Evaluation of Baxdrostat and Dapagliflozin on Heart Failure Incidence and Cardiovascular Mortality in High-Risk Patients: A Phase III Randomized Controlled Trial
- Trial ID
- 2024-514506-32-00
- Protocol
- D6973C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Objectives
The primary objective of this study is to evaluate whether the combination of **baxdrostat** and **dapagliflozin** is superior to placebo and dapagliflozin in reducing the risk of a heart failure (HF) event or cardiovascular (CV) death in participants at increased risk of developing heart failure. This is clinically relevant as it addresses the potential for improved therapeutic strategies in preventing adverse cardiovascular outcomes in a high-risk population.
Secondary objectives include:
- Determining whether baxdrostat/dapagliflozin is superior to placebo/dapagliflozin in reducing the risk of hospitalization for heart failure or cardiovascular death.
- Assessing the superiority of baxdrostat/dapagliflozin in reducing the risk of heart failure events.
- Evaluating the reduction in risk of cardiovascular death with baxdrostat/dapagliflozin compared to placebo/dapagliflozin.
- Investigating the reduction in risk of all-cause mortality with baxdrostat/dapagliflozin.
- Determining the effect of baxdrostat/dapagliflozin on reducing the risk of stroke or cardiovascular death.
- Assessing the reduction in risk of atrial fibrillation or cardiovascular death in participants without a history of atrial fibrillation at baseline.
- Evaluating the reduction in risk of myocardial infarction (MI) or cardiovascular death with baxdrostat/dapagliflozin.
Participants
The clinical trial involves a total of **7432 participants** aimed at evaluating the prevention of **heart failure**. The study population includes individuals of any sex and gender, aged 40 years and older, who have been diagnosed with type 2 diabetes mellitus and require treatment. Participants must have established cardiovascular disease, such as ischaemic heart disease, cerebrovascular disease, or peripheral arterial disease, and a history of hypertension with specific blood pressure criteria. The trial population was selected based on these health conditions and additional risk factors for heart failure, including age, urinary albumin-to-creatinine ratio, estimated glomerular filtration rate, history of polyvascular disease, atrial fibrillation or flutter, and NT-proBNP levels. Both male and female subjects are included, and the study does not involve a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled study designed to evaluate the effect of **Baxdrostat** in combination with **Dapagliflozin** compared to Dapagliflozin alone on the risk of incident heart failure and cardiovascular death in participants at increased risk of developing heart failure. The trial aims to determine if the combination therapy is superior in reducing the risk of heart failure events or cardiovascular death. The study is event-driven and is expected to conclude by December 17, 2029, with recruitment starting on March 28, 2025.
Participants will be randomly assigned to receive either the combination of Baxdrostat and Dapagliflozin or a placebo with Dapagliflozin. The trial will involve oral administration of the investigational products, which are provided in tablet form. The maximum treatment period for participants is 38 weeks. The study includes several key visits: an initial screening visit to assess eligibility, regular follow-up visits to monitor health status and treatment effects, and an end-of-study visit to evaluate the overall outcomes and collect final data.
Inclusion criteria require participants to be at least 40 years old, diagnosed with type 2 diabetes mellitus requiring treatment, and have established cardiovascular disease or a history of hypertension with specific blood pressure criteria. Participants must also have at least one additional risk factor for heart failure. Exclusion criteria are not specified in the provided data. The primary endpoint is the time to the first occurrence of any component of the composite of hospitalization for heart failure, heart failure without hospitalization, or cardiovascular death. Secondary endpoints include various composite measures of cardiovascular events and mortality.
Participant involvement is expected to last up to the maximum treatment period, with conditions for early termination including adverse events, withdrawal of consent, or protocol non-compliance. The trial is not categorized as low intervention, and the investigational products are not pediatric formulations. The study is conducted under the sponsorship of AstraZeneca AB, with Baxdrostat and Dapagliflozin being the active substances under investigation.
Treatment
The clinical trial involves the administration of **Baxdrostat**, a synthetic molecule developed by AstraZeneca AB. Baxdrostat is provided in the form of a **tablet** and is intended for **oral use**. The active substance, also named Baxdrostat, is of chemical origin. The trial does not specify a maximum daily dose or total dose amount, but the treatment period is set for a maximum of 38 weeks. The pharmaceutical form is consistent across the trial, ensuring uniformity in administration. Participant compliance will be monitored throughout the study to ensure adherence to the dosing schedule.
In addition to Baxdrostat, the trial includes the administration of **Forxiga 10 mg film-coated tablets**, which contain the active substance **dapagliflozin**. This medication is also a synthetic molecule and is administered orally. The film-coated tablets differ from the commercial product only in color and engraving, with the clinical product being green, plain, and diamond-shaped. The treatment period for Forxiga is also set for a maximum of 38 weeks, with no specified maximum daily or total dose amount. Compliance monitoring will be conducted to ensure participants adhere to the prescribed regimen.
The study employs a **placebo** control, referred to as Baxdrostat Placebo, to maintain the double-blind nature of the trial. The placebo is designed to mimic the appearance of the Baxdrostat tablet but contains no active substance. The placebo is administered orally, and its use is critical for evaluating the efficacy of Baxdrostat in combination with dapagliflozin compared to dapagliflozin alone. Compliance with placebo administration will be monitored to ensure the integrity of the trial results.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the time to the first occurrence of any components of the composite of **hospitalisation for heart failure (HF)**, HF without hospitalisation, or cardiovascular (CV) death. Secondary endpoints include the time to the first occurrence of any components of various composites, such as hospitalisation for HF and CV death, hospitalisation for HF and HF without hospitalisation, CV death, all-cause death, stroke and CV death, new diagnosis of atrial fibrillation and CV death, and myocardial infarction (MI) and CV death.
The trial is designed as a Phase III, randomised, double-blind, placebo-controlled, event-driven study. The efficacy parameters will be measured and collected at specified timepoints throughout the trial duration, which is estimated to end on December 17, 2029. The trial aims to determine if the combination of Baxdrostat and Dapagliflozin is superior to placebo and Dapagliflozin in reducing the risk of an HF event or CV death in participants with an increased risk of developing heart failure.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants of any sex and gender must be ≥ 40 years old at the time of signing the informed consent
- Diagnosed with T2DM and requiring treatment
- Established CV disease ((ischaemic heart disease, cerebrovascular disease, peripheral arterial disease)
- Documented history of HTN (diagnosed and/or treated) and an SBP ≥ 130 mmHg (either the most recent value within 4 weeks of screening or at the Screening Visit) and ≥ 120 mmHg at the Randomisation Visit.
- Local laboratory serum or plasma potassium must meet the following criteria at the Screening Visit, based on screening eGFR: o for participants with screening eGFR ≥ 45 mL/min/1.73 m2, potassium must be ≥ 3.0 and ≤ 4.8 mmol/L at the Screening Visit o for participants with screening eGFR < 45 mL/min/1.73 m2, potassium must be ≥ 3.0 and ≤ 4.5 mmol/L at the Screening Visit
- At least one additional risk factor for HF : o Age ≥ 70 years o UACR > 20 mg/g o eGFR < 60 mL/min/1.73 m2 o History of polyvascular disease (at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease) o History of atrial fibrillation or atrial flutter o NT-proBNP > 125 ng/L
- All WOCBP must have a negative pregnancy test result at screening, and not be at stage of breastfeeding.
Exclusion Criteria
- Previously confirmed diagnosis and treatment of chronic symptomatic heart failure (Heart failure stages C and D by the ACC/AHA classification)
- An eGFR < 30 mL/min/1.73 m2 at screening
- Known hyperkalaemia, defined as potassium ≥ 5.5 mmol/L within 3 months prior to screening
- Type 1 diabetes mellitus or uncontrolled T2DM with HbA1c >10.5% (> 91 mmol/mol) at screening
- Serum sodium < 135 mmol/L at screening, determined as per central laboratory assessment
- Stroke, transient ischaemic cerebral attack, valve implantation or valve replacement, carotid surgery, carotid angioplasty, or cardiac surgery, within 3 months prior to randomisation.
- Myocardial infarction within 3 months prior to randomisation, or within 1 month prior to randomisation when there is no further planned revascularisation.
- Percutaneous coronary intervention or Transcatheter Aortic Valve Replacement within 1 month prior to randomisation.
- Known severe hepatic impairment, defined as Child-Pugh Class C, based on records that confirm documented medical history.
- Documented history of adrenal insufficiency.
- Any dialysis (including for acute kidney injury) within 3 months prior to screening
- Any acute kidney injury within 3 months prior to screening.
- History or known allergy/hypersensitivity to the study treatment, as judged by the Investigator (eg, SGLT2i or active substance or excipients).
- History of organ transplant or bone marrow transplant, or planned organ transplant within 6 months following randomisation (including kidney transplant).
- Any use of mineralocorticoid receptor antagonists (such as spironolactone, eplerenone, or finerenone) or aldosterone synthase inhibitor within 4 weeks prior to screening and/or during the study.
- Use of potassium-sparing diuretics (such as triamterene or amiloride) and direct renin inhibitor (eg, aliskiren) at the time of screening
- Use of potassium binders (such as sodium zirconium cyclosilicate, patiromer, or sodium polystyrene sulfonate) within 4 weeks prior to screening
- To exclude participants with hereditary galactose intolerance, lactase deficiency, or glucose/galactose malabsorption.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 28 Mar 2025 | 174 |
 Czechia | Recruiting | 28 Mar 2025 | 279 |
 Denmark | Recruiting | 28 Mar 2025 | 185 |
 France | Recruiting | 28 Mar 2025 | 409 |
 Germany | Recruiting | 28 Mar 2025 | 461 |
 Greece | Recruiting | 28 Mar 2025 | 170 |
 Hungary | Recruiting | 28 Mar 2025 | 371 |
 Italy | Recruiting | 28 Mar 2025 | 277 |
 The Netherlands | Recruiting | 28 Mar 2025 | — |
 Poland | Recruiting | 28 Mar 2025 | 559 |
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 |
|---|---|---|---|---|---|---|
Forxiga 10 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 00 | 38 | PRD8495988 |
Baxdrostat | Test | TABLET | ORAL USE | 00 | 38 | PRD10361088 |
Baxdrostat | Test | TABLET | ORAL USE | 00 | 38 | PRD12913417 |
Baxdrostat | Test | TABLET | ORAL USE | 00 | 38 | PRD10361078 |
Baxdrostat Placebo | Placebo | N/A | — | — | — | N/A |