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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) (A DUE)

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ClinicalTrials.gov Identifier: NCT03904693
Recruitment Status : Recruiting
First Posted : April 5, 2019
Last Update Posted : April 14, 2021
Sponsor:
Information provided by (Responsible Party):
Actelion

Tracking Information
First Submitted Date  ICMJE April 4, 2019
First Posted Date  ICMJE April 5, 2019
Last Update Posted Date April 14, 2021
Actual Study Start Date  ICMJE July 29, 2019
Estimated Primary Completion Date December 15, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 4, 2019)
Change in Pulmonary Vascular Resistance (PVR) expressed as the ratio of geometric means of End of Double-Blind Treatment (EDBT) to baseline [ Time Frame: From baseline to EDBT (Week 16) ]
PVR is the resistance in the pulmonary vasculature that has to be overcome to push blood from the right side of the heart to the lungs. PVR measured by Right Heart Catheterization (RHC) has diagnostic and prognostic value as well as offers an objective judgement on treatment response and efficacy.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2020)
  • Change in 6-minute walk distance (6MWD) from baseline to EDBT [ Time Frame: From baseline to EDBT (Week 16) ]
    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 six minutes. This endpoint is associated with prognosis and clinical outcomes such as improvement of hemodynamics.
  • Change From Baseline in Cardiopulmonary Symptom Domain Score in PAH-SYMPACT to Week 16 [ Time Frame: From Baseline to Week 16 ]
    Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) is a PAH-specific patient-reported outcomes instrument that quantifies PAH symptoms and impacts. The Symptom part is a daily diary that contains 11 items. The respondent is asked to rate each of the items for the past 24 hours. The response options for each item range from 0 " "no [symptom] at all" to 4 "very severe".
  • Change From Baseline in Cardiovascular Symptom Domain Score in PAH-SYMPACT to Week 16 [ Time Frame: From Baseline to Week 16 ]
    PAH-SYMPACT is a PAH-specific patient-reported outcomes instrument that quantifies PAH symptoms and impacts. The Symptom part is a daily diary that contains 11 items. The respondent is asked to rate each of the items for the past 24 hours. The response options for each item range from 0 " "no [symptom] at all" to 4 "very severe".
  • Proportion of subjects with absence of worsening in World Health Organization (WHO) Functional Class (FC) from baseline to EDBT. [ Time Frame: From baseline to EDBT (Week 16) ]
    WHO FC reflects the severity of a PAH patient's symptoms and the impact of these symptoms on their activities of daily life. WHO FC is directly associated with prognosis and improvement in WHO FC correlates with survival in subjects with PAH.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 4, 2019)
  • Change in 6-minute walk distance (6MWD) from baseline to EDBT [ Time Frame: From baseline to Week 16 ]
    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 six minutes. This endpoint is associated with prognosis and clinical outcomes such as improvement of hemodynamics.
  • Change in PAH-SYMPACT™ Cardiopulmonary Symptoms domain score from baseline to EDBT [ Time Frame: From baseline to Week 16 ]
    PAH-SYMPACT™ is a PAH-specific patient-reported outcomes instrument that quantifies PAH symptoms and impacts. The Cardiopulmonary Symptoms domain consists of 6 items reported on a 5-point Likert scale (from 0 to 4).
  • Change in PAH-SYMPACT™ Cardiovascular Symptoms domain score from baseline to EDBT [ Time Frame: From baseline to Week 16 ]
    PAH-SYMPACT™ is a PAH-specific patient-reported outcomes instrument that quantifies PAH symptoms and impacts. The Cardiovascular Symptoms domain consists of 5 items reported on a 5-point Likert scale (from 0 to 4).
  • Change in PAH-SYMPACT™ Physical Impacts domain score from baseline to EDBT [ Time Frame: From baseline to Week 16 ]
    PAH-SYMPACT™ is a PAH-specific patient-reported outcomes instrument that quantifies PAH symptoms and impacts. The Physical Impacts domain consists of 7 items reported on a 5-point Likert scale (from 0 to 4).
  • Change in PAH-SYMPACT™ Cognitive/Emotional Impacts domain score from baseline to EDBT [ Time Frame: From baseline to Week 16 ]
    PAH-SYMPACT™ is a PAH-specific patient-reported outcomes instrument that quantifies PAH symptoms and impacts. The Cognitive/Emotional Impacts domain consists of 4 items reported on a 5-point Likert scale (from 0 to 4).
  • Proportion of subjects with absence of worsening in World Health Organization (WHO) Functional Class (FC) from baseline to EDBT. [ Time Frame: From baseline to Week 16 ]
    WHO FC reflects the severity of a PAH patient's symptoms and the impact of these symptoms on their activities of daily life. WHO FC is directly associated with prognosis and improvement in WHO FC correlates with survival in subjects with PAH.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE 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
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.

Detailed Description PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase [the first 2 weeks] and the maintenance phase [Week 3 through Week 16]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
In total, approximately 170 subjects are planned to be randomized into study to receive either FDC macitentan/tadalafil or macitentan 10 mg or tadalafil 40 mg given once daily (o.d.). Subjects will also receive matching placebos for the two other study treatments to maintain the masking ('blind'). Treatment allocation will be stratified based on prior PAH therapy ( i.e., treatment-naïve or treated by an Endothelin receptor antagonist [ERA] or a Phosphodiesterase type-5 inhibitor [PDE-5i] as a monotherapy) at baseline. Sample size will be re-estimated at interim analysis if study is not terminated early for efficacy/futility up to sample size of 120 to 250. After completion of double-blind treatment period, subjects will continue the study in an open-label treatment period for 24 months, during which all subjects will receive FDC macitentan/tadalafil. All assessments at end of double-blind treatment (EDBT) must be completed before subject enters open-label treatment (OLT) period.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
Intervention  ICMJE
  • Drug: FDC macitentan/tadalafil
    Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.
    Other Name: ACT-064992D
  • Drug: Macitentan 10 mg
    Film-coated tablet with 10 mg macitentan, to be administered orally once daily.
    Other Name: ACT-064992
  • Drug: Tadalafil 40 mg
    Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.
  • Drug: 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.
  • Drug: 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.
  • Drug: 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: FDC macitentan/tadalafil
    • Drug: Placebo macitentan
    • Drug: Placebo tadalafil
  • Active Comparator: Macitentan mono-therapy + Placebo tadalafil + Placebo FDC
    Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.
    Interventions:
    • Drug: Macitentan 10 mg
    • Drug: Placebo FDC
    • Drug: Placebo tadalafil
  • 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.
    Interventions:
    • Drug: Tadalafil 40 mg
    • Drug: Placebo FDC
    • Drug: Placebo macitentan
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 4, 2019)
170
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 17, 2024
Estimated Primary Completion Date December 15, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
  • Neither no history of PAH-specific treatment or currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the specified doses in the study protocol
  • Subject 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

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
  • 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.)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com
Listed Location Countries  ICMJE Australia,   Brazil,   Bulgaria,   Canada,   China,   Czechia,   Germany,   Hungary,   Italy,   Japan,   Malaysia,   Mexico,   Poland,   Russian Federation,   South Africa,   Spain,   Taiwan,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03904693
Other Study ID Numbers  ICMJE AC-077A301
2014-004786-25 ( EudraCT Number )
AC-077A301 ( Other Identifier: Actelion Pharmaceuticals Ltd )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: 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.
URL: https://www.janssen.com/clinical-trials/transparency
Responsible Party Actelion
Study Sponsor  ICMJE Actelion
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Wassim Fares, MD Actelion
PRS Account Actelion
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP