Clinical Trials List
Protocol NumberAC-077A301
NCT Number(ClinicalTrials.gov Identfier)NCT03904693
Completed
2019-08-30 - 2024-12-17
Phase III
Recruiting6
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
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Trial Applicant
Johnson & Johnson
-
Sponsor
Janssen Research & Development, LLC
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Trial scale
Multi-Regional Multi-Center
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Update
2026/02/01
Investigators and Locations
Co-Principal Investigator
- Hsien-Tzung Liao Division of Cardiovascular Diseases
- 黃偉銘 Division of Cardiovascular Diseases
- Chien-Chih Lai Division of Cardiovascular Diseases
- Wei-Sheng Chen Division of Cardiovascular Diseases
- 洪正中 Division of Cardiovascular Diseases
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Po-Sheng Chen Division of Cardiovascular Diseases
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- CHIEH-YU SHEN Division of General Internal Medicine
- KO-JEN LI Division of General Internal Medicine
- Shuenn Nan Chiu Division of Pediatrics
- SHUENN-WEN KUO Division of Thoracic Surgery
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- 蕭富致 Division of Cardiovascular Diseases
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- 吳書豪 Division of Cardiovascular Diseases
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Pulmonary Arterial Hypertension (PAH)
Objectives
Primary objective
This study has two co-primary objectives:
1. To evaluate the effect of the M/T FDC vs macitentan 10 mg alone on PVR at EDBT in
subjects with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve
or are currently being treated with an ERA as monotherapy.
2. To evaluate the effect of the M/T FDC vs tadalafil 40 mg alone on PVR at EDBT in
subjects with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve
or are currently being treated with a PDE-5i as monotherapy.
Secondary objectives
The secondary objectives are:
To evaluate the effect of the M/T FDC compared to the respective monotherapies on:
- Exercise capacity
- PAH symptoms and their impacts on subject’s life.
- WHO FC.
To evaluate the safety and tolerability of the M/T FDC in the subject population.
Test Drug
M/T FDC, Macitentan 10 mg+Tadalafil 40 mg
Active Ingredient
M/T FDC, Macitentan 10 mg+Tadalafil 40 mg
Dosage Form
film-coated tablet
Dosage
1
Endpoints
Primary efficacy endpoint
Change in PVR expressed as the ratio of geometric means of EDBT to baseline
Secondary efficacy endpoints
The secondary efficacy endpoints are listed here according to the hierarchical order that
will be statistically tested:
Change from baseline to EDBT in 6MWD.
This endpoint reflects the subjects’ exercise capacity and has been associated with
subjects’ prognosis / clinical outcomes including mortality [Benza 2012b,
Benza 2015] and hemodynamics. It has also been the basis for registration of
several of the currently approved PAH therapies.
Change from baseline to EDBT in PAH-SYMPACT™ Cardiopulmonary symptom
domain score.
Change from baseline to EDBT in PAH-SYMPACT™ Cardiovascular symptom
domain score.
Change from baseline to EDBT in PAH-SYMPACT™ Physical impact domain
score.
Change from baseline to EDBT in PAH-SYMPACT™ Cognitive/emotional impact
domain score.
Change in PVR expressed as the ratio of geometric means of EDBT to baseline
Secondary efficacy endpoints
The secondary efficacy endpoints are listed here according to the hierarchical order that
will be statistically tested:
Change from baseline to EDBT in 6MWD.
This endpoint reflects the subjects’ exercise capacity and has been associated with
subjects’ prognosis / clinical outcomes including mortality [Benza 2012b,
Benza 2015] and hemodynamics. It has also been the basis for registration of
several of the currently approved PAH therapies.
Change from baseline to EDBT in PAH-SYMPACT™ Cardiopulmonary symptom
domain score.
Change from baseline to EDBT in PAH-SYMPACT™ Cardiovascular symptom
domain score.
Change from baseline to EDBT in PAH-SYMPACT™ Physical impact domain
score.
Change from baseline to EDBT in PAH-SYMPACT™ Cognitive/emotional impact
domain score.
Inclution Criteria
1. Signed and dated ICF.
2. Male and female subjects ≥ 18 years old and ≤ 75 years old.
3. Confirmed diagnosis of symptomatic PAH in WHO FC II or III.
4. Symptomatic PAH belonging to one of the following subgroups of WHO Group 1
pulmonary hypertension [Simonneau 2013]:
Idiopathic.
Heritable.
Drug- or toxin-induced.
Associated with one of the following:
o Connective tissue disease.
o HIV infection.
o Portal hypertension.
o Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal
defect, ventricular septal defect, patent ductus arteriosus) with persistent
pulmonary hypertension documented by an RHC ≥ 1 year after surgical repair.
5. PAH diagnosis confirmed by hemodynamic evaluation at rest, evaluated within
5 weeks prior to randomization:
Mean pulmonary artery pressure (mPAP) 25 mmHg, 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)
6. Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH
7. No history of PAH-specific treatment5
or currently receiving a stable dose of ERA
or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the
following prespecified doses:
- Bosentan: 250 mg total daily dose
- Macitentan: 10 mg total daily dose
- Ambrisentan: 10 mg total daily dose
- Sildenafil: 60–120 mg total daily dose
- Tadalafil: 40 mg total daily dose
- Vardenafil: 10 mg total daily dose
8. Subject able to perform the 6MWT with a minimum distance of 100 m and maximum
distance of 450 m at Screening.
9. A woman of childbearing potential is eligible only if the following applies:
- Negative serum pregnancy test at Screening and a negative urine pregnancy test
at Randomization.
- Agreement to undertake monthly urine pregnancy tests during the study and up
to at least 30 days after study treatment discontinuation.
- Agreement to follow the contraception scheme from Screening up to at least
30 days after study treatment discontinuation.
2. Male and female subjects ≥ 18 years old and ≤ 75 years old.
3. Confirmed diagnosis of symptomatic PAH in WHO FC II or III.
4. Symptomatic PAH belonging to one of the following subgroups of WHO Group 1
pulmonary hypertension [Simonneau 2013]:
Idiopathic.
Heritable.
Drug- or toxin-induced.
Associated with one of the following:
o Connective tissue disease.
o HIV infection.
o Portal hypertension.
o Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal
defect, ventricular septal defect, patent ductus arteriosus) with persistent
pulmonary hypertension documented by an RHC ≥ 1 year after surgical repair.
5. PAH diagnosis confirmed by hemodynamic evaluation at rest, evaluated within
5 weeks prior to randomization:
Mean pulmonary artery pressure (mPAP) 25 mmHg, 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)
6. Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH
7. No history of PAH-specific treatment5
or currently receiving a stable dose of ERA
or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the
following prespecified doses:
- Bosentan: 250 mg total daily dose
- Macitentan: 10 mg total daily dose
- Ambrisentan: 10 mg total daily dose
- Sildenafil: 60–120 mg total daily dose
- Tadalafil: 40 mg total daily dose
- Vardenafil: 10 mg total daily dose
8. Subject able to perform the 6MWT with a minimum distance of 100 m and maximum
distance of 450 m at Screening.
9. A woman of childbearing potential is eligible only if the following applies:
- Negative serum pregnancy test at Screening and a negative urine pregnancy test
at Randomization.
- Agreement to undertake monthly urine pregnancy tests during the study and up
to at least 30 days after study treatment discontinuation.
- Agreement to follow the contraception scheme from Screening up to at least
30 days after study treatment discontinuation.
Exclusion Criteria
PAH treatments:
1. Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of
prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused
routes) in the 3-month period prior to start of treatment.
2. 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.
3. Hypersensitivity to any of the study treatments or any excipient of their formulations.
Other therapies:
4. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer (e.g., rifabutin,
rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s
Wort) in the 1-month period prior to start of treatment.
5. Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole,
voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) in
the 1-month period prior to start of treatment.
6. Treatment with doxazosin.
7. Treatment with any form of organic nitrate, either regularly or intermittently
8. Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of
treatment.
9. Treatment with another investigational drug in the 3-month period prior to start of
treatment.
Medical history/current medical conditions:
10. Body mass index (BMI) > 40 kg/m2 at Screening.
11. 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., any of the following:
o History of stable angina, or
o Known more than 50% stenosis in a coronary artery, or
o History of myocardial infarction, or
o History of or planned coronary artery bypass grafting and/or coronary artery
stenting.
12. Known presence of moderate or severe obstructive lung disease (forced expiratory
volume in 1 second [FEV1] / forced vital capacity [FVC] < 70%; and FEV1 < 65% of
predicted after bronchodilator administration) any time prior to Screening.
13. Known presence of moderate or severe restrictive lung disease (total lung capacity or
FVC < 60% of normal predicted value) any time prior to Screening.
14. Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive
or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias;
significant left ventricular dysfunction; or left ventricular outflow obstruction.
15. Known permanent atrial fibrillation.
16. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
17. Documented pulmonary veno-occlusive disease.
Criteria linked to macitentan/tadalafil use:
18. Hemoglobin < 100 g/L (<10 g/dL) at Screening.
19. Known severe hepatic impairment defined as Child Pugh Score C or a Model for EndStage Liver Disease (MELD) score ≥ 19.
6
20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
> 1.5 upper limit of normal (ULN) at Screening.
21. Severe renal impairment (Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) 2009 equation [Levey 2009] calculated creatinine clearance < 30 mL/min) at
Screening.
22. Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure
[DBP] < 50 mmHg) at Screening or Randomization.
23. Systemic hypertension (SBP > 160 or DBP > 100 mmHg) at Screening.
24. Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last
26 weeks prior to Screening.
25. Known bleeding disorder.
26. Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic
neuropathy, regardless of whether or not this episode was in connection with previous
PDE-5i treatment.
27. Hereditary degenerative retinal disorders, including retinitis pigmentosa.
28. History of priapism, conditions that predispose to priapism (e.g., sickle cell anemia,
multiple myeloma, or leukemia) or anatomical deformation of the penis (e.g.,
angulation, cavernosal fibrosis, or Peyronie’s disease).
General restrictions:
29. Difficulty swallowing large pills/tablets that would interfere with the ability to comply
with study treatment regimen.
30. Any planned surgical intervention (including organ transplant) during the double-blind
treatment period, except minor interventions.
31. Exercise training program for cardiopulmonary rehabilitation in the 12-week period
prior to Start of treatment, or planned to be started during the study.
32. Pregnant, planning to become pregnant or lactating.
33. Any known factor or disease that might interfere with treatment adherence, study
assessments, study conduct, or interpretation of the results as judged by the investigator
(e.g., drug or alcohol dependence, psychiatric disease, use of walking aids, etc.).
34. Known concomitant life-threatening disease with a life expectancy < 12 months.
1. Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of
prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused
routes) in the 3-month period prior to start of treatment.
2. 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.
3. Hypersensitivity to any of the study treatments or any excipient of their formulations.
Other therapies:
4. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer (e.g., rifabutin,
rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s
Wort) in the 1-month period prior to start of treatment.
5. Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole,
voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) in
the 1-month period prior to start of treatment.
6. Treatment with doxazosin.
7. Treatment with any form of organic nitrate, either regularly or intermittently
8. Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of
treatment.
9. Treatment with another investigational drug in the 3-month period prior to start of
treatment.
Medical history/current medical conditions:
10. Body mass index (BMI) > 40 kg/m2 at Screening.
11. 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., any of the following:
o History of stable angina, or
o Known more than 50% stenosis in a coronary artery, or
o History of myocardial infarction, or
o History of or planned coronary artery bypass grafting and/or coronary artery
stenting.
12. Known presence of moderate or severe obstructive lung disease (forced expiratory
volume in 1 second [FEV1] / forced vital capacity [FVC] < 70%; and FEV1 < 65% of
predicted after bronchodilator administration) any time prior to Screening.
13. Known presence of moderate or severe restrictive lung disease (total lung capacity or
FVC < 60% of normal predicted value) any time prior to Screening.
14. Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive
or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias;
significant left ventricular dysfunction; or left ventricular outflow obstruction.
15. Known permanent atrial fibrillation.
16. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
17. Documented pulmonary veno-occlusive disease.
Criteria linked to macitentan/tadalafil use:
18. Hemoglobin < 100 g/L (<10 g/dL) at Screening.
19. Known severe hepatic impairment defined as Child Pugh Score C or a Model for EndStage Liver Disease (MELD) score ≥ 19.
6
20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
> 1.5 upper limit of normal (ULN) at Screening.
21. Severe renal impairment (Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) 2009 equation [Levey 2009] calculated creatinine clearance < 30 mL/min) at
Screening.
22. Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure
[DBP] < 50 mmHg) at Screening or Randomization.
23. Systemic hypertension (SBP > 160 or DBP > 100 mmHg) at Screening.
24. Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last
26 weeks prior to Screening.
25. Known bleeding disorder.
26. Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic
neuropathy, regardless of whether or not this episode was in connection with previous
PDE-5i treatment.
27. Hereditary degenerative retinal disorders, including retinitis pigmentosa.
28. History of priapism, conditions that predispose to priapism (e.g., sickle cell anemia,
multiple myeloma, or leukemia) or anatomical deformation of the penis (e.g.,
angulation, cavernosal fibrosis, or Peyronie’s disease).
General restrictions:
29. Difficulty swallowing large pills/tablets that would interfere with the ability to comply
with study treatment regimen.
30. Any planned surgical intervention (including organ transplant) during the double-blind
treatment period, except minor interventions.
31. Exercise training program for cardiopulmonary rehabilitation in the 12-week period
prior to Start of treatment, or planned to be started during the study.
32. Pregnant, planning to become pregnant or lactating.
33. Any known factor or disease that might interfere with treatment adherence, study
assessments, study conduct, or interpretation of the results as judged by the investigator
(e.g., drug or alcohol dependence, psychiatric disease, use of walking aids, etc.).
34. Known concomitant life-threatening disease with a life expectancy < 12 months.
The Estimated Number of Participants
-
Taiwan
20 participants
-
Global
170 participants
