Effect of Dapagliflozin on Submaximal Exercise Tolerance in Heart Failure

This study will examine whether and how the FDA-approved drug dapagliflozin (Dapa) improves submaximal exercise endurance and skeletal muscle oxidative phosphorylation capacity (SkM OxPhos) in patients with heart failure and reduced left ventricular ejection fraction (HFrEF).

Study Overview

• Status: Completed
• Conditions: HFrEF
• Intervention / Treatment: Drug: Dapagliflozin 10Mg Tab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19054
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Diagnosis of HFrEF with NYHA Class II-III functional class, which has been present for at least two months
2. Left ventricular ejection fraction ≤ 40%
3. Stable medical therapy for at least 1 month
4. Plasma NT-proBNP level of: ≥ 200pg/mL; OR ≥ 125pg/mL if they were hospitalized for HF within the past 12 months; or ≥ 250 pg/mL if patient had atrial fibrillation/flutter on baseline ECG

Exclusion Criteria:

1. Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrollment or previous intolerance of an SGLT2 inhibitor
2. Type 1 diabetes mellitus
3. Age <18 years old
4. Pregnancy: Women of childbearing potential will undergo a urine pregnancy test during the screening visit.
5. Uncontrolled atrial fibrillation, as defined by a resting heart rate > 100 beats per minute at the time of the baseline assessment
6. Paroxysmal atrial fibrillation (Afib) or flutter with >1 hour of continuous Afib documented within the previous 6 months (prior to screening or randomization), direct-current (DC) cardioversion or ablation procedure for Afib within 6 months, or plan to attempt to restore sinus rhythm (with drug therapy, ablation, or DC cardioversion) within 6 months of randomization. Subjects with persistent Afib and no sinus rhythm documented in the prior 6 months are permitted.
7. Hemoglobin < 10 g/dL
8. eGFR < 25 mL/min/1.73m^2, or unstable or rapidly progressing renal disease at the time of randomization
9. Subject inability/unwillingness to exercise
10. Greater than moderate left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), moderate or greater mitral stenosis, severe right-sided valvular disease
11. Known hypertrophic, infiltrative, restrictive or inflammatory cardiomyopathy
12. Clinically significant pericardial disease, as per investigator judgment
13. Current angina due to clinically significant epicardial coronary disease, as per investigator judgment
14. Acute coronary syndrome or coronary intervention within the past 2 months
15. Primary pulmonary artery hypertension (WHO Group 1 Pulmonary Arterial Hypertension)

16. Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria (FEV1<50% predicted), treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, current use of supplemental oxygen aside from nocturnal oxygen for the treatment of obstructive sleep apnea.

    - Desaturation to <90% on the baseline maximal effort cardiopulmonary exercise test will also be grounds for exclusion

17. Clinically-significant ischemia, as per investigator's judgement, on stress testing without either (1) subsequent revascularization, (2) an angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgment; (3) a follow-up 'negative' stress test, particularly when using a more specific technique (i.e., a negative perfusion imaging test following a 'positive' ECG stress test)

    - Exercise induced regional wall motion abnormalities suggestive of ongoing ischemia during the baseline maximal effort cardiopulmonary exercise test will be exclusionary

18. Implantation of a CRT device within 12 weeks prior to enrollment or intent to implant a CRT device during the study period
19. Previous cardiac transplantation or implantation of a ventricular assist device, or implantation expected after randomization
20. Symptomatic bradycardia or second- or third-degree heart block, in the absence of a pacemaker
21. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)
22. Severe right ventricular dysfunction
23. Baseline resting seated systolic blood pressure > 180 mmHg or <90 mmHg
24. Orthostatic blood pressure response to the transition from supine to standing (>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing)
25. Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)

26. Any condition that, in the opinion of the investigator, will interfere with the completion of the study. This may include comorbid or psychiatric conditions that may impede successful completion of the protocol, or logistical concerns (e.g. inability to travel to the exercise unit).

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dapagliflozin 10mg; Active arm will be 6 weeks in duration, separated by a 2-week wash-out period.	Drug: Dapagliflozin 10Mg Tab; This will be a single-center randomized, placebo controlled, double-blind, 2-treatment, 2-phase cross-over trial in 27 HFrEF subjects: (A) Dapa 10 mg daily; (B) Placebo.
Placebo Comparator: Placebo; Placebo arm will be 6 weeks in duration, separated by a 2-week wash-out period.	Drug: Placebo; This will be a single-center randomized, placebo controlled, double-blind, 2-treatment, 2-phase cross-over trial in 27 HFrEF subjects: (A) Dapa 10 mg daily; (B) Placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary endpoint will be the change in submaximal exercise endurance (time to exhaustion at 75% of peak workload) between Dapa and placebo.	24 Months

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Amgen

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2021
• Primary Completion (Actual): June 1, 2023
• Study Completion (Actual): June 1, 2023

Study Registration Dates

• First Submitted: June 30, 2021
• First Submitted That Met QC Criteria: June 30, 2021
• First Posted (Actual): July 9, 2021

Study Record Updates

• Last Update Posted (Estimated): December 12, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 848538

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: No