Polydiuretic Therapy for Heart Failure With Preserved Ejection Fraction and Diabetes Mellitus

Polydiuretic Therapy for Heart Failure With Preserved Ejection Fraction and Diabetes Mellitus: A Pilot Trial

This is a single-center, non-randomzied pilot study investigating a combination of targeted therapies as possible treatment for heart failure with preserved ejection fraction (HFpEF).

The study interviention is a Low-Dose, Triple Polydiuretic Therapy (LDTPT, or polydiuretic) including loop diuretic (bumetanide), mineralocorticoid receptor antagonist (eplerenone), and Sodium-glucose co-transporter 2 inhibitors (SGLT2i) therapy (dapaglifozin).

Study Overview

• Status: Withdrawn
• Conditions: Diabetes Mellitus; HF - Heart Failure
• Intervention / Treatment: Drug: Bumetanide 0.5 mg, dapaglifozin 5 mg, eplerenone 25 mg

Detailed Description

Patients with HFpEF and diabetes mellitus will receive polydiuretic therapy consisting of bumetanide 0.5 mg + eplerenone 25 mg + dapaglifozin 5 mg on top of background therapy. These medicines are currently FDA approved and recommended by clinical practice guidelines for the treatment of HFpEF (bumetanide, eplerenone) and diabetes mellitus (dapaglifozin).

This study is designed to evaluate if combination pharmacotherapies with synergistic or additive diuretic properties can improve adherence, treatment efficacy, and effectiveness with fewer side effects

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adults (≥18 years old)
2. English speaker

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

   a. NB: Patients in which additional pharmacological or device therapy is contemplated, or should be considered, must not be enrolled until therapy has been optimized and is stable for ≥1 month.

4. NT-proBNP >600 pg/ml (or if hospitalized for heart failure within the previous 12 months, NT-proBNP ≥400 pg/ml) at enrolment (Visit 1)

   a. If concomitant atrial fibrillation at Visit 1, NT-proBNP must be ≥900 pg/ml (irrespective of history of heart failure hospitalization)

5. Type 2 diabetes mellitus, regardless of background insulin use

Exclusion Criteria:

1. Known contraindication to bumetanide, eplerenone, or dapagliflozin.
2. Symptomatic hypotension or systolic BP <95 mmHg at 2 out of 3 measurements at visit 1.
3. Current acute decompensated HF or hospitalization due to decompensated HF <4 weeks prior to enrolment.
4. Myocardial infarction, unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior to enrollment.
5. HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease.
6. Type 1 diabetes mellitus
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 5.5 mEq/L).
9. 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).
10. 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.
11. Participation in a concurrent interventional medical investigation or pharmacologic clinical trial. Patients in observational, natural history or epidemiological studies not involving an intervention are eligible.
12. Participant's responsible primary care or other responsible physician believes it is not appropriate for participant to participate in the study.
13. Inability or unwillingness to provide written informed consent.
14. Involvement in the planning and/or conduct of the study.
15. Receiving current treatment with sulfonylureas.
16. Unable to complete study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-Dose, Triple Polydiuretic Therapy (LDTPT); Polydiuretic therapy will consist of bumetanide 0.5 mg + eplerenone 25 mg + dapaglifozin 5 mg once daily for 4 weeks.	Drug: Bumetanide 0.5 mg, dapaglifozin 5 mg, eplerenone 25 mg; Low-Dose, Triple Polydiuretic Therapy (LDTPT) Treatment consists of: Loop diuretic (bumetanide 0.5 mg); Mineralocorticoid receptor antagonist (eplerenone 25 mg); Sodium-glucose co-transporter 2 inhibitor (SGLT2i): Farxiga® (dapagliflozin) 5 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NT-proBNP	Change in NT-proBNP after 4 weeks of treatment	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Systolic and Diastolic Blood pressure	Change in blood pressure after 4 weeks of treatment	4 weeks
Change in body weight	Change in weight after 4 weeks of treatment	4 weeks
Compliance	Overall compliance with polydiuretic as assessed by pill count	4 weeks

Collaborators and Investigators

• Sponsor: Northwestern University
• Investigators: Principal Investigator: Sadiya Khan, MD, Northwestern University

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2021
• Primary Completion (Actual): January 1, 2022
• Study Completion (Anticipated): March 30, 2022

Study Registration Dates

• First Submitted: December 7, 2020
• First Submitted That Met QC Criteria: January 5, 2021
• First Posted (Actual): January 6, 2021

Study Record Updates

• Last Update Posted (Actual): May 10, 2022
• Last Update Submitted That Met QC Criteria: May 4, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: HFpEF
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Heart Failure; Diabetes Mellitus; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Potassium Chloride Symporter Inhibitors; Eplerenone; Bumetanide
• Other Study ID Numbers: STU00213243

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes