Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure -Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68)

• ClinicalTrials.gov Identifier: NCT04363697
• Recruitment Status: Recruiting
• First Posted: April 27, 2020
• Last Update Posted: September 28, 2020
• Sponsor: The TIMI Study Group
• Collaborators: AstraZeneca; Worldwide Clinical Trials
• Information provided by (Responsible Party): The TIMI Study Group

Study Description

Brief Summary:

This is an international, multicenter, parallel-group, randomized, double-blind, placebo-controlled trial in patients with heart failure with reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤40%) who have been stabilized during hospitalization for acute heart failure, evaluating the effect of in-hospital initiation of dapagliflozin versus placebo on the clinical outcome of cardiovascular death or worsening heart failure.

Condition or disease	Intervention/treatment	Phase
Acute Heart Failure; Heart Failure With Reduced Ejection Fraction	Drug: Dapagliflozin; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 2400 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Trial to Evaluate the Effect of In-Hospital Initiation of Dapagliflozin on Clinical Outcomes in Patients With Heart Failure With Reduced Ejection Fraction Who Have Been Stabilized During Hospitalization for Acute Heart Failure DAPAgliflozin and Effect on Cardiovascular Events in ACuTe Heart Failure -Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68)
• Actual Study Start Date: September 24, 2020
• Estimated Primary Completion Date: July 31, 2022
• Estimated Study Completion Date: October 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dapagliflozin; Dapagliflozin 10 mg administered orally once daily for 2 months	Drug: Dapagliflozin; Dapagliflozin
Placebo Comparator: Placebo; Matching placebo administered orally once daily for 2 months	Drug: Placebo; Matched placebo

Outcome Measures

Primary Outcome Measures :

1. Cardiovascular (CV) death or worsening heart failure [ Time Frame: 2 months ]
   Time to first occurrence of CV death or worsening heart failure

Secondary Outcome Measures :

1. Composite CV death, rehospitalization for heart failure, urgent heart failure visit [ Time Frame: 2 months ]
   Time to first occurrence of composite of CV death, rehospitalization for heart failure, or urgent heart failure visit
2. Composite CV death, rehospitalization for heart failure [ Time Frame: 2 months ]
   Time to first occurrence of composite of CV death or rehospitalization for heart failure
3. Rehospitalization for heart failure, urgent heart failure visit [ Time Frame: 2 months ]
   Time to first occurrence of rehospitalization for heart failure or urgent heart failure visit
4. Readmission [ Time Frame: 2 months ]
   Readmission within 30 days of hospital discharge
5. CV death [ Time Frame: 2 months ]
   Time to CV death
6. Death [ Time Frame: 2 months ]
   Time to death

Other Outcome Measures:

1. Symptomatic hypotension [ Time Frame: 2 months ]
   Symptomatic hypotension leading to hospitalization or study drug discontinuation
2. Worsening renal function [ Time Frame: 2 months ]
   Worsening renal function resulting in at least a doubling of serum creatinine (sCr), hospitalization, study drug discontinuation, dialysis, or renal death

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Age ≥18 years (male or female)

2. Currently hospitalized for acute heart failure (AHF) defined as meeting all the following criteria:

   1. Presentation with worsening symptoms of heart failure (e.g., worsening dyspnea or dyspnea at rest, progressive fatigue, rapid weight gain, worsening edema/abdominal distention/anasarca)
   2. Objective signs or diagnostic testing consistent with volume overload (e.g., jugular venous distension, pulmonary basilar crackles, S3 gallop, ascites, hepatomegaly, peripheral edema, radiological evidence of pulmonary congestion, noninvasive or invasive hemodynamic evidence of elevated filling pressures)
   3. Intensification of heart failure therapy during admission defined as at least one of the following:

   i. Augmentation of oral diuretic therapy [e.g., ≥2x outpatient regimen dose, addition of a second diuretic agent, or new initiation of diuretic therapy in a previously naïve patient] ii. Initiation of intravenous diuretic therapy iii. Initiation of intravenous vasoactive agent (e.g., inotrope or vasodilator)

   The majority of enrolled patients should have an established history of heart failure with reduced ejection fraction (HFrEF) (defined as present for ≥2 months and for which the patient is on treatment). Trial leadership will monitor this proportion and may cap enrollment of patients without an established history of HFrEF (i.e., patients presenting with de novo HFrEF).

3. Most recent LVEF ≤40% within the past 12 months (including current hospitalization)
4. Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) (≥1600 pg/mL) or B-type natriuretic peptide (BNP) (≥400 pg/mL) during current hospitalization (NT-proBNP ≥2400 pg/mL or BNP ≥600 pg/mL if patient in atrial fibrillation) (NB: for patients treated with angiotensin receptor neprilysin inhibitor (ARNI) in the 4 weeks prior to randomization, only NT-proBNP values should be used)

5. Eligible patients will be randomized no earlier than 24 hours and up to seven days after presentation while still hospitalized once they have been stabilized, as defined by:

   1. No increase (i.e., intensification) in the dose of intravenous diuretics during the 24 hours prior to randomization
   2. No use of intravenous vasodilators or inotropes during the 24 hours prior to randomization

Patients with and without type 2 diabetes are eligible for participation in the trial. The trial leadership will monitor the proportion of patients with and without type 2 diabetes and may cap enrollment of one subgroup to ensure adequate representation of the other.

Exclusion Criteria:

1. Symptomatic hypotension in the past 24 hours
2. Use of two or more inotropic agents during the index hospitalization
3. Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 as measured by the Chronic kidney disease epidemiology collaboration equation (CKD-EPI) equation at screening or rapidly progressive renal disease
4. Use of an Sodium-glucose cotransporter-2 (SGLT2) inhibitor within the last 30 days
5. Prior intolerance of SGLT2 inhibitors
6. Type 1 diabetes mellitus or history of diabetic ketoacidosis
7. In patients with diabetes on insulin or a sulfonylurea, a history of recurrent major hypoglycemia (i.e., resulting in severe impairment in consciousness or behavior, or requiring emergency external assistance)
8. Implantation of a cardiac resynchronization therapy (CRT) device or valve repair or replacement within 3 months prior to randomization or intent to do so during the trial
9. ST-segment elevation myocardial infarction or coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within 3 months prior to randomization or intent to undergo coronary revascularization during the trial
10. Untreated sustained ventricular arrhythmias or Mobitz type II or third-degree heart block (i.e., without an implantable cardioverter defibrillator [ICD] or pacemaker, respectively)
11. History of heart transplantation, current transplant listing, or history of mechanical circulatory support (either durable or temporary)
12. History of heart failure due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, uncorrected primary valvular disease, or complex congenital heart disease
13. History of cirrhosis with evidence of portal hypertension
14. Women of child-bearing potential (unless using adequate contraception) or currently breastfeeding
15. Current participation in a clinical trial with an unlicensed drug or device
16. Study center employees or their family members
17. Any condition that, in the opinion of the investigator, would make trial participation not in the best interest of the subject, or would compromise compliance with the trial protocol (e.g., active severe infection, active malignancy)

Contacts and Locations

Contacts

Contact: Abby Cange; 800-385-4444; acange@bwh.harvard.edu

Locations

United States, Massachusetts

TIMI Study Group; Recruiting

Boston, Massachusetts, United States, 02115

Contact: TIMI Study Group 617-278-0145

Sponsors and Collaborators

The TIMI Study Group

AstraZeneca

Worldwide Clinical Trials

More Information

• Responsible Party: The TIMI Study Group
• ClinicalTrials.gov Identifier: NCT04363697
• Other Study ID Numbers: D1690C00078
• First Posted: April 27, 2020
• Last Update Posted: September 28, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Heart Failure; Myocardial Infarction; Infarction; Heart Diseases; Cardiovascular Diseases; Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Vascular Diseases; 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs