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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The Brigham And Women’s Hospital Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

14 Feb 2023 → 2 Jun 2025

Decision date (initial)

2024-11-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

The Brigham And Women’s Hospital Inc.

External identifiers

EU CT number

2024-517612-29-00

EudraCT number

2022-001262-35

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety

To assess the effect of in-hospital initiation of dapagliflozin, as compared with placebo, on the clinical outcome of cardiovascular death or
worsening heart failure in patients who have been stabilized during hospitalization for acute heart failure.

Secondary objectives 1

1. To evaluate the safety and tolerability of in-hospital initiation of dapagliflozin in this patient population.

Conditions and MedDRA coding

acute heart failure

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. To evaluate the safety and tolerability of in-hospital initiation of dapagliflozin in this patient population.
2. Currently hospitalized for AHF defined as meeting all the following criteria: a) 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) b) 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) c) Intensification of AHF 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 (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 heart failure (i.e., patients presenting with de novo heart failure).
3. Left ventricular ejection fraction (LVEF) measured within the past 12 months (including during the current hospitalization)
4. Elevated NT-proBNP or BNP during current hospitalization: a) For patients with LVEF ≤40%: NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL (NT-proBNP ≥2400 pg/mL or BNP ≥600 pg/mL if patient in atrial fibrillation or atrial flutter) b) For patients with LVEF >40%: NT-proBNP ≥1200 pg/mL or BNP ≥300 pg/mL (NT-proBNP ≥1800 pg/mL or BNP ≥450 pg/mL if patient in atrial fibrillation or atrial flutter)
5. Eligible patients will be randomized no earlier than 24 hours and up to 14 days after presentation while still hospitalized once they have been stabilized, as defined by: a) No increase (i.e., intensification) in the dose of intravenous diuretics during the 12 hours prior to randomization b) No use of intravenous vasodilators or inotropes during the 24 hours prior to randomization Patients across the spectrum of LVEF are eligible for participation in the trial. Trial leadership will monitor the proportion of patients with various LVEFs and may cap enrollment of certain subgroups to ensure a broad population. In addition, patients with and without type 2 diabetes are eligible for participation in the trial. 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 17

1. Symptomatic hypotension in the past 24 hours
2. Concurrent use of two or more intravenous inotropic agents during the index hospitalization
3. eGFR <25 ml/min/1.73 m2 as measured by the CKD-EPI equation at screening or rapidly progressive renal disease
4. Current use of an SGLT2 inhibitor
5. Prior intolerance of SGLT2 inhibitors, including hypersensitivity to dapagliflozin, or to any excipient (inactive substance) in the study drug
6. Type 1 diabetes mellitus or history of diabetic ketoacidosis
7. (Only applies to patients with T2DM who are on insulin and/or a sulfonylurea) 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 30 days 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 30 days 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 ICD or pacemaker, respectively)
11. History of heart transplantation or current transplant listing; mechanical circulatory support use (either durable or temporary) during the index hospitalization
12. History of heart failure due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, uncorrected primary valvular disease, complex congenital heart disease, or heart failure felt to be due to a transient process (e.g., stress [takotsubo] cardiomyopathy, tachycardia-induced cardiomyopathy) expected to resolve within 2 months.
13. History of end-stage liver disease
14. Women of child-bearing potential (unless using highly effective contraception method) or currently breastfeeding
15. Current participation in a clinical trial with an unlicensed drug or device
16. Study staff 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Time to first occurrence of cardiovascular death or worsening heart failure defined as: 1. Worsening HF during the index admission requiring at least one of the following: a) initiation or re-initiation of inotropic therapy for ≥24 hours b) mechanical circulatory support c) invasive ventilatory support for heart failure d) heart transplantation
2. Time to first occurrence of cardiovascular death or worsening heart failure defined as: 2. Readmission for worsening heart failure
3. Time to first occurrence of cardiovascular death or worsening heart failure defined as: 3. Worsening heart failure leading to an urgent visit with administration of intravenous diuretic therapy (e.g., outpatient setting, emergency department) without associated hospital admission

Secondary endpoints 2

1. Symptomatic hypotension leading to hospitalization or study drug discontinuation
2. Worsening renal function that results in at least a doubling of serum creatinine, hospitalization, study drug discontinuation, dialysis, or renal death

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The Brigham And Women’s Hospital Inc.

Sponsor organisation

The Brigham And Women’s Hospital Inc.

Address

75 Francis Street

City

Boston

Postcode

02115-6110

Country

United States

Scientific contact point

Organisation

The Brigham And Women’s Hospital Inc.

Contact name

Wiviott Stephen

Public contact point

Organisation

The Brigham And Women’s Hospital Inc.

Contact name

Wiviott Stephen

Third parties 2

Locations

3 EU/EEA countries · 51 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications