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Prospective, Multi-center, Double-blind, Randomized, Active-controlled, Triple-dummy, Parallel-group, Group-sequential, Adaptive Phase 3 Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies with the Corresponding Fixed Dose Combination in Subjects with Pulmonary Arterial Hypertension (PAH), Followed by an Open-label Treatment Period with Macitentan and Tadalafil Fixed Dose Combination Therapy

Clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed-dose combination therapy in subjects with pulmonary arterial hypertension (PAH)

187

Double-blind (DB) Period: The baseline characteristics were based on the full analysis set (FAS) (N= 186) which included all randomized participants who received at least one dose of study treatment (for participants in FDC, at least one dose of either macitentan or tadalafil). The median age was 48.0, 51.0, and 54.0 years for macitentan/tadalafil fixed dose combination (M/T FDC), macitentan, and tadalafil groups, respectively. 76.6% participants in the macitentan/tadalafil fixed dose combination (M/T FDC) group, 82.9% participants in the macitentan group, and 77.3% participants in the tadalafil group were female. All participants were classified as WHO FC II or III. WHO FC II included 60.7%, 31.4%, and 43.2% and WHO FC III included 39.3%, 68.6%, and 56.8% participants in M/T FDC, macitentan, and tadalafil groups respectively. The leading etiology was idiopathic PAH, followed by PAH associated with connective tissue disease. The median time since diagnosis in all groups was less than (<) 0.5 years. The median PVR at DB baseline was 723.5, 794.0, and 690.7 dyne-seconds per centimeter raise to the power 5 (dyn.sec/cm^5) and median 6MWD was 373.0, 368.0, and 378.5 meters (m) of M/T FDC, macitentan, and tadalafil groups, respectively. Open-label (OL) Period: The baseline characteristics for participants entering the OL period were based on the open-label set (OLS) (n= 169) which included all participants who received at least one dose of OL study treatment in the OL period. The median age of study participants (as assessed at DB baseline) was 50 years (range: 18 to 80 years). At OL baseline, no participant was in WHO FC IV, with the proportion in FC I, II, and III being 8.9%, 60.9%, and 30.2%, respectively. Median PVR at OL baseline was 475.16 dyn.sec/cm^5 (range: 50.1 to 2241.9 dyn.sec/cm^5) and median 6MWD was 410.0 m (range: 120 to 565 m).

DB Period (Week 1 to Week 16) Of the 294 participants screened, 187 participants were randomized (all randomized analysis set; 108 to M/T FDC, 35 to macitentan, and 44 to tadalafil) across 16 countries/territories. Most screen failures were due to not meeting eligibility criteria. Participants were randomized to receive either M/T FDC, macitentan 10 mg, or tadalafil 40 mg, orally, once daily. Treatment allocation was stratified by treatment status at baseline, that is treatment-naive (50 participants to M/T FDC, 24 to macitentan, and 25 to tadalafil), or prior an endothelin receptor antagonist (ERA) (21 participants to M/T FDC and 11 to macitentan) or prior phosphodiesterase type-5 inhibitor (PDE-5i) as a monotherapy (37 participants to M/T FDC and 19 to tadalafil). Out of 187 randomized participants, 186 participants received at least 1 dose of study intervention. 1 participant in M/T FDC did not receive any treatment. Most participants completed study participation in the DB period. A total of 8.3% participants in the M/T FDC group and 2.3% of participants in the tadalafil group prematurely discontinued the study during the DB period. Reasons for study participation discontinuation were death (2.8%), participant decision (3.7%) and physician decision (1.9%). OL Period (Week 17 to Week 120) Of the 186 participants who were treated with at least one dose of DB study intervention (DB-macitentan [n=35], DB-tadalafil [n=44] and DB-M/T FDC [n=107]), 169 participants completed the DB period and entered the OL extension period. Of these, 85.2% of participants completed the 24-month OL period and 14.8% of participants discontinued. The most common reasons for premature study participation discontinuation in the OL period were: 13 due to withdrawal of consent and 5 due to death. Of the 169 participants who received M/T FDC in the OL period, 79.9% completed the study treatment and 20.1% discontinued. The most common reasons for study intervention discontinuation in the OL period were: 11 due to AEs and 5 due to withdrawal by participant.

DB Period Safety analyses were based on the safety analysis set (n=107) which included all participants who received at least one dose of study treatment in the DB treatment period. The proportion of all adverse events (AEs) reported during the DB period of the study was higher in the M/T FDC group (82.2%) than in the macitentan group (71.4%) and similar to the tadalafil group (79.5%).The proportion of participants randomized to M/T FDC who experienced at least 1 AE in the DB period was higher in the treatment-naive stratum (87.8%) than in the prior ERA (76.2%) and the prior PDE-5i (78.4%) strata. There were 3 serious adverse events (SAEs) (2 treatment emergent) with fatal outcome in the M/T FDC group, and none in the macitentan or tadalafil groups; all were considered not related to study intervention by the investigator. There was a higher proportion of participants with SAEs and discontinuations of study intervention due to AEs in the M/T FDC group compared to the monotherapy groups, but no clear pattern of events by preferred term (PT) was apparent. Among adverse event of special interest (AESI), hypotension, anemia, and edema were reported more frequently in the M/T FDC group as compared to macitentan and tadalafil. Hepatic events were overall infrequent. Most AESI were of mild to moderate intensity and were clinically manageable. Decreases in hemoglobin were more common and pronounced in the M/T FDC group. OL Period Safety analyses were based on the combination safety set (n=185) which included all participants who randomized to M/T FDC in the DB period and who received at least one dose of M/T FDC DB study treatment (that is, at least one dose of macitentan and tadalafil) and all participants who received at least one dose of M/T FDC study treatment (that is, at least one dose of macitentan and tadalafil) in the OL period. In participants who received M/T FDC during the combined DB+OL period: The incidence and pattern of AEs reported during the combined DB+OL period was consistent with the safety profile of M/T FDC as observed in the 16-week DB period. The overall incidence of AEs was 94.1%. The most frequently reported treatment-emergent adverse events (TEAEs) by PT (greater than [>]10% of all treated participants in the M/T FDC total group) were: coronavirus disease of 2019 (COVID-19) (25.4%), headache (15.1%), anemia (12.4%), and peripheral edema (11.9%). A total of 14 participants died during the study. Of these, 7 (3.8%) deaths were reported during the treatment-emergent period (2 deaths in the DB period and 5 in the OL period). None of the deaths were considered by the investigator to be related to study intervention. Serious AEs were reported in 62 (33.5%) participants; 6 participants had SAEs considered by the investigator to be related to study intervention. Serious AEs reported in >2 participants were right ventricular failure (3.2%); COVID-19 (2.7%); dyspnea and pneumonia (2.2% each); bronchitis and PAH worsening (1.6% each). Treatment-emergent AEs leading to premature discontinuation of study intervention were reported in 19 (10.3%) participants, with decreased hemoglobin being the most common reason for study intervention discontinuation (2 participants). The incidence of treatment-emergent AESI was as follows: hypotension (6.5%), anemia (24.9%), edema (18.4%), and hepatic disorders (5.9%). A total of 28 (15.8%) participants had at least one hemoglobin value of less than (<)100 grams per liter (g/L). Treatment-emergent ALT or AST elevations to greater than or equal to (>=)3*ULN were reported in 6 participants.

Primary Efficacy Endpoint: The analysis of the primary endpoint was based on two comparisons of interest. Participants contributing to the comparison of M/T FDC (n=70) vs macitentan (n=35) were from the treatment-naive and prior ERA strata. Participants contributing to the comparison of M/T FDC (n=86) vs tadalafil (n=44) were from the treatment-naive and prior PDE5i strata. The analyses for primary efficacy endpoint was based on FAS (n= 35 [macitentan], 70 [M/T FDC prior ERA strata], 44 [tadalafil], 86 [M/T FDC Treatment-naive and prior PDE-5i strata]) which included all randomized participants who received at least one dose of study treatment (for participants in FDC, at least one dose of either macitentan or tadalafil). Change in PVR Expressed as the Ratio of Geometric Means of EDBT to Baseline Geometric mean (95% CI) values for change from baseline in PVR were 0.55 (0.50 to 0.60) for M/T FDC Vs 0.77 (0.69 to 0.87) for macitentan were from the treatment-naive and prior ERA strata and 0.56 (0.52 to 0.60) for M/T FDC vs 0.78 (0.72 to 0.84) for tadalafil were from the treatment-naive and prior PDE5i strata. A highly statistically significant and clinically meaningful treatment effect was observed for both the M/T FDC versus macitentan and the M/T FDC versus tadalafil comparisons, and the treatment effect was consistent across all subgroups. Based on the analysis of covariance (ANCOVA) model run at each stage with treatment group, stratum, and baseline value as covariates, the median unbiased estimates of the geometric means ratios (95% adjusted repeated confidence limits [RCL]) were: 0.71 (0.61, 0.82) between M/T FDC and macitentan (29% reduction in PVR with M/T FDC compared to macitentan, p<0.0001); 0.72 (0.64, 0.80) between M/T FDC and tadalafil (28% reduction in PVR with M/T FDC compared to tadalafil, p<0.0001).

Secondary Efficacy Endpoints: Change From Baseline to EDBT in 6MWD The analyses for 6MWD were based on FAS which included all randomized participants who received at least one dose of study treatment (for participants in FDC, at least one dose of either macitentan or tadalafil). Mean (SD) values for change from baseline in 6MWD were 38.5 (70.42), 52.9 (88.23), 15.9 (45.04), and 43.4 (78.03) for macitentan, M/T FDC prior ERA strata, tadalafil, M/T FDC prior PDE-5i strata groups, respectively. The difference in 6MWD change from baseline to EDBT was not statistically significant between M/T FDC and macitentan or between M/T FDC and tadalafil. Based on the ANCOVA model run at each stage with treatment group, stratum, and baseline value as covariates, the median unbiased estimates of change from baseline to EDBT (adjusted RCL) and combined p-values were: M/T FDC versus macitentan: 16.04m (-17.0,49.08), p=0.3802; M/T FDC versus tadalafil: 25.37 m (-0.93,51.59), p=0.0591 given these 6MWD results, and in accordance with the predefined hierarchical testing procedure,subsequent secondary endpoints (PAH-SYMPACT and Absence of Worsening in WHO FC) could not be formally tested. Change From Baseline in PAH-SYMPACT in Cardiopulmonary Symptom Domain Scores to EDBT The analyses for PAH-SYMPACT was based on PAH-SYMPACT symptoms of participants contributing to the comparison of M/T FDC (n=66) vs macitentan (n=33) were from the treatment-naive and prior ERA strata. Participants contributing to the comparison of M/T FDC (n=81) vs tadalafil (n=89) were from the treatment-naive and prior PDE5i strata. Mean (SD) values for change from baseline in PAH-SYMPACT in cardiopulmonary symptoms were -0.20 (0.394) for M/T FDC vs -0.14 (0.478) for macitentan were from the treatment-naive and prior ERA strata and -0.15 (0.404) for M/T FDC vs -0.13 (0.554) for tadalafil were from the treatment-naive and prior PDE5i strata. Change From Baseline in PAH-SYMPACT in Cardiovascular Symptom Domain Scores to EDBT The analyses for PAH-SYMPACT was based on PAH-SYMPACT symptoms analysis set which included all participants included in the FAS for whom at least one baseline value of symptoms domain was provided. Mean (SD) values for change from baseline in PAH-SYMPACT in cardiovascular symptoms were -0.15 (0.394) for M/T FDC vs -0.14 (0.473) for macitentan were from the treatment-naive and prior ERA strata and -0.10 (0.318) for M/T FDC vs -0.18 (0.612) for tadalafil were from the treatment-naive and prior PDE5i strata. Percentage of Participants With Absence of Worsening in WHO FC From Baseline to EDBT The analyses for WHO FC was based on FAS which included all randomized participants who received at least one dose of study treatment (for participants in FDC, at least one dose of either macitentan or tadalafil). The study was adaptive with two stages: Stage 1 and Stage 2. Percentage of participants with absence of worsening in WHO FC from Baseline to EDBT by Stage were Stage 1 (pre interim analysis [IA] with SSRE): class I (5.6%, 5.3%, 4.5%, 12.8%), class II (55.6%, 57.9%, 63.6%, 59.6%), class III (38.9%, 23.7%,31.8%, 25.5%), class IV (0%,0%,0%,0%); Stage 2 (post-IA): class I (11.8%, 9.4%, 9.1%, 7.7%), class II (52.9%, 75.0%, 54.5%, 61.5%), class III (35.3%, 15.6%, 36.4%, 25.6%), class IV (0%, 0%, 0%, 0%) for macitentan, M/T FDC prior ERA strata, tadalafil, M/T FDC prior PDE-5i strata groups, respectively.

DB Period Data from 16-week DB treatment period support both efficacy and safety of M/T FDC for the treatment of participants with PAH. OL Period Long-term exposure to M/T FDC was well tolerated with no new safety findings identified during combined DB+OL period. The nature of AEs in M/T FDC group was consistent with the expected safety profile for macitentan and tadalafil, and AEs were manageable. Increases in 6MWD as observed in the DB period were maintained or further improved during 24-month OL period.

Sept. 27, 2025

Jan. 30, 2024

https://www.sciencedirect.com/science/article/pii/S073510972308138X?via%3Dihub#tbl4

Yes

Sakurai Satomi

Janssen Pharmaceutical K.K.

5-2, Nishi-kanda 3-chome, Chiyoda-ku, Tokyo

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Medical Information Center

Janssen Pharmaceutical K.K.

5-2, Nishi-kanda 3-chome, Chiyoda-ku, Tokyo

+81-120-183-275

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

completed

Oct. 23, 2020

Interventional

Parallel Assignment Randomized

treatment purpose

3

- Signed and dated informed consent form (ICF).

- Confirmed diagnosis of symptomatic PAH in WHO FC II or III.

- Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension:
> Idiopathic.
> Heritable.
> Drug- or toxin-induced.
> Associated with connective tissue disease, HIV infection, portal hypertension or congenital heart disease with simple systemic-to-pulmonary shunt with persistent pulmonary hypertension documented by a right heart catheterization (RHC) >= 1 year after surgical repair.

- PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading), evaluated within 5 weeks prior to randomization:
> mean pulmonary artery pressure (mPAP) >= 25mmHg,
AND
> Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) =< 15 mmHg,
AND
> Pulmonary vascular resistance (PVR) >= 3 WU (i.e., >= 240 dyn*sec*cm-5)
- Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH. (Participants for whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy).

- Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the prespecified doses in the study protocol or no history of PAH-specific treatment.

- Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at
Screening.

- A woman of childbearing potential must:
> have negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization.
> agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation.
> agree to follow the contraception scheme from Screening up to at least 30 days after study treatment
discontinuation.

- Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclinreceptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment.
- Treatment with combination therapy of ERA and PDE- 5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy.
- Hypersensitivity to any of the study treatments or any excipient of their formulations.
- Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month period prior to start of treatment.
- Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1- month period prior to start of treatment.
- Treatment with doxazosin.
- Treatment with any form of organic nitrate, either regularly or intermittently
- Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment.
- Treatment with another investigational drug in the 3- month period prior to start of treatment.
- Body mass index (BMI) > 40 kg/m2 at Screening.
- Known 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 (even if well controlled).
> Coronary artery disease, i.e. history of stable angina or known more than 50% stenosis in a coronary artery or history of myocardial infarction or history of or planned coronary artery bypass grafting and/or coronary artery stenting.
- Known presence of moderate or severe obstructive lung disease any time prior to Screening as specified in study protocol.
- Known presence of moderate or severe restrictive lung disease any time prior to Screening as specified in study protocol.
- Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive leftsided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction, in the opinion of the investigator.
- Known permanent atrial fibrillation, in the opinion of the investigator.
- Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
- Documented pulmonary veno-occlusive disease.
- Hemoglobin < 100 g/L (<10 g/dL) at Screening.
- Known severe hepatic impairment as specified in study protocol.
- Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 * upper limit of normal (ULN) at Screening.
- Severe renal impairment at Screening as specified in study protocol.
- Systemic hypotension at Screening or Randomization and systemic hypertension at Screening as specified in study protocol.
- Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening.
- Known bleeding disorder, in the opinion of the investigator
- Loss of vision in one or both eyes because of nonarteritic anterior ischemic optic neuropathy
- Hereditary degenerative retinal disorders, including retinitis pigmentosa.
- Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen.
- Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions.
- Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to Start of treatment, or planned to be started during the study.
- Pregnant, planning to become pregnant or lactating.
- Any known factor or disease that might interfere with treatment adherence, full participation in the study or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence etc.).
- Known concomitant life-threatening disease with a life expectancy less than (<) 12 months
- Calcium channel blocker treatment initiated, or dose changed within 3 months prior to right heart catheterization (RHC) at screening

Both

pulmonary arterial hypertension

investigational material(s)
Generic name etc : ACT-064992D
INN of investigational material : -
Therapeutic category code : 219 Other cardiovascular agents
Dosage and Administration for Investigational material : Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.

control material(s)
Generic name etc : Macitentan
INN of investigational material : -
Therapeutic category code : 219 Other cardiovascular agents
Dosage and Administration for Investigational material : Film-coated tablet with 10 mg macitentan, to be administered orally once daily.
Generic name etc : Tadalafil
INN of investigational material : -
Therapeutic category code : 219 Other cardiovascular agents
Dosage and Administration for Investigational material : Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : FDC therapy + Placebo macitentan + Placebo tadalafil , Macitentan mono-therapy + Placebo tadalafil + Placebo FDC, Tadalafil mono-therapy + Placebo macitentan + Placebo FDC

efficacy
Change in Pulmonary Vascular Resistance (PVR) expressed as the ratio of geometric means of End of
Double-Blind Treatment (EDBT) to baseline

efficacy
Change in 6-minute walk distance (6MWD) from baseline to EDBT
efficacy
Change From Baseline in Cardiopulmonary Symptom Domain Score in PAH-SYMPACT to Week 16
efficacy
Change From Baseline in Cardiovascular Symptom Domain Score in PAH-SYMPACT to Week 16
efficacy
Proportion of subjects with absence of worsening in World Health Organization (WHO) Functional Class (FC) from baseline to EDBT.

Nov. 29, 2019