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

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).

• Macitentan (Drug), also known as ACT-064992,, Opsumit: Participants will receive Macitentan film-coated tablets orally od.
• Placebo (Drug): Participant will receive matching placebo tablets orally od.

Primary outcomes

• Change From Baseline in 6-minute Walk Distance (6MWD) at Week 28 [Baseline (Day 1), Week 28]: Change from baseline in 6MWD as measured by 6-minute walk test (6MWT) at Week 28 was reported. The purpose of the 6MWT was to quantify exercise tolerance and capacity. This standardized test measured the distance an individual was able to walk over a total of six minutes on a hard, flat surface with no obstacles. The goal was for the individual to walk as far as possible in 6 minutes.

Secondary outcomes

• Time to First Clinical Event Committee (CEC) Confirmed Clinical Worsening up to End-of Double-blind-treatment (EODBT) Period [From Baseline (Day 1) up to EODBT: median 24.5 weeks (min 3.9 weeks; max 160.4 weeks) for macitentan, median 44 weeks (min 4 weeks; max 147.9 weeks) for placebo]: Time (months) to first CEC-confirmed clinical worsening up to EODBT were reported. Clinical worsening was defined as the occurrence of at least one of the following events: 1) All-cause death; 2) Heart and/or lung transplantation; 3) Unplanned pulmonary hypertension (PH)-related hospitalization; 4) PH-related deterioration from baseline identified by at least one of the following: a) Persistent increase in World Health Organization functional class (WHO FC) that could not be explained by another cause (for example, viral infection); b) Persistent deterioration by at least 15 percent (%) in exercise capacity; as measured by the 6MWD; c) New or worsened signs or symptoms of right heart failure; 5) Rescue pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA) procedure due to worsening of PH.
• Number of Participants With Improvement in World Health Organization Functional Class (WHO FC) From Baseline to Week 28 [From Baseline (Day 1) up to Week 28]: Number of participants with improvement in WHO FC from baseline to Week 28 were reported. Improvement (decrease) in WHO FC from baseline to Week 28 was calculated for each participant. WHO FC test was used to assess disease severity. Four functional classes (FC) were defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). For the analysis purpose, these WHO FC class values were transformed to a scale with scores ranged from 1 to 4; where a score of 1 corresponded to WHO FC Class I and a score of 4 corresponded to WHO FC Class IV. The higher scores indicate greater symptom severity or worse impact. Improvement was considered when a participant changed from a higher class to a lower class.
• Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score [From Baseline (Day 1) up to Week 28]: The cardiopulmonary symptoms domain consisted of 6 items: shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area and cough and were reported on a 5-point Likert scale from 0 (no symptom at all) to 4 (very severe symptoms), with higher score indicating more symptom. The symptoms part of the PAH-SYMPACT was administered daily over a 7-day period. The recall period of symptom items was the last 24 hours. The mean individual symptom item score was determined for each of the 6 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items, ranged from 0=no cardiopulmonary symptoms to 4=severe cardiopulmonary symptoms. A higher score indicated more severe symptoms experienced.
• Change From Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score [From Baseline (Day 1) up to Week 28]: The cardiovascular symptoms domain consisted of 5 items: heart palpitations (fluttering), rapid heartbeat, chest pain, chest tightness, and lightheadedness and were reported on a 5-point Likert scale ranged from 0 (no symptoms at al) to 4 (very severe symptoms), with high score indicating more symptom. The symptoms part of PAH-SYMPACT was administered daily over a 7-day period. The recall period of symptom items was the last 24 hours. An average Cardiovascular Symptoms domain score was determined based on the daily scores of the 5 items. The mean individual symptom item score was determined for each of the 5 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items, ranged from 0=no cardiovascular symptoms to 4=severe cardiovascular symptoms. Higher score indicated more severe symptoms experienced.
• Change From Baseline to Week 28 in Euro Quality of Life-5-Dimension-5-Level (EQ-5D-5L) Utility Score and Visual Analog Scale (VAS) Score [From Baseline (Day 1) up to Week 28]: The EQ-5D-5L was a generic measure of health status. The EQ-5D-5L consisted of 2 parts: EQ-5D-5L utility score (descriptive system) and VAS score. EQ-5D-5L descriptive system consisted of 5-item questionnaire that assessed 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each questionnaire had 5 response levels: 1 =no problems, 2 =slight problems, 3 =moderate problems, 4 =severe problems and 5 =extreme problems. The scores for the 5 questionnaires were used to compute a single utility score which ranged from 0 to 1, where higher score indicated better health state and lower score indicated worse health state. EQ-5D-5L VAS rated current health state on a vertical scale with a score ranged from 0 (worst imaginable health state) to 100 (best imaginable health state), higher scores indicated a better health state.
• Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity [From Baseline (Day 1) up to Week 28]: Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity were assessed. Daily life physical activity of participant was assessed using accelerometer which was provided to the participant at screening and was worn daily during waking hours up to Week 28. For each scheduled visit, the 14 days prior to the visit were considered as the assessment period for physical activity. To be considered evaluable for a given timepoint, actigraphy variables should have been measured for at least 7 complete days (consecutive or not). A complete day is defined as a record of at least 7 waking hours of data. Proportion of time spent in moderate to vigorous physical activity was the estimated number of minutes spent in moderate or higher physical activity as calculated using the Staudenmayer '15 technique as proportion of the total minutes of algorithmically detected wear time and excluding the minutes that fall within a sleep period.

Sex: All, ages: 18 Years to 80 Years

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

Participant flow

Outcome results

• Change From Baseline in 6-minute Walk Distance (6MWD) at Week 28 (Primary), Least squares mean, Meters: Double Blind (DB) Period: Macitentan 9.7 +/- 5.81; DB Period: Placebo 25.8 +/- 5.78 (p 0.974)
• Time to First Clinical Event Committee (CEC) Confirmed Clinical Worsening up to End-of Double-blind-treatment (EODBT) Period (Secondary), Median, Months: Double Blind (DB) Period: Macitentan NA (19.0 to NA); DB Period: Placebo NA (NA to NA)
• Number of Participants With Improvement in World Health Organization Functional Class (WHO FC) From Baseline to Week 28 (Secondary), Count of participants, Participants: Double Blind (DB) Period: Macitentan 7; DB Period: Placebo 6
• Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score (Secondary), Mean, score on a scale: Double Blind (DB) Period: Macitentan -0.089 +/- 0.5856; DB Period: Placebo -0.060 +/- 0.3767
• Change From Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score (Secondary), Mean, Score on a scale: Double Blind (DB) Period: Macitentan -0.141 +/- 0.4530; DB Period: Placebo -0.101 +/- 0.2818
• Change From Baseline to Week 28 in Euro Quality of Life-5-Dimension-5-Level (EQ-5D-5L) Utility Score and Visual Analog Scale (VAS) Score (Secondary), Mean, Score on a scale: Double Blind (DB) Period: Macitentan 0.0472 +/- 0.26700; DB Period: Placebo 0.0050 +/- 0.15010
• Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity (Secondary), Mean, Percent of minutes per day: Double Blind (DB) Period: Macitentan 0.821 +/- 3.9249; DB Period: Placebo -0.833 +/- 4.5160

Adverse events

Time frame: DB period:DB Day 1 to 30 days post EODBT (median exposure[ME]:24.5 weeks[wks], [min 3.9 wks; max 160.4 wks] on macitentan, ME:44 wks [min 4 wks; max 147.9 wks] on placebo); OL period: OL Day 1 to study termination (ME:72 wks [min 8.1 wks; max 84.6 wks]).

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Limitations of the trial such as small numbers of participants analysed or technical problems leading to unreliable data.

68 more sites not listed.

• Results publication: Inacio Cazeiro D, Azaredo Raposo M, Guimaraes T, Lousada N, Jenkins D, R Inacio J, Moreira S, Mineiro A, Freitas C, Martins S, Ferreira R, Luis R, Cardim N, Pinto FJ, Placido R. Chronic thromboembolic pulmonary hypertension: A comprehensive review of pathogenesis, diagnosis, and treatment strategies. Rev Port Cardiol. 2025 Feb;44(2):121-137. doi: 10.1016/j.repc.2024.04.006. Epub 2024 Jun 28. English, Portuguese. PMID 38945473

• Study Protocol (PDF, 2020-12-16)
• Statistical Analysis Plan (PDF, 2024-03-18)

• Actelion Clinical Trial, Study director, Actelion

NIH grants: 2019