Evaluation of Dapagliflozin Propanediol Monohydrate on Cardiovascular Outcomes in Stabilized Acute Heart Failure Patients: A Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2024-517612-29-00
- Protocol
- D1690C00078
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this multicenter, randomized, double-blind, parallel group, placebo-controlled trial is to assess the effect of in-hospital initiation of **dapagliflozin** on the clinical outcome of cardiovascular death or worsening heart failure in patients who have been stabilized during hospitalization for **acute heart failure**. This evaluation is clinically relevant as it aims to determine whether early intervention with dapagliflozin can improve survival and reduce the progression of heart failure in a critical patient population.
Secondary objectives include:
- Evaluating the safety and tolerability of in-hospital initiation of dapagliflozin in this patient population.
Participants
The clinical trial involves a total of **1400 participants** who are currently hospitalized for **acute heart failure**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their hospitalization status for acute heart failure, with specific criteria regarding the presentation of worsening symptoms and objective signs of volume overload. The trial does not focus on a vulnerable population, and individuals with and without type 2 diabetes are eligible. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to assess the effect of in-hospital initiation of dapagliflozin on clinical outcomes in this patient population.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, parallel-group, placebo-controlled study to evaluate the effect of in-hospital initiation of **dapagliflozin** on clinical outcomes in patients stabilized during hospitalization for **acute heart failure**. The trial aims to assess the impact of dapagliflozin compared to placebo on the primary endpoint of time to first occurrence of cardiovascular death or worsening heart failure. The study is expected to run until July 31, 2025, with recruitment having commenced on March 8, 2023.
Participants will be involved in the trial for a maximum of two months, during which they will receive either dapagliflozin 10 mg film-coated tablets or a matching placebo, administered orally once daily. The trial includes several key visits: an inclusion (screening) visit, follow-up visits, and an end-of-study visit. The inclusion visit will confirm eligibility based on criteria such as current hospitalization for acute heart failure, stabilization status, and specific laboratory markers. Follow-up visits will monitor safety, tolerability, and clinical outcomes, while the end-of-study visit will assess the final outcomes and any adverse events.
Participants may be terminated early from the study if they experience symptomatic hypotension leading to hospitalization or study drug discontinuation, worsening renal function resulting in significant clinical interventions, or if they no longer meet the inclusion criteria. The trial leadership will monitor the proportion of patients with various left ventricular ejection fractions and those with or without type 2 diabetes to ensure a representative sample. The study's methodology ensures rigorous assessment of the primary and secondary endpoints, contributing valuable data on the safety and efficacy of dapagliflozin in this patient population.
Treatment
The clinical trial involves the administration of **Dapagliflozin Cipla 10 mg Filmtabletten**, which is an experimental medication. The active substance in this medication is **dapagliflozin propanediol monohydrate**, a chemical compound. The pharmaceutical form of the medication is a film-coated tablet, and it is administered orally. The dosage is set at 10 mg once daily, with a maximum treatment period of 2 months. The medication is manufactured by CIPLA EUROPE NV and is authorized for use in Germany under the marketing authorization number 7004057.00.00. The administration of the drug will be monitored to ensure compliance with the dosing schedule.
In addition to the experimental medication, a **matching placebo** is used in the study. The placebo is administered orally once daily for a duration of 2 months, mirroring the administration schedule of the experimental drug. The placebo is designed to be indistinguishable from the active medication in appearance and administration route, ensuring the double-blind nature of the trial. The use of a placebo allows for the assessment of the true efficacy and safety of dapagliflozin by providing a comparator group within the study.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoints include the time to the first occurrence of cardiovascular death or worsening heart failure. Worsening heart failure is further defined by specific criteria such as the initiation or re-initiation of inotropic therapy for at least 24 hours, mechanical circulatory support, invasive ventilatory support for heart failure, heart transplantation, readmission for worsening heart failure, or an urgent visit leading to the administration of intravenous diuretic therapy without associated hospital admission.
Secondary endpoints focus on symptomatic hypotension leading to hospitalization or study drug discontinuation, and worsening renal function resulting in at least a doubling of serum creatinine, hospitalization, study drug discontinuation, dialysis, or renal death. These endpoints will be measured and collected throughout the trial duration, with specific timepoints and methods not explicitly detailed in the provided data.
The trial is designed as a multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the effect of in-hospital initiation of **dapagliflozin** on clinical outcomes in patients stabilized during hospitalization for acute heart failure. The trial aims to provide comprehensive data on the efficacy of dapagliflozin in improving clinical outcomes related to cardiovascular health in this patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- To evaluate the safety and tolerability of in-hospital initiation of dapagliflozin in this patient population.
- 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).
- Left ventricular ejection fraction (LVEF) measured within the past 12 months (including during the current hospitalization)
- 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)
- 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
- Symptomatic hypotension in the past 24 hours
- Concurrent use of two or more intravenous inotropic agents during the index hospitalization
- eGFR <25 ml/min/1.73 m2 as measured by the CKD-EPI equation at screening or rapidly progressive renal disease
- Current use of an SGLT2 inhibitor
- Prior intolerance of SGLT2 inhibitors, including hypersensitivity to dapagliflozin, or to any excipient (inactive substance) in the study drug
- Type 1 diabetes mellitus or history of diabetic ketoacidosis
- (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)
- 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
- 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
- Untreated sustained ventricular arrhythmias or Mobitz type II or third-degree heart block (i.e., without an ICD or pacemaker, respectively)
- History of heart transplantation or current transplant listing; mechanical circulatory support use (either durable or temporary) during the index hospitalization
- 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.
- History of end-stage liver disease
- Women of child-bearing potential (unless using highly effective contraception method) or currently breastfeeding
- Current participation in a clinical trial with an unlicensed drug or device
- Study staff or their family members
- 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)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 08 Mar 2023 | 250 |
 Hungary | Not Recruiting | 08 Mar 2023 | 150 |
 Poland | Not Recruiting | 08 Mar 2023 | 600 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Dapagliflozin Cipla 10 mg Filmtabletten | Test | FILMTABLETTEN | ORAL USE | 10 | 2 | PRD11134638 |
Matching placebo administered orally once daily for 2 months | Placebo | N/A | — | — | — | N/A |