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A prospective, randomized, double-blind, multicenter, placebo-controlled, parallel group, adaptive Phase 3 study with open-label extension to evaluate efficacy and safety of macitentan 75 mg in inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension

A study to evaluate efficacy and safety of macitentan 75 mg in inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension

127

Baseline characteristics included participants in the "full analysis set," that is, all randomized participants assigned to a study intervention. The mean age was 64.7 and 60.3 years in the macitentan 75 mg and placebo groups,respectively. Fewer participants were Asian (28.1%) in the macitentan 75 mg group compared to placebo group (41.3%), respectively. At Baseline,mean Six-minute Walk distance (6MWD) was 373.7 meters (m), median N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was 222.9 nanogram per liter (ng/L), and 62.2% of participants were in World Health Organization Functional Class (WHO-FC) II and 37.8% in WHO-FC III.

A total of 127 participants (64 participants in the macitentan 75 mg group, and 63 participants in the placebo group) were enrolled and treated with study intervention in this study. All participants were prematurely discontinued from the study due to early termination of study after recommendation of the Independent Data Monitoring Committee (IDMC). This recommendation was based on the pre-planned interim analysis (IA). Most DB study intervention discontinuations were a result of study being terminated by sponsor (65.6% in the macitentan 75 mg group and 82.5% in the placebo group), followed by discontinuations due to AE (17.2% in the macitentan 75 mg group and 4.8% in the placebo group), respectively.

The safety analysis included all participants who received at least one dose of study intervention. The proportion of participants with at least 1 adverse event (AEs) was 87.5% in the macitentan 75 mg group and 82.5% in the placebo group. Serious AEs were reported for 26.6% participants in the macitentan 75 mg group and for 22.2% participants in the placebo group. Serious AEs that were assessed as related to study treatment by the investigator were reported in 3 participants on macitentan 75 mg, and 1 participant on placebo. There was a higher percentage of participants who discontinued study intervention due to AEs in the macitentan 75 mg group compared to the placebo group (21.9% vs 7.9%). AEs leading to discontinuations reported in more than 1 participant in the macitentan 75 mg group were: ALT/AST increased, hypotension, fluid retention, headache, and peripheral edema. Adverse Events of Special Interest (AESI) (edema/fluid retention, hemoglobin decrease/anemia, and hypotension) were more frequently reported in the macitentan 75 mg group as compared to the placebo group. The majority of AESI were mild or moderate and non-serious. There was one treatment-emergent death in the macitentan group. This was due to neoplasm and was considered as unrelated to study treatment according to the investigator. The type of AEs in the macitentan 75mg group were consistent with the studied chronic thromboembolic pulmonary hypertension (CTEPH) population and the known safety profile of previously studied macitentan 10 mg in CTEPH.

Primary Efficacy Endpoint: The primary efficacy endpoint was Change from Baseline to Week 28 in exercise capacity (Six-minute Walk distance [6MWD], as measured by the Six-minute Walk test [6MWT]). Primary efficacy analysis was based on a full analysis set, that is all randomized participants assigned to a study intervention. Mean change from Baseline to Week 28 in 6MWD The primary endpoint of this study was not met: the mean change from Baseline to Week 28 in exercise capacity was not higher in the macitentan 75 mg group compared to placebo. Under the primary estimand, the mean change from Baseline to Week 28 in 6MWD, estimated from a Mixed Model Repeated Measures (MMRM), was not statistically significantly higher in the macitentan 75 mg group. Treatment effect estimates favored placebo (mean difference: -16.1 meters (m) [95% confidence limit (CL): -32.34 m; 0.16 m]; 1-sided p-value=0.974). The primary estimand treatment effect estimates were impacted by intercurrent events:premature discontinuations and administration of rescue therapy occurred more often in the macitentan 75 mg group. The supplementary treatment policy estimand targeting treatment effect irrespective of study intervention discontinuation or initiation of rescue therapy, mean change from baseline in 6MWD at Week 28, was similar in the 2 intervention groups (mean difference: -3.6 m [95% CL: -20.97 m; 13.83 m]; 1-sided p=0.658). Secondary Efficacy Endpoint: Secondary endpoints were not formally tested since the primary endpoint was not met. The key secondary efficacy endpoint was time to first Clinical event committee (CEC)-confirmed clinical worsening) based on full analysis set. Time to First Clinical Worsening up to End-of double-blind-treatment (EODBT) Period: Clinical worsening is 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 WHO-FC that cannot 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 worsening signs or symptoms of right heart failure; 5) Rescue pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA) procedure due to worsening of PH. Overall, a limited incidence of events was observed with 4 participants (6.3%) in the macitentan 75 mg group and 9 participants (14.3%) in the placebo group who experienced a CEC-confirmed clinical worsening event up to end of DB treatment. The most frequently reported first event type was PH-related deterioration.

On 30-August-2023, the Sponsor decided to prematurely stop the study for futility based on recommendation from IDMC following pre-planned interim analysis (IA). Results of final analysis confirmed the results of the IA. The primary endpoint of the study was not met, mean change from Baseline to Week 28 in 6MWD was not higher in macitentan 75 mg group compared to placebo. The safety data reported were consistent with the studied population and known safety profile of previously studied macitentan 10 mg.

Dec. 20, 2024

Yes

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Data Access (YODA) Project site at yoda.yale.edu

https://jrct.mhlw.go.jp/latest-detail/jRCT2051200150

Nakano Masayoshi

Janssen Pharmaceutical K.K.

3-5-2 Nishikanda Chiyoda-ku, Tokyo

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Medical Information Center

Janssen Pharmaceutical K.K.

3-5-2 Nishikanda Chiyoda-ku, Tokyo

+81-120-183-275

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Complete

May. 19, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- 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

- 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

Both

Chronic thromboembolic pulmonary hypertension

Macitentan
Participant will receive macitentan at a dose of 10 milligram (mg) once daily (OD) for 4 weeks, followed by a dose of macitentan 37.5 mg for another 4 weeks and continue with the target dose of macitentan 75 mg. Participants who have reached the target dose of 75 mg, completed the Double-blind (DB) period up to Week 28 (either on treatment or in Post-treatment observation period [PTOP]) at minimum, may be eligible for transitioning into the Open label (OL) extension period once all participants have completed the DB part of the study, or earlier if they experienced a Clinical event committee (CEC) confirmed clinical worsening event.

Placebo
Participants will receive placebo tablets matching the macitentan 10 mg, macitentan 37.5mg and macitentan 75 mg tablets, respectively. Participants who completed the DB period as per protocol either on treatment or in PTOP are eligible for transitioning to the OL extension period and will receive macitentan 75 mg after an 8-week double-dummy uptitration (macitentan 10 mg for 4 weeks, followed by 37.5 mg for another 4 weeks).

Change From Baseline to Week 28 in 6- minute Walk Distance [6MWD]
Baseline up to Week 28
Change from baseline to week 28 in 6MWD as measured by 6-minute walk test [6MWT]) will be reported. The purpose of the six-minute walk test (6MWT) is to quantify exercise tolerance and capacity. This standardized test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in 6 minutes.

- Time to Clinical Worsening up to End-of double-blind-treatment (EODBT) Period
Up to EODBT (variable duration per participant, up to 3.5 years)
Time to first Clinical Event Committee (CEC) confirmed clinical worsening up to EODBT will be reported. Clinical worsening is 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 cannot 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 worsening 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 WHO Functional Class (WHO FC) From Baseline to Week 28
Baseline up to Week 28
Improvement in WHO FC from baseline to Week 28 will be calculated for each participant. WHO FC test is used to assess disease severity. Four functional classes (FC) are defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). Improvement is considered when a participant changes from a higher class to a lower class.

- Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms Based on (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score
Baseline up to Week 28
The Cardiopulmonary Symptoms domain consists of 6 items (shortness of breath,fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area and cough) reported on a 5-point Likert scale (from 0 to 4). The value 0 means "no symptom" and value 4 corresponds to "very severe symptoms". The symptoms part of the PAH-SYMPACT will be administered daily over a 7-day period. The recall period of symptom items is the last 24 hours. An average Cardiopulmonary Symptoms domain score is determined based on the daily scores of the 6 items. Questionnaires to be completed at site at screening for training purpose. PAH-SYMPACT to be performed at home, during the 7-day period prior to the scheduled visit.

- Change from Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score
Baseline up to Week 28
The Cardiovascular Symptoms domain consists of 5 items (heart palpitations [fluttering], rapid heartbeat, chest pain, chest tightness, and lightheadedness) reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "no symptoms" and value 4 corresponds to "very severe symptoms". The symptoms part of the PAH-SYMPACT will be administered daily over a 7-day period. The recall period of symptom items is the last 24 hours. An average Cardiovascular Symptoms domain score is determined based on the daily scores of the 5 items. Questionnaires to be completed at site at screening for training purpose. PAH-SYMPACT to be performed at home, during the 7-day period prior to the scheduled visit.

- Change from baseline to Week 28 in Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L) Utility Score
Baseline up to Week 28
The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).

- Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity
Baseline up to Week 28
Change from baseline to week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity will be assessed.

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Mar. 10, 2021

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