A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension

The purpose of the study is to evaluate the effect of macitentan 75 mg versus placebo on exercise capacity at Week 28 in participants with chronic thromboembolic pulmonary hypertension (CTEPH).

CTEPH is one of the leading causes of severe pulmonary hypertension (PH), classified within World Health Organization (WHO) group 4 PH. It is a rare, progressive pulmonary vascular disease that if left untreated, leads to progressively increasing pulmonary vascular resistance (PVR) and eventually right ventricle failure and death. Histopathologic findings including endothelial cell dysfunction and distal pulmonary arterial remodeling are shared between PAH and CTEPH, and PH-specific therapies (that is, riociguat) have shown efficacy in inoperable and persistent/recurrent CTEPH. The endothelin receptor antagonist macitentan offers a different mode of action and addresses an important unmet medical need for an alternative treatment option in this indication. This study will assess the effect of macitentan 75 mg on exercise capacity in CTEPH. The total duration of the study is approximately 6 years. The study comprises of a screening period (at least 14 days and up to 60 days), a double-blind (DB) treatment period (28 weeks \[minimum duration\] up to 3.5 years), an open-label (OL) extension period (starts at end-of-DB-treatment \[EODBT\] and will end for all participants 104 weeks after the last participant has completed DB Week 28). The DB period consists of an 8-week up-titration phase and a maintenance phase. The maintenance phase is divided into a 28-week fixed duration part, at the end of which primary endpoint is assessed, and a variable duration part. The duration of the DB period for an individual participant depends on the timepoint of entry into the study and whether a CEC-confirmed clinical worsening event occurred. Participants who discontinue DB study intervention during the 28-week fixed duration part will be followed until Week 28 in a post-treatment observation period (PTOP).

Eligibility Criteria:
Inclusion Criteria:

* Chronic thromboembolic pulmonary hypertension (CTEPH) (World Health Organization \[WHO\] Group 4) fulfilling one of the following criteria: a) inoperable due to the localization of the obstruction being surgically inaccessible (that is, distal disease), b) persistent/recurrent CTEPH after balloon pulmonary angioplasty (BPA), and deemed inoperable due to the localization of the obstruction being surgically inaccessible (that is, distal disease), c) persistent/recurrent CTEPH after rescue pulmonary endarterectomy (PEA)
* 6-minute walk distance (6MWD) greater than or equal to (\>=) 100 meter (m) and less than or equal to (\<=) 450 meters (m), documented by an eligibility and a baseline 6-minute walk test (6MWT). The baseline 6MWD must not differ by more than 15 percent (%) from the eligibility test
* World Health Organization functional class (WHO FC) \>= II
* Participants are to receive riociguat as per local standard of care, unless it is contraindicated or unavailable

Exclusion Criteria:

* Acute pulmonary embolism within 3 months prior to or during Screening
* Planned balloon pulmonary angioplasty (BPA) during the fixed duration part of the double-blind period
* Significant obstructive and restrictive lung disease
* Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements, in particular with 6MWT (for example, intermittent claudication).
* Symptomatic coronary artery disease requiring an intervention within 3 months prior to or during Screening or anticipated during the fixed duration part of the study
* Decompensated cardiac failure if not under close supervision
* Known and documented life-threatening cardiac arrhythmias
* Acute myocardial infarction within 6 months prior to, or during Screening
* Cerebrovascular events (including transient ischemic attack) within 3 months prior to, or during Screening
* Known or suspicion of pulmonary veno-occlusive disease (PVOD)
* Administration of ERAs, intravenous prostacyclins / prostacyclin analogs, or investigational treatment within 90 days prior to Randomization
* Change in dose or initiation of Phosphodiesterase type-5 (PDE-5) inhibitors, oral, inhaled or subcutaneous (SC) prostacyclins / prostacyclin analogues, prostacyclin receptor agonists or riociguat, a) within 90 days prior to Randomization, or b) anticipated during the fixed duration part of the double-blind \[DB\] period
* Hypotension, that is, systolic blood pressure (SBP) less than (\<) 90 millimeters of mercury (mmHg) or diastolic blood pressure (DBP) \<50 mmHg at Screening.
* Severe renal dysfunction with an estimated Glomerular Filtration Rate \<30 milliliters per minute per 1.73 meter square (mL/min/1.73 m\^2) using the Chronic Kidney Disease Epidemiology Collaboration formula at Screening
* Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based on records that confirm documented medical history
* Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than or equal to (\>=) 1.5\*upper limit of normal (ULN) at Screening
* Hemoglobin \<100 g/L (\<10 gram per deciliter \[g/dL\]) at Screening