  4 weeks

• Systolic and Diastolic Blood Pressure

  4 weeks

• Body Weight

  4 weeks

Other Outcomes (2)

• Exploratory Endpoint

  4 weeks

• Incidence of Serious adverse events and Adverse events of special interest (safety and tolerability)

  4 weeks

Study Arms (2)

Patients receiving low dose combination polydiuretic therapy

EXPERIMENTAL

This patient group will receive a low dose combination polydiuretic therapy treatment consisting of: bumetanide 0.5 mg (loop diuretic), eplerenone 25 mg (mineralocorticoid receptor antagonist) and empagliflozin 10mg (sodium-glucose co-transporter 2 inhibitor) daily on top of their background therapy.

Drug: Low dose combination polydiuretic therapy

Comparator group receiving monotherapy empagliflozin

ACTIVE COMPARATOR

This comparator patient group will receive empagliflozin 10mg (sodium-glucose co-transporter 2 inhibitor) daily on top of their background therapy.

Drug: Comparator monotherapy empagliflozin

Interventions

Low dose combination polydiuretic therapy DRUG

Low dose combination polydiuretic therapy treatment consists of: Loop diuretic bumetanide 0.5 mg Mineralocorticoid receptor antagonist eplerenone 25 mg Sodium-glucose co-transporter 2 inhibitor (SGLT2i): empagliflozin 10mg

Also known as: Eplerenone (inspra), Bumetanide (Burinex) and Empagliflozin (jardiance)

Patients receiving low dose combination polydiuretic therapy

Comparator monotherapy empagliflozin DRUG

Sodium-glucose co-transporter 2 inhibitor (SGLT2i): empagliflozin 10mg

Also known as: Empagliflozin, Jardiance

Comparator group receiving monotherapy empagliflozin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have provided written informed consent
• Adults ≥ 18 years old
• Established diagnosis of NYHA Class II - IV heart failure with preserved ejection fraction, which has been present for at least 2 months
• Left ventricular ejection fraction ≥50% on echocardiography within the last 12 months prior to study enrolment, and no previous echocardiogram with EF \< 40% NB: Patients in which additional pharmacological or device therapy is contemplated, or should be considered, must not be enrolled until therapy has been optimised and is stable for ≥ 1 month.
• NT-proBNP \>300 pg/ml (or if hospitalised for heart failure within the previous 12 months, NT-proBNP ≥400 pg/ml) at enrolment. If concomitant atrial fibrillation at Visit 1, NT-proBNP must be ≥900 pg/ml (irrespective of history of heart failure hospitalisation)

You may not qualify if:

• Known contraindication to bumetanide, eplerenone, or empagliflozin.
• Concurrently prescribed prohibited medications which are mineralocorticoid receptor antagonists (Spironolactone and Eplerenone) and SGLT2i agents.
• Symptomatic hypotension or systolic BP \<95 mmHg at 2 out of 3 measurements at Visit 0
• Current acute decompensated HF or hospitalisation due to decompensated HF \<4 weeks prior to enrolment.
• Myocardial infarction, unstable angina, stroke, or transient ischaemic attack (TIA) within 12 weeks prior to enrolment.
• HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease or reduced EF \< 50%
• Symptomatic bradycardia or second or third-degree heart block without a pacemaker.
• Evidence of secondary cause of hypertension e.g., renal artery stenosis; significant renal impairment (eGFR \<50 ml/min/1.73 m2), raised serum potassium (above lab normal limit of 5.0 mEq/L).
• Previous history of ketoacidosis
• Women who are pregnant, breast feeding or of childbearing potential and are not using and do not plan to continue using medically acceptable form of contraception throughout the study (pharmacological or barrier methods).
• Concomitant illness, physical impairment or mental condition which in the opinion of the study team / primary care physician could interfere with the conduct of the study including outcome assessment.
• Participation in a concurrent interventional medical investigation or pharmacologic clinical trial. Participants in observational, natural history or epidemiological studies not involving an intervention are eligible.
• Participant's responsible primary care or other responsible physician believes it is not appropriate for participant to participate in the study.
• Inability or unwillingness to provide written informed consent.
• Involvement in the planning and/or conduct of the study.

Sponsors & Collaborators

• The George Institute: lead
• Victor Chang Cardiac Research Institute: collaborator
• St Vincent's Centre for Applied Medical Research: collaborator
• Royal Prince Alfred Hospital, Sydney, Australia: collaborator

Study Sites (2)

Royal Prince Alfred Hospital

Camperdown, New South Wales, 2050, Australia

Location

St Vincent's Hospital Sydney

Darlinghurst, New South Wales, 2010, Australia

Location

Related Publications (3)

• Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Pina IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27.

  PMID: 34449189 BACKGROUND

• Sahle BW, Owen AJ, Mutowo MP, Krum H, Reid CM. Prevalence of heart failure in Australia: a systematic review. BMC Cardiovasc Disord. 2016 Feb 6;16:32. doi: 10.1186/s12872-016-0208-4.

  PMID: 26852410 BACKGROUND

• Bozkurt B, Coats AJ, Tsutsui H, Abdelhamid M, Adamopoulos S, Albert N, Anker SD, Atherton J, Bohm M, Butler J, Drazner MH, Felker GM, Filippatos G, Fonarow GC, Fiuzat M, Gomez-Mesa JE, Heidenreich P, Imamura T, Januzzi J, Jankowska EA, Khazanie P, Kinugawa K, Lam CSP, Matsue Y, Metra M, Ohtani T, Francesco Piepoli M, Ponikowski P, Rosano GMC, Sakata Y, SeferoviC P, Starling RC, Teerlink JR, Vardeny O, Yamamoto K, Yancy C, Zhang J, Zieroth S. Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J Card Fail. 2021 Apr;27(4):387-413. doi: 10.1016/j.cardfail.2021.01.022. Epub 2021 Mar 1.

  PMID: 33663906 BACKGROUND

MeSH Terms

Interventions

Eplerenone; Bumetanide; empagliflozin

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sulfonamides; Amides; meta-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds

Study Officials

• Clare Arnott

  The George Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: The randomisation allocation will be blinded to all participants, physicians, and study team members, except an unblinded study statistician and study drug manufacturer. All individual, standard, and regulatory approved medications will be over-encapsulated and concealed by identical packaging, labelling, and administration scheduling.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This pilot research project will be a multi-centre, double-blinded randomised control trial (1:1) of the use of a low dose combination polypill (bumetanide 0.5mg + eplerenone 25mg + empagliflozin 10mg) versus empagliflozin 10mg alone on top of their background therapy. There will be 15 patients per arm (n=30 across two sites).

Study Record Dates

• First Submitted: November 7, 2021
• First Posted: November 22, 2021
• Study Start: October 1, 2022
• Primary Completion: May 1, 2024
• Study Completion: May 1, 2024
• Last Updated: November 21, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2)