Clinical Trial to Evaluate the Efficacy and Safety in Concomitant Administration of Macitentan and Dapagliflozin in Patients With Heart Failure With Mildly Reduced and Preserved Ejection Fraction (HFmrEF and HFpEF) and Combined Pre- and Post-capillary Pulmonary Hypertension (CpcPH)

Official title

A Multicenter, Randomized, Double-Blind, Exploratory Clinical Trial to Evaluate the Efficacy and Safety in Concomitant Administration of Macitentan and Dapagliflozin in Patients With Heart Failure With Mildly Reduced and Preserved Ejection Fraction (HFmrEF and HFpEF) and Combined Pre- and Post-capillary Pulmonary Hypertension (CpcPH)

Overview

This clinical trial will evaluate whether combination therapy with Dapagliflozin + Macitentan improves outcomes compared to Dapagliflozin + placebo in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH). The study will measure changes in pulmonary vascular resistance, NT-proBNP, 6-minute walk distance, and quality of life (KCCQ scores) over 24 weeks. Participants will be randomly assigned to one of two groups, take study medication for 24 weeks, and undergo regular clinical, laboratory, and safety assessments.

Interventions

• Drug Combination therapy
  Macitentan 10mg, Dapagliflozin 10mg or 5mg po tablet q.d. in 24 weeks
• Drug Monotherapy
  Macitentan placebo, Dapagliflozin 10mg or 5mg po tablet q.d. in 24 weeks

Primary outcome measures

• Hierarchical outcome component(Change in PVR, Change in NT-proBNP, Change in 6MWD, Change in KCCQ-CSS) [Time frame: Baseline, 24 week]

Secondary outcome measures (12)

• Change in Pulmonary Vascular Resistance (PVR) from Baseline to Week 24 [Time frame: Baseline, 24 week]
• Change in Mean Pulmonary Arterial Pressure (mPAP) from Baseline to Week 24 [Time frame: Baseline, 24 week]
• Change in Pulmonary Arterial Wedge Pressure (PAWP) from Baseline to Week 24 [Time frame: Baseline, 24 week]
• Change in 6-Minute Walk Distance from Baseline to Week 24 [Time frame: Baseline, 24 week]
• Change in Oxygen Saturation (SpO2) Difference Before and After 6-Minute Walk Test from Baseline to Week 24 [Time frame: Baseline, 24 week]
• Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from Baseline to Week 24 [Time frame: Baseline, 24 week]
• Change in Tricuspid Regurgitation Velocity (TRV) from Baseline to Week 24 [Time frame: Baseline, 24 week]
• Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) from Baseline to Week 24 [Time frame: Baseline, 24 week]
• Use of Intravenous Diuretics During Treatment Period (Visit 2 to Visit 4) [Time frame: Baseline, 24 week]
• Rate of Hospitalization Due to Heart Failure During Treatment Period (Visit 2 to Visit 4) [Time frame: Baseline, 24 week]
• Number of Days Hospitalized for Heart Failure During Treatment Period (Visit 2 to Visit 4) [Time frame: Baseline, 24 week]
• Number of Deaths (Cardiovascular and All-Cause) During Treatment Period (Visit 2 to Visit 4) [Time frame: Baseline, 24 week]

Eligibility criteria

Inclusion criteria

<Screening Visit (Visit 1)>

• A male or female adults aged 19 years or older in South Korea
• LVEF greater than 40% on echocardiogram performed within 12 weeks prior to screening
• Presence of heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) accompanied by combined pre- and post-capillary pulmonary hypertension (CpcPH)
• Meeting all of the following criteria on RHC performed within 48 weeks prior to screening:

• mPAP > 20 mmHg
• PVR > 2 Wood units (WU)
• PAWP > 15 mmHg
• World Health Organization Functional Class (WHO-FC) II or III at the time of screening
• If taking any of the following medications at the time of screening, the participant must have been on a stable dose for at least 3 months:

• Renin-angiotensin system inhibitors
• Beta-blockers
• Mineralocorticoid receptor antagonists (aldosterone antagonists)
• Sodium-glucose cotransporter-2 (SGLT2) inhibitors
• Ivabradine

<Baseline Visit (Visit 2)>

1\. World Health Organization Functional Class (WHO-FC) II or III at the time of baseline visit

Exclusion criteria

<Screening Visit (Visit 1)>

• Known hypersensitivity to the active ingredients (Macitentan, Dapagliflozin) or any excipients of the investigational medicinal product
• Pregnant or breastfeeding women, or those who do not agree to use at least two appropriate contraceptive methods\* (self or partner) during the clinical trial period and for 30 days after the last administration of the investigational medicinal product (for male participants, those who do not agree to refrain from sperm donation)

\*: a. Surgical sterilization (e.g., vasectomy) or intrauterine device (IUD; copper IUD or hormone-releasing intrauterine system), b. Non-oral hormonal contraceptive or spermicide in combination with a barrier method, c. Cervical cap or diaphragm used in combination with a male condom.

• Participants with type 1 diabetes mellitus or secondary diabetes mellitus
• Participants with metabolic acidosis, such as diabetic ketoacidosis
• Participants diagnosed with pulmonary hypertension other than WHO Group 2 pulmonary hypertension (i.e., WHO Group 1, 3, 4, or 5)

• Group 1: Pulmonary arterial hypertension
• Group 3: Pulmonary hypertension associated with lung diseases and/or hypoxia
• Group 4: Chronic thrombo-embolic pulmonary hypertension
• Group 5: Pulmonary hypertension with unclear and/or multifactorial mechanisms
• Participants who meet the following criteria on RHC performed within 12 weeks prior to screening:

a. PAWP ≤ 15 mmHg

• History of taking any of the following medications within 4 weeks prior to screening:

• Calcium channel blockers
• Endothelin receptor antagonists
• Phosphodiesterase type 5 inhibitors (PDE5i)
• Riociguat
• Prostacyclin (PC) analogs or prostacyclin receptor agonists
• Activin signaling inhibitors
• History of any of the following medical conditions, surgeries, or procedures:

• Myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention (PCI) within 3 months prior to screening
• Uncontrolled tachycardia (>110 bpm) due to atrial fibrillation or atrial flutter
• History of heart transplantation or implantation of a ventricular assist device, or planned to undergo such procedures
• eGFR ≤ 30 mL/min/1.73 m² or AST or ALT ≥ 2.5 × ULN
• Urinary tract infection, genital infection (including fungal infections), or voiding disorder within 24 weeks prior to screening
• Hemoglobin < 9 g/dL at the time of screening
• Participants with genetic disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
• Known hypersensitivity to soybean oil or history of soybean oil allergy
• Known hypersensitivity to soy or peanuts
• Participation in another clinical trial involving administration/application of an investigational medicinal product or medical device within 3 months prior to screening

<Baseline Visit (Visit 2)>

• Participants who, upon re-confirmation of inclusion/exclusion criteria at the baseline visit, have any disqualifying condition
• Any other condition that, in the opinion of the investigator, makes the participant unsuitable for participation in this clinical trial

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

South Korea · 15 centers

• Pusan National University Hospital — Busan
• Chungbuk National University Hospital — Chungju
• Keimyung University Dongsan Hospital — Daegu
• Chungnam National University Hospital — Daejeon
• Chonnam National University Hospital — Gwangju
• Incheon Sejong Hospital — Incheon
• Gachon University Gil Hospital — Incheon
• Seoul National University Hospital — Seoul
• … and 7 more centers

Identifiers

NCT: NCT07147114 · MD-CpcPH

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗