Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial

PHASE4RECRUITING

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.

info
Simpliy with AI

Study details:

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.

info
Simplify with AI

Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • 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)
  • Exclusion criteria

  • 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.
  • info
    Simplify with AI

    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2022-10-01

    Primary completion: 2023-12-31

    Study completion finish: 2024-06-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE4

    trial

    Trial ID

    NCT05129722

    Intervention or treatment

    DRUG: Low dose combination polydiuretic therapy

    DRUG: Comparator monotherapy empagliflozin

    Conditions

    • Heart Failure With Preserved Ejection Fraction
    Image related to Heart Failure With Preserved Ejection Fraction
    • Condition: Heart Failure With Preserved Ejection Fraction

    • DRUG: Low dose combination polydiuretic therapy and other drugs

    • Camperdown, New South Wales, Australia and more

    • Sponsor: The George Institute

    Find a site

    Closest Location:

    Royal Prince Alfred Hospital

    Research sites nearby

    Select from list below to view details:

    • Royal Prince Alfred Hospital

      Camperdown, New South Wales, Australia

    • St Vincent's Hospital Sydney

      Darlinghurst, New South Wales, Australia

    Loading...

    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    EXPERIMENTAL: Patients receiving low dose combination polydiuretic therapy
    • 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
    • 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
    ACTIVE_COMPARATOR: Comparator group receiving monotherapy empagliflozin
    • 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
    • Sodium-glucose co-transporter 2 inhibitor (SGLT2i): empagliflozin 10mg

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    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 outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    NT-proBNPChange in NT-proBNP (ng/L) from baseline to 4 weeks4 weeks
    NYHA ClassChange in NYHA Class (I-IV) from baseline to 4 weeks4 weeks
    6-minute Walk Test (6MWT) distanceChange in 6MWT distance (metres) from baseline to 4 weeks4 weeks
    Systolic and Diastolic Blood PressureChange in systolic and diastolic blood pressure (mmHg) from baseline to 4 weeks4 weeks
    Body WeightChange in body weight from baseline to 4 weeks (Kg)4 weeks
    Haemoglobin A1cChange in haemoglobin A1c (mmol//mol and %) from baseline to 4 weeks4 weeks
    Haemoglobin and haematocritChange in haemoglobin (g/L) and haematocrit from baseline to 4 weeks4 weeks
    Renal FunctionChange in renal function measured by creatinine(umol/L) and estimated glomerular filtration rate (ml/min/1.73m2) from baseline to 4 weeks4 weeks
    PotassiumChange in blood potassium concentration (mmol/L) from baseline to 4 weeks4 weeks
    Total Diuretic DoseChange in total diuretic dose from baseline to 4 weeks4 weeks
    Pill BurdenNumber of pills taken during 4-week trial period4 weeks

    Frequently Asked Questions

    Please note: some questions and answers are submitted by anonymous patients or using AI, and have not been verified by Clinrol

    No questions submitted. Be the first to ask a question!

    You may be eligible to participate in this trial based on your search.Apply for study
    Are you running this trial? If you're a clinic or sponsor, you can claim this study.Claim this trial

    References

    Clinical Trials Gov: Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial

    Other trails to consider

    Top searched conditions