The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension

The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension: A Multi-center, Double-blind, Placebo-controlled, Phase 3b Study

The objective of this clinical trial is to compare the efficacy and safety of an initial triple oral treatment regimen (macitentan, tadalafil, selexipag) versus an initial dual oral treatment regimen (macitentan, tadalafil, placebo) in newly diagnosed, treatment-naïve patients with pulmonary arterial hypertension.

Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure.

2. Male or female ≥ 18 and ≤ 75 years of age at screening.

3. Initial PAH diagnosis < 6 months prior to enrollment.

4. RHC performed between Day -28 and Day 1, meeting all the following criteria:

   • Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg.
   • Pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg.
   • PVR ≥ 480 dyn•sec/cm5 (≥ 6 Wood Units).
   • Negative vasoreactivity test mandatory in idiopathic, heritable, and drug/toxin induced PAH (at this or a previous RHC).

5. Symptomatic PAH belonging to one of the following subgroups:

   • Idiopathic.
   • Heritable.
   • Drug or toxin induced.
   • Associated with one of the following: connective tissue disease; HIV infection; congenital heart disease.

6. 6-minute walk distance (6MWD) ≥ 50 m at screening.

7. Women of childbearing potential must not be pregnant, must perform regular pregnancy tests, and use reliable contraception.

Exclusion Criteria:

1. Any PAH-specific drug therapy at any time.

2. Cardio pulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Day 1).

3. Body mass index (BMI) > 40 kg/m2 at screening.

4. Presence of three or more of the following risk factors for heart failure with preserved ejection fraction at screening:

   • BMI > 30 kg/m2.

   • Diabetes mellitus of any type.

   • Essential hypertension.

   • Coronary artery disease, i.e., any of the following:

     • History of stable angina or
     • More than 50% stenosis in a coronary artery (by coronary angiography) or
     • History of myocardial infarction or
     • History of or planned coronary artery bypass grafting and/or coronary artery stenting.

5. Acute myocardial infarction ≤ 12 weeks prior to screening.

6. Stroke ≤ 12 weeks prior to screening.

7. Known permanent atrial fibrillation.

8. SBP < 90 mmHg at screening or Day 1.

9. Ongoing or planned treatment with organic nitrates and/or doxazosin.

10. Presence of one or more of the following signs of relevant lung disease at any time up to screening:

    • Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
    • Forced vital capacity (FVC) < 60% of predicted.
    • Forced expiratory volume in one second (FEV1) < 60% of predicted.

11. Known or suspected pulmonary veno-occlusive disease (PVOD).

12. Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by aspartate aminotransferase (AST) > ULN (assessed by central laboratory at screening); and/or Child-Pugh Class C.

13. Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN (assessed by central laboratory at screening).

14. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m2) assessed by central laboratory at screening.

15. Ongoing or planned dialysis.

16. Hemoglobin < 100 g/L assessed by central laboratory at screening.

17. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).

18. Loss of vision in one or both eyes because of non-arteritic ischemic optic neuropathy (NAION).

19. Treatment with strong inducers of cytochrome P450 3A4 (CYP3A4; e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤ 28 days prior to Day 1.

20. Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) and/or strong inhibitors of CYP2C8 (e.g., gemfibrozil) ≤ 28 days prior to Day 1.

21. Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to Day 1).

22. Hypersensitivity to any of the 3 study treatments or any excipient of their formulations.

23. Pregnancy, breastfeeding, or intention to become pregnant during the study.

24. Concomitant life-threatening disease with a life expectancy < 12 months.

25. Alcohol abuse.

26. Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.