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Heart Failure With Preserved Ejection FractionPhase 4NCT05129722

Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial

A Phase 4 study testing Low dose combination polydiuretic therapy and Comparator monotherapy empagliflozin in people with Heart Failure With Preserved Ejection Fraction, run by The George Institute at 2 sites in Australia.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Low dose combination polydiuretic therapy and Comparator monotherapy empagliflozin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
3 participants
Where
2 sitesAustralia
Study dates
1 Oct 2022to 1 May 2024
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)

Who cannot join

  • 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%
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  • 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.

Trial locations and contacts

2 sites in 1 country.

Australia2 sites

  • Royal Prince Alfred Hospital

    Camperdown, New South Wales, 2050

  • St Vincent's Hospital Sydney

    Darlinghurst, New South Wales, 2010

Other trials in Australia

About this study

Official title: Polydiuretic Therapy for Heart Failure With Preserved Ejection Fraction: A Pilot Trial

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.

Read the detailed description

Heart failure with preserved ejection fraction (HFpEF) refers to a complex syndrome of clinical heart failure without impairment of systolic cardiac function. HFpEF accounts for more than half of patients with heart failure, and this prevalence continues to increase in population studies. Unlike Heart failure with reduced ejection fraction (HFrEF), there are few therapeutic agents that are proven to improve outcomes such as heart failure hospitalisation in this group. The recently published EMPEROR Preserved trial demonstrated that empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), reduced the composite outcome of heart failure hospitalisation and cardiovascular death by 21% (95% CI: 10% to 31%) among patients with HFpEF. This was the first study to meet this clinical endpoint in HFpEF patients. In addition to reducing hospitalisation and CV death, additional therapies in HFpEF are aimed at providing symptomatic relief, through intravascular volume management with diuretics, and treating coexisting illnesses. However, patients may experience diuretic resistance that leads to lower efficacy of diuresis despite increasing doses; this, in turn, can lead to progression of renal dysfunction and other side effects.

Researchers and clinicians must develop strategies to help improve efficacy of diuresis and avoid diuretic resistance, which may be possible through the use of multiple diuretics at lower doses and including newer agents such as sodium-glucose cotransporter 2 (SGLT2) inhibitors.

This multi-centre, double-blinded, randomised (1:1), proof-of-concept, pilot 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. There will be 15 patients per arm (n=30 across two sites). The study will recruit patients from the community including cardiology clinics, primary care providers and will be undertaken in the Royal Prince Alfred (RPA) Cardiology Clinic and St Vincent's Hospital, Sydney, Australia Cardiology Clinic.

The primary implementation hypothesis for this study is that it is feasible to recruit 30 participants to this trial over 6 months and to complete 4 weeks of follow up, with adherence to the protocol and study related procedures (screening, randomisation, study drug allocation, follow-up procedures, and retention) in >/=80% of participants.

There are several secondary hypotheses including that the proposed polydiuretic, as compared to SGLT2i, empagliflozin monotherapy on top of usual care will: increase medication compliance, improve rates of optimal medical therapy, reduce N-terminal pro hormone BNP, improve New York Heart Association (NYHA) Class, reduce fluid overload, improve blood pressure, and body weight at 4 weeks alongside exploratory outcomes of change in their KCCQ. Additionally, the safety hypotheses include that patients will have no increase in Adverse events, Serious Adverse Events, or Adverse events of special interest.

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. This combination of agents draws upon the existing nature of evidence based therapies used in HFpEF that target the kidney.

Being tested
Low dose combination polydiuretic therapy, Comparator monotherapy empagliflozin
Keywords
Heart Failure with Preserved Ejection Fraction, HFpEF, Clinical Trial, SGLT2i, Sodium glucose co-transporter 2 inhibitor

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Low dose combination polydiuretic therapyDrug

    Also called Eplerenone (inspra), Bumetanide (Burinex) and Empagliflozin (jardiance)

    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

  • Comparator monotherapy empagliflozinDrug

    Also called Empagliflozin, Jardiance

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

Study groups in NCT05129722
Study groupRoleWhat they receive
Patients receiving low dose combination polydiuretic therapyExperimentalThis 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.
Receives: Drug: Low dose combination polydiuretic therapy
Comparator group receiving monotherapy empagliflozinActive comparatorThis comparator patient group will receive empagliflozin 10mg (sodium-glucose co-transporter 2 inhibitor) daily on top of their background therapy.
Receives: Drug: Comparator monotherapy empagliflozin

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 6 months

Secondary outcomes (11)

  1. NT-proBNP

    Change in NT-proBNP (ng/L) from baseline to 4 weeks

    Measured: 4 weeks

  2. NYHA Class

    Change in NYHA Class (I-IV) from baseline to 4 weeks

    Measured: 4 weeks

  3. 6-minute Walk Test (6MWT) distance

    Change in 6MWT distance (metres) from baseline to 4 weeks

    Measured: 4 weeks

  4. Systolic and Diastolic Blood Pressure

    Change in systolic and diastolic blood pressure (mmHg) from baseline to 4 weeks

    Measured: 4 weeks

  5. Body Weight

    Change in body weight from baseline to 4 weeks (Kg)

    Measured: 4 weeks

  6. Haemoglobin A1c

    Change in haemoglobin A1c (mmol//mol and %) from baseline to 4 weeks

    Measured: 4 weeks

  7. Haemoglobin and haematocrit

    Change in haemoglobin (g/L) and haematocrit from baseline to 4 weeks

    Measured: 4 weeks

  8. Renal Function

    Change in renal function measured by creatinine(umol/L) and estimated glomerular filtration rate (ml/min/1.73m2) from baseline to 4 weeks

    Measured: 4 weeks

  9. Potassium

    Change in blood potassium concentration (mmol/L) from baseline to 4 weeks

    Measured: 4 weeks

  10. Total Diuretic Dose

    Change in total diuretic dose from baseline to 4 weeks

    Measured: 4 weeks

  11. Pill Burden

    Number of pills taken during 4-week trial period

    Measured: 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Nov 2021
  2. Study start1 Oct 2022
  3. Primary completion1 May 2024
  4. Study completion1 May 2024

Why it stopped: Difficulties in recruitment at both sites.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
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).
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
3 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05129722
Sponsor's protocol ID
2021/PID02198
Status last verified
Nov 2024
First submitted
7 Nov 2021
Last updated
21 Nov 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 34449189

  • 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.

    PubMed 26852410

  • 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.

    PubMed 33663906

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Low dose combination polydiuretic therapy and Comparator monotherapy empagliflozin in people with Heart Failure With Preserved Ejection Fraction, run by The George Institute at 2 sites in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 21 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Difficulties in recruitment at both sites.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Feasibility of recruitment and compliance with study protocol (30 participants and 80% participant completion of study protocol) (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05129722, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Nov 2024; AzTrials last refreshed its copy on 28 Oct 2026.

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