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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03904693




Registration number
NCT03904693
Ethics application status
Date submitted
4/04/2019
Date registered
5/04/2019

Titles & IDs
Public title
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)
Scientific title
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
Secondary ID [1] 0 0
2014-004786-25
Secondary ID [2] 0 0
AC-077A301
Universal Trial Number (UTN)
Trial acronym
A DUE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH) 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - FDC macitentan/tadalafil
Treatment: Drugs - Macitentan 10 mg
Treatment: Drugs - Tadalafil 40 mg
Treatment: Drugs - Placebo FDC
Treatment: Drugs - Placebo macitentan
Treatment: Drugs - Placebo tadalafil

Experimental: FDC therapy + Placebo macitentan + Placebo tadalafil - Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.

Active comparator: Macitentan mono-therapy + Placebo tadalafil + Placebo FDC - Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.

Active comparator: Tadalafil mono-therapy + Placebo macitentan + Placebo FDC - Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.


Treatment: Drugs: FDC macitentan/tadalafil
Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.

Treatment: Drugs: Macitentan 10 mg
Film-coated tablet with 10 mg macitentan, to be administered orally once daily.

Treatment: Drugs: Tadalafil 40 mg
Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.

Treatment: Drugs: Placebo FDC
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.

Treatment: Drugs: Placebo macitentan
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.

Treatment: Drugs: Placebo tadalafil
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline
Timepoint [1] 0 0
Baseline, EDBT (up to 16 weeks)
Secondary outcome [1] 0 0
Change From Baseline in 6-minutes Walking Distance (6MWD) to EDBT
Timepoint [1] 0 0
Baseline, EDBT (up to 16 weeks)
Secondary outcome [2] 0 0
Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT
Timepoint [2] 0 0
Baseline, EDBT (up to 16 weeks)
Secondary outcome [3] 0 0
Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT
Timepoint [3] 0 0
Baseline, EDBT (up to 16 weeks)
Secondary outcome [4] 0 0
Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline to EDBT
Timepoint [4] 0 0
Baseline, EDBT (up to 16 weeks)

Eligibility
Key inclusion criteria
* 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) = 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)
* 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* 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
* 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 left-sided 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 non-arteritic anterior ischemic optic neuropathy
* Hereditary degenerative retinal disorders, including retinitis pigmentosa
* History of priapism, conditions that predispose to priapism (example, sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease)
* 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 double-blind period of 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
29/07/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
27/09/2024
Sample size
Target
Accrual to date
Final
187
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 0 0
Pulmonary Arterial Hypertension Clinic - Hobart
Recruitment hospital [3] 0 0
Core Research Group - Milton
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
7000 - Hobart
Recruitment postcode(s) [3] 0 0
4064 - Milton
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Georgia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Iowa
Country [5] 0 0
United States of America
State/province [5] 0 0
Kentucky
Country [6] 0 0
United States of America
State/province [6] 0 0
Michigan
Country [7] 0 0
United States of America
State/province [7] 0 0
Minnesota
Country [8] 0 0
United States of America
State/province [8] 0 0
Missouri
Country [9] 0 0
United States of America
State/province [9] 0 0
Nevada
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
North Dakota
Country [12] 0 0
United States of America
State/province [12] 0 0
Ohio
Country [13] 0 0
United States of America
State/province [13] 0 0
Oregon
Country [14] 0 0
United States of America
State/province [14] 0 0
Pennsylvania
Country [15] 0 0
United States of America
State/province [15] 0 0
South Dakota
Country [16] 0 0
United States of America
State/province [16] 0 0
Texas
Country [17] 0 0
United States of America
State/province [17] 0 0
West Virginia
Country [18] 0 0
United States of America
State/province [18] 0 0
Wisconsin
Country [19] 0 0
Brazil
State/province [19] 0 0
Belo Horizonte
Country [20] 0 0
Brazil
State/province [20] 0 0
Botucatu
Country [21] 0 0
Brazil
State/province [21] 0 0
Fortaleza
Country [22] 0 0
Brazil
State/province [22] 0 0
Goiania
Country [23] 0 0
Brazil
State/province [23] 0 0
Porto Alegre
Country [24] 0 0
Brazil
State/province [24] 0 0
Sao Paulo
Country [25] 0 0
Brazil
State/province [25] 0 0
São Paulo
Country [26] 0 0
Bulgaria
State/province [26] 0 0
Sofia
Country [27] 0 0
Canada
State/province [27] 0 0
Alberta
Country [28] 0 0
Canada
State/province [28] 0 0
British Columbia
Country [29] 0 0
Canada
State/province [29] 0 0
Ontario
Country [30] 0 0
China
State/province [30] 0 0
Beijing
Country [31] 0 0
China
State/province [31] 0 0
Changsha
Country [32] 0 0
China
State/province [32] 0 0
Guangzhou
Country [33] 0 0
China
State/province [33] 0 0
Nanjing
Country [34] 0 0
China
State/province [34] 0 0
Shanghai
Country [35] 0 0
China
State/province [35] 0 0
Shenyang
Country [36] 0 0
China
State/province [36] 0 0
Tian Jin
Country [37] 0 0
China
State/province [37] 0 0
Xi'An
Country [38] 0 0
Czechia
State/province [38] 0 0
Praha 2
Country [39] 0 0
Germany
State/province [39] 0 0
Bonn
Country [40] 0 0
Germany
State/province [40] 0 0
Dresden
Country [41] 0 0
Germany
State/province [41] 0 0
Giessen
Country [42] 0 0
Germany
State/province [42] 0 0
Greifswald
Country [43] 0 0
Germany
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Hamburg
Country [44] 0 0
Germany
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Heidelberg
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Germany
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Papenburg
Country [46] 0 0
Germany
State/province [46] 0 0
Regensburg
Country [47] 0 0
Germany
State/province [47] 0 0
Würzburg
Country [48] 0 0
Hungary
State/province [48] 0 0
Budapest
Country [49] 0 0
Hungary
State/province [49] 0 0
Pecs
Country [50] 0 0
Hungary
State/province [50] 0 0
Szeged
Country [51] 0 0
Italy
State/province [51] 0 0
Bari
Country [52] 0 0
Italy
State/province [52] 0 0
Brescia
Country [53] 0 0
Italy
State/province [53] 0 0
Milano
Country [54] 0 0
Italy
State/province [54] 0 0
Monza
Country [55] 0 0
Italy
State/province [55] 0 0
Nuoro
Country [56] 0 0
Italy
State/province [56] 0 0
Pavia
Country [57] 0 0
Italy
State/province [57] 0 0
Roma
Country [58] 0 0
Japan
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Bunkyo
Country [59] 0 0
Japan
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Chiba
Country [60] 0 0
Japan
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Fukuoka
Country [61] 0 0
Japan
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Fukushima
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Japan
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Gunma
Country [63] 0 0
Japan
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Hiroshima
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Japan
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Isehara
Country [65] 0 0
Japan
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Kagoshima City
Country [66] 0 0
Japan
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Kanazawa
Country [67] 0 0
Japan
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Kobe
Country [68] 0 0
Japan
State/province [68] 0 0
Kumamoto-City
Country [69] 0 0
Japan
State/province [69] 0 0
Kurume
Country [70] 0 0
Japan
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Kyoto
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Japan
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Matsumoto
Country [72] 0 0
Japan
State/province [72] 0 0
Mitaka
Country [73] 0 0
Japan
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Nagasaki-shi
Country [74] 0 0
Japan
State/province [74] 0 0
Okayama
Country [75] 0 0
Japan
State/province [75] 0 0
Sapporo-shi
Country [76] 0 0
Japan
State/province [76] 0 0
Sapporo
Country [77] 0 0
Japan
State/province [77] 0 0
Sendai
Country [78] 0 0
Japan
State/province [78] 0 0
Suita-Shi
Country [79] 0 0
Japan
State/province [79] 0 0
Tokyo
Country [80] 0 0
Japan
State/province [80] 0 0
Tsukuba City
Country [81] 0 0
Japan
State/province [81] 0 0
Tsu
Country [82] 0 0
Malaysia
State/province [82] 0 0
Kuala Lumpur
Country [83] 0 0
Malaysia
State/province [83] 0 0
Kuching
Country [84] 0 0
Mexico
State/province [84] 0 0
Mexico
Country [85] 0 0
Mexico
State/province [85] 0 0
Monterrey
Country [86] 0 0
Poland
State/province [86] 0 0
Bialystok
Country [87] 0 0
Poland
State/province [87] 0 0
Bydgoszcz
Country [88] 0 0
Poland
State/province [88] 0 0
Gdansk
Country [89] 0 0
Poland
State/province [89] 0 0
Katowice
Country [90] 0 0
Poland
State/province [90] 0 0
Lodz
Country [91] 0 0
Poland
State/province [91] 0 0
Lublin
Country [92] 0 0
Poland
State/province [92] 0 0
Otwock
Country [93] 0 0
Poland
State/province [93] 0 0
Szczecin
Country [94] 0 0
Poland
State/province [94] 0 0
Wroclaw
Country [95] 0 0
Russian Federation
State/province [95] 0 0
Barnaul
Country [96] 0 0
Russian Federation
State/province [96] 0 0
Kemerovo
Country [97] 0 0
Russian Federation
State/province [97] 0 0
Moscow
Country [98] 0 0
Russian Federation
State/province [98] 0 0
Moscva
Country [99] 0 0
Russian Federation
State/province [99] 0 0
Saint-Petersburg
Country [100] 0 0
Russian Federation
State/province [100] 0 0
Samara
Country [101] 0 0
South Africa
State/province [101] 0 0
Durban
Country [102] 0 0
South Africa
State/province [102] 0 0
Lenasia
Country [103] 0 0
Spain
State/province [103] 0 0
Barcelona
Country [104] 0 0
Spain
State/province [104] 0 0
Madrid
Country [105] 0 0
Spain
State/province [105] 0 0
Salamanca
Country [106] 0 0
Spain
State/province [106] 0 0
Santander
Country [107] 0 0
Spain
State/province [107] 0 0
Toledo
Country [108] 0 0
Spain
State/province [108] 0 0
Valencia
Country [109] 0 0
Taiwan
State/province [109] 0 0
Kaohsiung
Country [110] 0 0
Taiwan
State/province [110] 0 0
Tainan
Country [111] 0 0
Taiwan
State/province [111] 0 0
Taipei
Country [112] 0 0
Taiwan
State/province [112] 0 0
Taoyuan
Country [113] 0 0
Turkey
State/province [113] 0 0
Adana
Country [114] 0 0
Turkey
State/province [114] 0 0
Ankara
Country [115] 0 0
Turkey
State/province [115] 0 0
Bursa
Country [116] 0 0
Turkey
State/province [116] 0 0
Istanbul
Country [117] 0 0
Turkey
State/province [117] 0 0
Izmir
Country [118] 0 0
Turkey
State/province [118] 0 0
Kartal Istanbul
Country [119] 0 0
Turkey
State/province [119] 0 0
Konya
Country [120] 0 0
Turkey
State/province [120] 0 0
Mersin

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Actelion
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Hany Rofael, MD
Address 0 0
Janssen, LP
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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.
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://www.janssen.com/clinical-trials/transparency


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT03904693