DAPAPROTECTOR: DAPAgliflozine to Attenuate Cardiac RemOdeling afTEr aCuTe myOcardial Infarction

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05764057

Collaborator

AstraZeneca (Industry)

450

Enrollment

Location

Arms

30.1

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Recent clinical trials have proven the cardiovascular benefits of new medications for patients with heart failure with reduced ejection fraction (HFrEF), especially sodium-glucose co-transporter 2 (SGLT2) inhibitors. There are no existing randomized clinical trials evaluating the efficacy and safety of dapagliflozin (nor any other SGLT2-inhibitor) to limit cardiac remodeling in patients with acute myocardial infarction (AMI) and left ventricular (LV) dysfunction.

Preventing cardiac remodeling, an established predictor of subsequent heart failure (HF) and cardiovascular death, is likely to translate into benefit in reducing clinical events in post-MI patients.

Condition or Disease	Intervention/Treatment	Phase
AMI STEMI NSTEMI Left Ventricular Dysfunction	Drug: Dapagliflozin propanediol (FORXIGA™/FARXIGA™1) Drug: Placebo comparator	Phase 3

Detailed Description

DAPA-PROTECTOR is a prospective multicenter, randomized, double blind, phase III trial.

Patients with confirmed AMI (e.g., STEMI or very high-risk NSTEMI) with LV dysfunction (LVEF≤45%) after completion of percutaneous coronary intervention (PCI) will be assessed for eligibility. Patients will be randomized (in a 1:1 ratio) to receive dapagliflozin (10mg once day) or placebo for 6 months, on top of standard of care as recommended in current guidelines. Treatment will be prescribed as soon as possible after admission (and before day-3). The first TTE (TTE-1) will be performed before randomization to confirm inclusion criteria (LVEF≤45%). Four visits are scheduled: at randomization (Visit 1), at discharge (Visit 2) at Month 3 ±2 weeks (Visit 3), and at Month 6 ±1 month (Visit 4). After randomization, Visit 2 and Visit 3 will be scheduled to check the tolerance of the drug and dispensing of treatment. Finally, the last visit (Visit 4) will be scheduled to collect clinical follow-up and to perform a TTE (TTE-2). Efficacy criteria will be assessed from randomization to Month 6 by TTE. All TTE results will be anonymized and centralized at a Corelab with assessment by independent cardiologists unaware of the patient treatment group.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

450 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

DAPAgliflozine to Attenuate Cardiac RemOdeling afTEr aCuTe myOcardial Infarction

Anticipated Study Start Date :

Mar 1, 2023

Anticipated Primary Completion Date :

Sep 1, 2025

Anticipated Study Completion Date :

Sep 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin 10mg daily + standard of care Dapagliflozin 10mg per day will be administered orally, as in clinical practice	Drug: Dapagliflozin propanediol (FORXIGA™/FARXIGA™1) Dapagliflozin (10 mg per day; per os) on top of standard of care as recommended in current guidelines* for 6 months (experimental group) *All patients will receive optimal medical therapy (including antithrombotic, beta-blockers, statins, angiotensin converting enzyme inhibitors or angiotensin receptor blocker or sacubitril/valsartan, diuretics, antagonists of the mineralocorticoid receptor) according to their clinical condition as recommended.
Placebo Comparator: Placebo + standard of care Placebo will be administered orally	Drug: Placebo comparator Placebo daily on top of standard of care as recommended in current guidelines* for 6 months (control group) *All patients will receive optimal medical therapy (including antithrombotic, beta-blockers, statins, angiotensin converting enzyme inhibitors or angiotensin receptor blocker or sacubitril/valsartan, diuretics, antagonists of the mineralocorticoid receptor) according to their clinical condition as recommended.

Arm

Intervention/Treatment

Experimental: Dapagliflozin 10mg daily + standard of care

Dapagliflozin 10mg per day will be administered orally, as in clinical practice

Drug: Dapagliflozin propanediol (FORXIGA™/FARXIGA™1)

Dapagliflozin (10 mg per day; per os) on top of standard of care as recommended in current guidelines* for 6 months (experimental group) *All patients will receive optimal medical therapy (including antithrombotic, beta-blockers, statins, angiotensin converting enzyme inhibitors or angiotensin receptor blocker or sacubitril/valsartan, diuretics, antagonists of the mineralocorticoid receptor) according to their clinical condition as recommended.

Placebo Comparator: Placebo + standard of care

Placebo will be administered orally

Drug: Placebo comparator

Placebo daily on top of standard of care as recommended in current guidelines* for 6 months (control group) *All patients will receive optimal medical therapy (including antithrombotic, beta-blockers, statins, angiotensin converting enzyme inhibitors or angiotensin receptor blocker or sacubitril/valsartan, diuretics, antagonists of the mineralocorticoid receptor) according to their clinical condition as recommended.

Outcome Measures

Primary Outcome Measures

Change in left ventricular ejection fraction (LVEF) from baseline to Month 6 (±1 month) by TTE [6 months (±1 month) from randomization]
Two primary endpoints will allow to evaluate two independent and potent predictors of mortality after AMI: 1) Cardiac systolic function, assessed by change in left ventricular ejection fraction (LVEF) from baseline to Month 6 (±1 month) by TTE; 2) Remodeling, assessed by change in left atrium volume (LAV) from baseline to Month 6 (±1 month) by TTE, in order to assess the efficacy of dapagliflozin, in addition to standard recommended therapy compared to standard recommended therapy alone (i.e. with placebo) on cardiac systolic function and remodeling by transthoracic echocardiography (TTE).
Change in left atrium volume (LAV) from baseline to Month 6 (±1 month) by TTE [6 months (±1 month) from randomization]
Two primary endpoints will allow to evaluate two independent and potent predictors of mortality after AMI: 1) Cardiac systolic function, assessed by change in left ventricular ejection fraction (LVEF) from baseline to Month 6 (±1 month) by TTE; 2) Remodeling, assessed by change in left atrium volume (LAV) from baseline to Month 6 (±1 month) by TTE, in order to assess the efficacy of dapagliflozin, in addition to standard recommended therapy compared to standard recommended therapy alone (i.e. with placebo) on cardiac systolic function and remodeling by transthoracic echocardiography (TTE).

Secondary Outcome Measures

Change in left ventricular end-systolic volume (LVESV) [6 months (±1 month) from randomization]
Comparison in each group from baseline to Month 6 (±1 month) using TTE. To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction.
Change in left ventricular end-diastolic volume (LVEDV) [6 months (±1 month) from randomization]
Comparison in each group from baseline to Month 6 (±1 month) using TTE. To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction.
Change in LV global longitudinal strain (LS) [6 months (±1 month) from randomization]
Comparison in each group from baseline to Month 6 (±1 month) using TTE. To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction.
Change in left atrial strain (LAS) [6 months (±1 month) from randomization]
Comparison in each group from baseline to Month 6 (±1 month) using TTE. To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction.
Duration of hospital stay (index hospitalization) [6 months (±1 month) from randomization]
Comparison between both groups (experimental vs. placebo) To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction.
All-cause mortality at 6-months [6 months (±1 month) from randomization]
Comparison between both groups (experimental vs. placebo) Comparison between both groups (experimental vs. placebo) To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction
Cardiovascular death or worsening HF at 6-months [6 months (±1 month) from randomization]
Comparison between both groups (experimental vs. placebo) To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction
Number of re-admission due to HF at 6-months [6 months (±1 month) from randomization]
Comparison between both groups (experimental vs. placebo) To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction
Change from baseline to Month 6 (±1 month) in LVESV, LVEDV, LAV, LVEF, LV global LS, LAS and pulmonary congestion (normal lung, mild, moderate or severe ultrasound lung comets [ULCs]) using TTE at month 6 [6 months (±1 month) from randomization]
Comparison between both groups (experimental vs. placebo) To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction
Change from baseline to Month 6 (±1 month) in plasma levels of NT-pro BNP and HBA1C [6 months (±1 month) from randomization]
Comparison between both groups (experimental vs. placebo) To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction
Change in body weight from baseline to Month 6 (±1 month) [6 months (±1 month) from randomization]
Comparison between both groups (experimental vs. placebo) To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction
Adverse events [6 months (±1 month) from randomization]
Comparison between both groups (experimental vs. placebo) of Adverse events with particular focus to those potentially related to dapagliflozin complications (e.g., all symptoms of volume depletion, major hypoglycemia, genital infections, diabetes ketoacidosis, changes in liver function parameters [ASAT, ALAT ≥3]. To assess the efficacy and safety of dapagliflozin compared to placebo in addition to optimal secondary prevention in the prevention of cardiac dysfunction after AMI with LV dysfunction.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥18 years;
STEMI (e.g., ST elevation above the J-point of ≥0.1 millivolt in ≥two contiguous leads or left bundle branch block) or very high-risk NSTEMI (e.g., dynamic ECG changes or ongoing chest pain or acute heart failure or hemodynamic instability independent of ECG changes or life-threatening ventricular arrhythmias) with LV dysfunction (LVEF ≤45%); after completion of PCI or angiography procedure
eGFR ≥30 mL/Min per 1.73m²;
Systolic blood pressure (SBP) before first dosing >110 mmHg;
Diastolic blood pressure (DBP) before first dosing >70 mmHg;
Ability to provide written informed consent and willing to participate in the 6-month follow-up period.
Affiliation to a national health care system (AME are not allowed).

Exclusion Criteria:

Exclusion Criteria :

Cardiogenic shock (SBP <90 mmHg with clinical signs of low output or patients requiring inotropic agents) at randomization;
Referred to surgery for coronary artery bypass grafting (CABG) or treatment of acute complications (e.g. ventricular septal rupture);
Any other form of diabetes than diabetes type 2
History of diabetic ketoacidosis (DKA);
Blood pH <7.32;
; Known contra-indication to SGLT-2 inhibitors (hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption);
1 episode of severe hypoglycemia within the last 6 months under treatment with insulin or sulfonylurea;
Acute symptomatic urinary tract infection (UTI) or genital infection at the time of randomization;
Concomitant treatment (and/or within the 4 weeks prior to the baseline visit) with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin)
Echocardiographic examination of insufficient quality to permit adequate analysis of the study end-points.
Impossibility to evaluate cardiac remodeling using TTE (e.g., pacemaker or defibrillator …);
Atrial fibrillation rhythm at randomization;
Life expectancy <6 month;
Known pregnancy at time of randomization;
Breastfeeding women
Females of childbearing potential without adequate contraceptive methods (i.e. sterilization, intrauterine device, vasectomized partner; or medical history of hysterectomy)
Current participation in another interventional trial. Patients under guardianship or curatorship