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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03904693




Registration number
NCT03904693
Ethics application status
Date submitted
4/04/2019
Date registered
5/04/2019
Date last updated
23/05/2024

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
Active, not recruiting
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
24/09/2024
Actual
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
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United States of America
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California
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Georgia
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Illinois
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Iowa
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Kentucky
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Michigan
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Minnesota
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Missouri
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Nevada
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North Carolina
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North Dakota
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Ohio
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Oregon
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Pennsylvania
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South Dakota
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Texas
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West Virginia
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Wisconsin
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Brazil
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Belo Horizonte
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Botucatu
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Fortaleza
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Goiania
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Porto Alegre
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Sao Paulo
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São Paulo
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Sofia
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Kobe
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Kumamoto-City
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Kurume
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Kyoto
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Matsumoto
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Mitaka
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Okayama
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Sapporo
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Sendai
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Tokyo
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Tsu
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Kuching
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Monterrey
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Bialystok
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Bydgoszcz
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Gdansk
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Katowice
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Lodz
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Lublin
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Otwock
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Szczecin
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Wroclaw
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Russian Federation
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Barnaul
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Kemerovo
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Moscow
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Russian Federation
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Moscva
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Samara
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South Africa
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Durban
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Lenasia
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Spain
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Barcelona
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Madrid
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Salamanca
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Santander
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Toledo
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Valencia
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Taiwan
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Kaohsiung
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Tainan
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Taipei
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Taoyuan
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Turkey
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Adana
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Ankara
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Turkey
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Bursa
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Istanbul
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Izmir
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Kartal Istanbul
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Turkey
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Konya
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Turkey
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Mersin

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

Ethics approval
Ethics application status

Summary
Brief summary
Combination therapy in pulmonary arterial hypertension (PAH) has been the subject of active
investigation for more than a decade, with the benefit of targeting different pathways known
to be involved in the pathogenesis of the disease. Adherence to prescribed therapy has an
impact on clinical outcomes. Reducing the pill/tablet count and frequency has a major impact
on patients' adherence to therapies and therefore the observed clinical outcomes. One way to
simplify treatment is to use fixed-dose combination (FDC) products that combine multiple
treatments targeting different pathways into a single tablet.

This study aims to demonstrate that the FDC of macitentan and tadalafil is more effective
than therapy with 10 mg of macitentan alone or 40 mg of tadalafil alone. This phase 3 study
will evaluate the efficacy and safety at 16 weeks of an FDC (macitentan 10 mg and tadalafil
40 mg) against these two PAH-approved therapies given as monotherapy to further confirm the
added value of the FDC.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03904693
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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03904693