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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05129722




Registration number
NCT05129722
Ethics application status
Date submitted
7/11/2021
Date registered
22/11/2021
Date last updated
25/05/2023

Titles & IDs
Public title
Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial
Scientific title
Polydiuretic Therapy for Heart Failure With Preserved Ejection Fraction: A Pilot Trial
Secondary ID [1] 0 0
2021/PID02198
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure With Preserved Ejection Fraction 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Low dose combination polydiuretic therapy
Treatment: Drugs - Comparator monotherapy empagliflozin

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.

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.


Treatment: Drugs: 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

Treatment: Drugs: Comparator monotherapy empagliflozin
Sodium-glucose co-transporter 2 inhibitor (SGLT2i): empagliflozin 10mg
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Feasibility of recruitment and compliance with study protocol (30 participants and 80% participant completion of study protocol)
Timepoint [1] 0 0
6 months
Secondary outcome [1] 0 0
NT-proBNP
Timepoint [1] 0 0
4 weeks
Secondary outcome [2] 0 0
NYHA Class
Timepoint [2] 0 0
4 weeks
Secondary outcome [3] 0 0
6-minute Walk Test (6MWT) distance
Timepoint [3] 0 0
4 weeks
Secondary outcome [4] 0 0
Systolic and Diastolic Blood Pressure
Timepoint [4] 0 0
4 weeks
Secondary outcome [5] 0 0
Body Weight
Timepoint [5] 0 0
4 weeks
Secondary outcome [6] 0 0
Haemoglobin A1c
Timepoint [6] 0 0
4 weeks
Secondary outcome [7] 0 0
Haemoglobin and haematocrit
Timepoint [7] 0 0
4 weeks
Secondary outcome [8] 0 0
Renal Function
Timepoint [8] 0 0
4 weeks
Secondary outcome [9] 0 0
Potassium
Timepoint [9] 0 0
4 weeks
Secondary outcome [10] 0 0
Total Diuretic Dose
Timepoint [10] 0 0
4 weeks
Secondary outcome [11] 0 0
Pill Burden
Timepoint [11] 0 0
4 weeks

Eligibility
Key inclusion criteria
1. Have provided written informed consent

2. Adults = 18 years old

3. Established diagnosis of NYHA Class II - IV heart failure with preserved ejection
fraction, which has been present for at least 2 months

4. 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.

5. 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)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known contraindication to bumetanide, eplerenone, or empagliflozin.

2. Concurrently prescribed prohibited medications which are mineralocorticoid receptor
antagonists (Spironolactone and Eplerenone) and SGLT2i agents.

3. Symptomatic hypotension or systolic BP <95 mmHg at 2 out of 3 measurements at Visit 0

4. Current acute decompensated HF or hospitalisation due to decompensated HF <4 weeks
prior to enrolment.

5. Myocardial infarction, unstable angina, stroke, or transient ischaemic attack (TIA)
within 12 weeks prior to enrolment.

6. HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis,
hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease or
reduced EF < 50%

7. Symptomatic bradycardia or second or third-degree heart block without a pacemaker.

8. 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).

9. Previous history of ketoacidosis

10. 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).

11. 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.

12. 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.

13. Participant's responsible primary care or other responsible physician believes it is
not appropriate for participant to participate in the study.

14. Inability or unwillingness to provide written informed consent.

15. Involvement in the planning and/or conduct of the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/10/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2024
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 0 0
St Vincent's Hospital Sydney - Darlinghurst
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2010 - Darlinghurst

Funding & Sponsors
Primary sponsor type
Other
Name
The George Institute
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Victor Chang Cardiac Research Institute
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
St Vincent's Centre for Applied Medical Research
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05129722
Trial related presentations / 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.
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.
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 Mar 1:S1071-9164(21)00050-6. doi: 10.1016/j.cardfail.2021.01.022. Online ahead of print.
Public notes

Contacts
Principal investigator
Name 0 0
Clare Arnott
Address 0 0
The George Institute
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Clare Arnott
Address 0 0
Country 0 0
Phone 0 0
+61 2 8052 4823
Fax 0 0
Email 0 0
carnott@georgeinstitute.org.au
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05129722