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)

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)

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.

Inclusion Criteria:

<Screening Visit (Visit 1)>

1. A male or female adults aged 19 years or older in South Korea

2. LVEF greater than 40% on echocardiogram performed within 12 weeks prior to screening

3. 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)

4. Meeting all of the following criteria on RHC performed within 48 weeks prior to screening:

   1. mPAP > 20 mmHg
   2. PVR > 2 Wood units (WU)
   3. PAWP > 15 mmHg

5. World Health Organization Functional Class (WHO-FC) II or III at the time of screening

6. 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:

   1. Renin-angiotensin system inhibitors
   2. Beta-blockers
   3. Mineralocorticoid receptor antagonists (aldosterone antagonists)
   4. Sodium-glucose cotransporter-2 (SGLT2) inhibitors
   5. 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)>

1. Known hypersensitivity to the active ingredients (Macitentan, Dapagliflozin) or any excipients of the investigational medicinal product

2. 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.

3. Participants with type 1 diabetes mellitus or secondary diabetes mellitus

4. Participants with metabolic acidosis, such as diabetic ketoacidosis

5. Participants diagnosed with pulmonary hypertension other than WHO Group 2 pulmonary hypertension (i.e., WHO Group 1, 3, 4, or 5)

   1. Group 1: Pulmonary arterial hypertension
   2. Group 3: Pulmonary hypertension associated with lung diseases and/or hypoxia
   3. Group 4: Chronic thrombo-embolic pulmonary hypertension
   4. Group 5: Pulmonary hypertension with unclear and/or multifactorial mechanisms

6. Participants who meet the following criteria on RHC performed within 12 weeks prior to screening:

   a. PAWP ≤ 15 mmHg

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

   1. Calcium channel blockers
   2. Endothelin receptor antagonists
   3. Phosphodiesterase type 5 inhibitors (PDE5i)
   4. Riociguat
   5. Prostacyclin (PC) analogs or prostacyclin receptor agonists
   6. Activin signaling inhibitors

8. History of any of the following medical conditions, surgeries, or procedures:

   1. Myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention (PCI) within 3 months prior to screening
   2. Uncontrolled tachycardia (>110 bpm) due to atrial fibrillation or atrial flutter
   3. History of heart transplantation or implantation of a ventricular assist device, or planned to undergo such procedures

9. eGFR ≤ 30 mL/min/1.73 m² or AST or ALT ≥ 2.5 × ULN

10. Urinary tract infection, genital infection (including fungal infections), or voiding disorder within 24 weeks prior to screening

11. Hemoglobin < 9 g/dL at the time of screening

12. Participants with genetic disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

13. Known hypersensitivity to soybean oil or history of soybean oil allergy

14. Known hypersensitivity to soy or peanuts

15. 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)>

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