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.

Study Overview

• Status: Recruiting
• Conditions: HFpEF; Group 2 Pulmonary Hypertension; Combined Pre- and Post-capillary Pulmonary Hypertension; CpcPH; HFmrEF
• Intervention / Treatment: Drug: Combination therapy; Drug: Monotherapy

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Wook-Jin Chung, MD, PhD; Phone Number: 82-32-460-3663; Email: heart@gilhospital.com

Study Locations

• South Korea
  • Busan, South Korea, 49241
    • Recruiting
    • Pusan National University Hospital
  • Chungju, South Korea, 28644
    • Not yet recruiting
    • Chungbuk National University Hospital
  • Daegu, South Korea, 42601
    • Recruiting
    • Keimyung University Dongsan Hospital
  • Daejeon, South Korea, 35015
    • Recruiting
    • Chungnam National University Hospital
  • Gwangju, South Korea, 61469
    • Recruiting
    • Chonnam National University Hospital
  • Incheon, South Korea, 405-760
    • Recruiting
    • Gachon University Gil Hospital
    • Contact: Wook-Jin Chung, MD,PhD; Phone Number: 82-32-460-3663; Email: heart@gilhospital.com
  • Incheon, South Korea, 21080
    • Not yet recruiting
    • Incheon Sejong Hospital
  • Seoul, South Korea, 05505
    • Recruiting
    • Asan Medical Center
  • Seoul, South Korea, 03080
    • Recruiting
    • Seoul National University Hospital
  • Seoul, South Korea, 06351
    • Not yet recruiting
    • Samsung Medical Center
  • Seoul, South Korea, 03722
    • Not yet recruiting
    • Yonsei University Health System, Severance Hospital
  • Seoul, South Korea, 06591
    • Recruiting
    • The Catholic University of Korea, Seoul St.Mary
  • Seoul, South Korea, 08308
    • Not yet recruiting
    • Koera University Guro Hospital
  • Wŏnju, South Korea, 26426
    • Recruiting
    • Yonsei University, Wonju Severance Christian Hospital
  • Yangsan, South Korea, 50612
    • Not yet recruiting
    • Pusan National University Yangsan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination therapy group; Maciten Tab. 10mg	Drug: Combination therapy; Macitentan 10mg, Dapagliflozin 10mg or 5mg po tablet q.d. in 24 weeks; Other Names: Maciten Tab. 10mg
Placebo Comparator: Monotherapy group; Dapozin Tab. 10mg or 5mg	Drug: Monotherapy; Macitentan placebo, Dapagliflozin 10mg or 5mg po tablet q.d. in 24 weeks; Other Names: Dapozin Tab. 10mg or 5mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hierarchical outcome component(Change in PVR, Change in NT-proBNP, Change in 6MWD, Change in KCCQ-CSS)	The hierarchical composite variable includes the rate of change in Pulmonary Vascular Resistance (PVR), NT-proBNP, change in 6-minute walk distance, and change in KCCQ-CSS score. All possible pairwise comparisons between combination therapy group and monotherapy group subjects (e.g., 2 subjects in combination group and 3 in monotherapy group yield 6 pairs) are classified as Win, Loss, or Tie based on the following definitions. If the subject in the pair meeting the criteria belongs to the combination group, it is evaluated as a Win; if in the monotherapy group, a Loss.	Baseline, 24 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pulmonary Vascular Resistance (PVR) from Baseline to Week 24	PVR (Wood Units, WU) is measured by Right Heart Catheterization (RHC).	Baseline, 24 week
Change in Mean Pulmonary Arterial Pressure (mPAP) from Baseline to Week 24	mPAP (mmHg) is measured by RHC.	Baseline, 24 week
Change in Pulmonary Arterial Wedge Pressure (PAWP) from Baseline to Week 24	PAWP (mmHg) is measured by RHC.	Baseline, 24 week
Change in 6-Minute Walk Distance from Baseline to Week 24	Distance (meters) measured by 6-minute walk test.	Baseline, 24 week
Change in Oxygen Saturation (SpO2) Difference Before and After 6-Minute Walk Test from Baseline to Week 24	Oxygen saturation (%) difference before and after the 6-minute walk test.	Baseline, 24 week
Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from Baseline to Week 24	NT-proBNP (pg/mL) measured by clinical laboratory tests.	Baseline, 24 week
Change in Tricuspid Regurgitation Velocity (TRV) from Baseline to Week 24	TRV (m/s) measured by echocardiography.	Baseline, 24 week
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) from Baseline to Week 24	TAPSE (mm) measured by echocardiography.	Baseline, 24 week
Use of Intravenous Diuretics During Treatment Period (Visit 2 to Visit 4)	The number of intravenous diuretic administrations collected via concomitant medication records.	Baseline, 24 week
Rate of Hospitalization Due to Heart Failure During Treatment Period (Visit 2 to Visit 4)	Number of hospitalizations for heart failure compared between groups during treatment period.	Baseline, 24 week
Number of Days Hospitalized for Heart Failure During Treatment Period (Visit 2 to Visit 4)	Total days of hospitalization for heart failure compared between groups during treatment.	Baseline, 24 week
Number of Deaths (Cardiovascular and All-Cause) During Treatment Period (Visit 2 to Visit 4)	Cardiovascular and all-cause mortality events compared between groups.	Baseline, 24 week
Change in Mean Right Atrial Pressure (mRAP) from Baseline to Week 24	mRAP (mmHg) measured by RHC.	Baseline, 24 week
Change in Cardiac Index (CI) from Baseline to Week 24	Cardiac Index (L/min/m²) measured by RHC.	Baseline, 24 week
Change in Mixed Venous Oxygen Saturation (SvO2) from Baseline to Week 24	SvO2 (%) measured by RHC.	Baseline, 24 week
Change in Left Atrial Volume Index (LAVI) from Baseline to Week 24	LAVI (mL/m²) measured by echocardiography and body measurements.	Baseline, 24 week
Change in Tricuspid Valve Systolic Tissue Velocity (TV S' velocity) from Baseline to Week 24	TV S' velocity (cm/s) measured by echocardiography.	Baseline, 24 week
Change in Right Atrial Area (RA area) from Baseline to Week 24	RA area (cm²) measured by echocardiography.	Baseline, 24 week
Change in Presence of Pericardial Effusion from Baseline to Week 24	Presence or absence of pericardial effusion evaluated by echocardiography.	Baseline, 24 week
Change in Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) from Baseline to Week 24	KCCQ-OSS measured by questionnaire.	Baseline, 24 week

Collaborators and Investigators

• Sponsor: Gachon University Gil Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2025
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: August 21, 2025
• First Submitted That Met QC Criteria: August 21, 2025
• First Posted (Actual): August 28, 2025

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Therapeutics; Combined Modality Therapy
• Other Study ID Numbers: MD-CpcPH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No