Initial Dual Oral Combination Therapy Versus Standard-of-care Initial Oral Monotherapy Prior to Balloon Pulmonary Angioplasty in Patients with Inoperable Chronic Thromboembolic Pulmonary Hypertension

Inclusion Criteria:

1. Signed informed consent.

2. Male or female ≥18 and ≤ 80 years of age at inclusion.

3. Newly diagnosed and treatment-naïve subjects with CTEPH judged as inoperable due tosurgically inaccessible lesions but eligible for balloon pulmonary angioplasty,riociguat and macitentan by multidisciplinary team assessment and fulfilling thefollowing criteria:

4. Symptomatic pulmonary hypertension (PH) in WHO FC ≥ II.

5. Confirmation of diagnosis based on 2 of the 3 following methods: i. Ventilation-perfusion lung scan ii. Digital subtraction pulmonary angiography (DSA) iii. CT pulmonary angiography (CTPA).

6. Confirmation of inoperability based on CTPA scan and/or DSA.

7. Right-heart catheterization (RHC) in the 12-week period prior to screening visit orduring screening period showing the following:

8. Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg

9. Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg or left ventricular enddiastolic pressure ≤ 15 mmHg

10. PVR at rest ≥ 400 dyn.sec.cm-5.

11. Subject anticoagulated (with either vitamin K antagonists or direct oralanticoagulants [e.g., factor IIa inhibitors, factor Xa inhibitors]), or treated withunfractionated heparin or low molecular weight heparin for at least 3 months priorto baseline RHC.

12. 6MWD ≥ 50m

13. Women of childbearing potential must:

14. Have a negative pre-treatment serum pregnancy test

15. Agree to use reliable contraception from screening up to 1 month followingdiscontinuation of the last study treatment.

Exclusion Criteria:

1. Previous pulmonary endarterectomy.

2. Previous balloon pulmonary angioplasty.

3. Any PAH-targeted therapy (e.g., any endothelin receptor antagonist (ERA),phosphodiesterase-5 inhibitor (PDE-5i), soluble guanylate cyclase stimulator,prostacyclin, prostacyclin analog, or prostacyclin receptor agonist) at any timeprior to inclusion.

4. Ongoing or planned treatment with organic nitrates.

5. Known moderate-to-severe restrictive lung disease (i.e., total lung capacity < 60%of predicted value) or obstructive lung disease (i.e., forced expiratory volume inone second [FEV1] < 60% of predicted, with FEV1 / forced vital capacity < 65%) orknown significant chronic lung disease diagnosed by chest imaging (e.g.,interstitial lung disease, emphysema).

6. Symptomatic coronary artery disease requiring nitrate use or intervention (e.g.,Percutaneous Coronary Intervention, Coronary Artery Bypass Graft) anticipated in the 6-month period after inclusion.

7. Acute myocardial infarction ≤ 12 weeks prior to inclusion.

8. Left heart failure with an ejection fraction less than 40%.

9. Cerebrovascular events (e.g., transient ischemic attack, stroke) ≤ 12 weeks prior toinclusion.

10. History of life-threatening hemoptysis (>100 mL in 24 h) or subjects who havepreviously undergone bronchial arterial embolization for hemoptysis.

11. Hemoglobin < 100 g/L.

12. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 ×upper limit of the normal range.

13. Documented severe hepatic impairment (with or without cirrhosis) according toNational Cancer Institute organ dysfunction working group criteria, defined as totalbilirubin > 3 × upper limit of the normal range (ULN) accompanied by aspartateaminotransferase (AST) > ULN; and/or Child-Pugh Class C.

14. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m²).

15. Systolic blood pressure <95mmHg.

16. Treatment with strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., rifabutin,rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort) ≤ 28 daysprior to inclusion.

17. Treatment with strong multi pathway P-glycoprotein (P-gp)/ breast cancer resistanceprotein (BCRP) inhibitors (e.g., lopinavir/ritonavir) ≤ 28 days prior to inclusion.

18. Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole,voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir)or a moderate dual CYP3A4/CYP2C9 inhibitor (e.g., fluconazole, amiodarone) orco-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors ≤ 28 days prior to inclusion.

19. Known hypersensitivity to riociguat or macitentan or to any excipient of theirformulation.

20. History of severe allergic-like reaction to intravascular administration ofiodinated contrast media (including diffuse edema or facial edema with dyspnea,diffuse erythema with hypotension, laryngeal edema with stridor and/or hypoxia,bronchospasm, anaphylactic shock with hypotension and tachycardia).

21. Subject who cannot remain in a supine position for at least 120 min for any reason.

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

23. Subjects with underlying medical disorders and anticipated life expectancy < 12months (eg active cancer disease with localized and/or metastasized tumor mass).

24. Alcohol abuse (at investigator discretion)

25. Subject not covered by social security service.

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