Adding macitentan to dapagliflozin for people with HFmrEF/HFpEF and combined pre- and post-capillary pulmonary hypertension

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 test will see if adding macitentan to dapagliflozin helps adults with HFmrEF or HFpEF who also have combined pre- and post-capillary pulmonary hypertension.

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 64 (estimated)
• Ages: 19 Years and up
• Sex: All
• Sponsor: Gachon University Gil Medical Center (Academic / other)
• Locations: 15 sites (Busan and 14 other locations)
• Trial ID: NCT07147114 on ClinicalTrials.gov

What this trial studies

This randomized, double-blind Phase 4 trial compares dapagliflozin plus macitentan versus dapagliflozin plus placebo over 24 weeks in adults with HFmrEF or HFpEF and combined pre- and post-capillary pulmonary hypertension. Participants are randomly assigned to one of two groups and receive study medication with scheduled clinical, laboratory, and safety assessments. The study measures changes in pulmonary vascular resistance, NT-proBNP, 6-minute walk distance, and KCCQ quality-of-life scores. Eligibility requires LVEF >40% and right heart catheterization confirming mPAP >20 mmHg, PVR >2 WU, and PAWP >15 mmHg, with WHO functional class II–III.

Who should consider this trial

Good fit: Adults (≥19 years) in South Korea with HFmrEF or HFpEF, LVEF >40%, hemodynamic confirmation of combined pre- and post-capillary pulmonary hypertension on right heart catheterization, and WHO functional class II–III are the intended participants.

Not a fit: Patients with LVEF ≤40%, isolated pre-capillary pulmonary hypertension, WHO functional class IV, unstable comorbidities, or who cannot attend the Korean study sites are unlikely to benefit from or qualify for this trial.

Why it matters

Potential benefit: If successful, the combination could reduce pulmonary vascular resistance and improve symptoms, exercise capacity, and quality of life.

How similar studies have performed: SGLT2 inhibitors like dapagliflozin have shown benefits in heart failure, but endothelin receptor antagonists such as macitentan have limited and mixed evidence in Group 2 pulmonary hypertension, making this combination relatively novel.

Eligibility criteria

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

Where this trial is running

Busan and 14 other locations

• Pusan National University Hospital — Busan, South Korea (Recruiting)
• Chungbuk National University Hospital — Chungju, South Korea (Not_yet_recruiting)
• Keimyung University Dongsan Hospital — Daegu, South Korea (Recruiting)
• Chungnam National University Hospital — Daejeon, South Korea (Recruiting)
• Chonnam National University Hospital — Gwangju, South Korea (Recruiting)
• Incheon Sejong Hospital — Incheon, South Korea (Not_yet_recruiting)
• Gachon University Gil Hospital — Incheon, South Korea (Recruiting)
• Seoul National University Hospital — Seoul, South Korea (Recruiting)
• Yonsei University Health System, Severance Hospital — Seoul, South Korea (Not_yet_recruiting)
• Asan Medical Center — Seoul, South Korea (Recruiting)
• Samsung Medical Center — Seoul, South Korea (Not_yet_recruiting)
• The Catholic University of Korea, Seoul St.Mary — Seoul, South Korea (Recruiting)
• Koera University Guro Hospital — Seoul, South Korea (Not_yet_recruiting)
• Yonsei University, Wonju Severance Christian Hospital — Wŏnju, South Korea (Recruiting)
• Pusan National University Yangsan Hospital — Yangsan, South Korea (Not_yet_recruiting)

Study contacts

• Study coordinator: Wook-Jin Chung, MD, PhD

Conditions Combined Pre- and Post-capillary Pulmonary Hypertension; CpcPH; HFmrEF; HFpEF; Group 2 Pulmonary Hypertension