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

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

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

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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

Resource links provided by the National Library of Medicine


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




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



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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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04363697


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

Locations
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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
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Responsible Party: The TIMI Study Group
ClinicalTrials.gov Identifier: NCT04363697    
Other Study ID Numbers: D1690C00078
First Posted: April 27, 2020    Key Record Dates
Last Update Posted: September 28, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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