Clinical Trial Results:
Prospective, Multicenter, Open-label Study Evaluating the Effects of First-line Oral Combination Therapy of Macitentan and TadalafIl in Patients with Newly Diagnosed Pulmonary Arterial Hypertension
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Summary
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EudraCT number |
2015-002078-19 |
Trial protocol |
FR |
Global end of trial date |
10 Sep 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Sep 2019
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First version publication date |
21 Sep 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AC-055-405
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02968901 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Actelion Pharmaceuticals
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Sponsor organisation address |
21 Boulevard De La Madeleine, Paris, France, 75001
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Public contact |
Clinical Registry Group, Actelion Pharmaceuticals, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Actelion Pharmaceuticals, ClinicalTrialsEU@its.jnj.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Sep 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Sep 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective of this study was to document the effect of first line dual oral combination therapy with macitentan 10 milligram (mg) and tadalafil 40 mg on pulmonary vascular resistance (PVR) in treatment-naïve subjects with newly diagnosed pulmonary arterial hypertension (PAH).
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included monitoring of adverse events (AEs), serious adverse events (SAEs), clinical laboratory parameters (liver function tests [LFTs], creatinine, hemoglobin and biomarkers of myocardial stress), vital signs, electrocardiograms (ECG), weight, height and physical examination.
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Background therapy |
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Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Nov 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
France: 46
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Worldwide total number of subjects |
46
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EEA total number of subjects |
46
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
25
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From 65 to 84 years |
21
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||
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Pre-assignment
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Screening details |
A total of 46 subjects were enrolled and treated with macitentan and tadalafil. Of these, 2 subjects discontinued the study and 44 subjects entered the extension period of whom 39 subjects completed this OPTIMA study and were enrolled into the UMBRELLA (AC-055-314 [NCT03422328]) study. | ||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Macitentan 10 mg / Tadalafil 40 mg | ||||||||||||||||
Arm description |
Subjects received macitentan 10 mg film-coated tablets and tadalafil 40 mg (2*20 mg) tablets administered orally once daily starting on Day 1 of Open-label period up to Day 15. Subject were then continued to Maintenence treatment period (Day 15 to End of treatment 1 [EOT1]) and then to Extension period (EOT1 to End of treatment 2 (EOT2). EOT1, defined as the earliest of the followings: a. Visit 3 at Week 16 ± 1 week; b. Pulmonary arterial hypertension (PAH) progression requiring intake of other PAH-specific drug(s); c. Sponsor decision to stop the trial;d. Subject or investigator decision to discontinue both study treatments. EOT2, defined as the earliest time at which one of the following occurred: a. Commercial availability and reimbursement of macitentan in France; b. Sponsor decision to stop the trial; c. Subject or investigator decision to discontinue both study treatments. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Macitentan 10 mg
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Investigational medicinal product code |
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Other name |
Opsumit®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received macitentan 10 mg once daily.
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Investigational medicinal product name |
Tadalafil 40 mg
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Investigational medicinal product code |
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Other name |
Adcirca®)
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received tadalafil 40 mg once daily.
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Baseline characteristics reporting groups
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Reporting group title |
Macitentan 10 mg / Tadalafil 40 mg
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Reporting group description |
Subjects received macitentan 10 mg film-coated tablets and tadalafil 40 mg (2*20 mg) tablets administered orally once daily starting on Day 1 of Open-label period up to Day 15. Subject were then continued to Maintenence treatment period (Day 15 to End of treatment 1 [EOT1]) and then to Extension period (EOT1 to End of treatment 2 (EOT2). EOT1, defined as the earliest of the followings: a. Visit 3 at Week 16 ± 1 week; b. Pulmonary arterial hypertension (PAH) progression requiring intake of other PAH-specific drug(s); c. Sponsor decision to stop the trial;d. Subject or investigator decision to discontinue both study treatments. EOT2, defined as the earliest time at which one of the following occurred: a. Commercial availability and reimbursement of macitentan in France; b. Sponsor decision to stop the trial; c. Subject or investigator decision to discontinue both study treatments. | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Macitentan 10 mg / Tadalafil 40 mg
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Reporting group description |
Subjects received macitentan 10 mg film-coated tablets and tadalafil 40 mg (2*20 mg) tablets administered orally once daily starting on Day 1 of Open-label period up to Day 15. Subject were then continued to Maintenence treatment period (Day 15 to End of treatment 1 [EOT1]) and then to Extension period (EOT1 to End of treatment 2 (EOT2). EOT1, defined as the earliest of the followings: a. Visit 3 at Week 16 ± 1 week; b. Pulmonary arterial hypertension (PAH) progression requiring intake of other PAH-specific drug(s); c. Sponsor decision to stop the trial;d. Subject or investigator decision to discontinue both study treatments. EOT2, defined as the earliest time at which one of the following occurred: a. Commercial availability and reimbursement of macitentan in France; b. Sponsor decision to stop the trial; c. Subject or investigator decision to discontinue both study treatments. | ||
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End point title |
Pulmonary Vascular Resistance (PVR) Ratio between Baseline and Week 16 as Assessed by Right Heart Catheterization (RHC) [1] | ||||||||
End point description |
PVR was calculated and assessed by RHC. PVR [dyn.sec/cm−5] was calculated as mPAP-PCWP/CO*80 (If PCWP was missing, LVEDP was used instead). Here, mPAP, PCWP, CO and LVEDP means Mean pulmonary arterial pressure, Pulmonary capillary wedge pressure, Cardiac output and Left ventricular end-diastolic pressure respectively. A geometric mean ratio of Week 16 to baseline <1 corresponded to an improvement (reduction in PVR from baseline). The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
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End point type |
Primary
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End point timeframe |
Baseline and Week 16
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects with Clinically Meaningful Improvement in PVR at Week 16 (decrease of >=30 Percent [%] from Baseline to Week 16) | ||||||||
End point description |
Percentage of subjects with clinically meaningful improvement in PVR at Week 16 (decrease of >=30% from baseline to Week 16) were reported. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
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End point type |
Secondary
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End point timeframe |
Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline to Week 16 in Mean Right Atrial Pressure (mRAP) | ||||||||
End point description |
Change from baseline to Week 16 in mRAP was reported. mRAP is the mean blood pressure in the right atrium of the heart. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline to Week 16 in Mean Pulmonary Arterial Pressure (mPAP) | ||||||||
End point description |
Change from baseline to Week 16 in mean pulmonary arterial pressure (mPAP) was reported. mPAP is the mean blood pressure inside the pulmonary artery which moves the blood from the heart to the lungs. Monitoring of mPAP can detect small changes in the function of the heart. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline to Week 16 in Cardiac Index (CI) | ||||||||
End point description |
Change from Baseline to Week 16 in cardiac index (CI) was reported. The cardiac index is an assessment of the function of the heart and relates the cardiac output to the subject's body size (the patient's body surface area). The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline to Week 16 in Total Pulmonary Resistance (TPR) | ||||||||
End point description |
Change from Baseline to Week 16 in total pulmonary resistance (TPR) was reported. TPR is the resistance the pulmonary circulation that must be overcome in order for the blood flow to occur. It takes into account the blood pressure in the pulmonary arteries and the cardiac output. It is an important measurement to monitor the function of the pulmonary circulation and detect disease progression or improvement. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline to Week 16 in Mixed Venous Oxygen Saturation (SvO2) | ||||||||
End point description |
Change from baseline to Week 16 in mixed venous oxygen saturation (SvO2) was reported. SVO2 help assess tissue oxygen delivery. It describes the percentage of oxygen bound to hemoglobin in the blood which returns to the heart. This reflects the amount of residual oxygen in the blood after oxygen extraction by the tissues throughout the body. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement. Here 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline to Week 16 in 6-Minute Walk Distance (6MWD) | ||||||||
End point description |
Change from baseline to Week 16 in 6-minute walk distance (6MWD) was reported. The purpose of the six minute walk is to test exercise tolerance and capacity. The 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. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
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End point type |
Secondary
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End point timeframe |
Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline to Week 16 in World Health Organization Functional Class (WHO-FC) (Change from WHO-FC III to WHO-FC I, from WHO-FC III to WHO-FC II, and WHO-FC II to WHO-FC I) | ||||||||||||||
End point description |
Changes from baseline to Week 16 in WHO FC were dichotomized as worsening (that is, change > 0) versus no change or improvement (change <= 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (example. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (example. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Subjects in class IV manifest signs of right heart failure. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement. Here 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Week 16
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Subjects with Improvement or Worsening of WHO-FC from Baseline to Week 16 | ||||||||||||
End point description |
Percentage of subjects with improvement/worsening of WHO-FC from Baseline to Week 16 were reported. WHO FC were dichotomized as worsening (that is, change > 0) versus no change or improvement (change <= 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (example. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (example. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Subjects in class IV manifest signs of right heart failure. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement. Here 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline to Week 16 in N-terminal pro B-type Natriuretic Peptide (NT-proBNP) | ||||||||
End point description |
Change from baseline to Week 16 in NT-proBNP was reported. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement. Here 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to 34 months
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Adverse event reporting additional description |
Safety analysis set included all subjects who received at least one dose of any of the two study treatments.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Macitentan 10 mg / Tadalafil 40 mg
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Reporting group description |
Subjects received macitentan 10 mg and tadalafil 40 mg once daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Oct 2015 |
The overall reason for global amendment 1 was to clarify the eligibility criterias. Inclusion criterion 6 was clarified: only congenital heart disease corrected with simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus), with persistent PAH >= 1 year after surgical repair. |
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29 Mar 2016 |
The overall reason for the amendment was to clarify the eligibility criteria and include new committee. An adjudication committee has been set up to determine if a subject can be included despite of a Diffusing capacity of the lung for carbon monoxide (DLCO) greater than (<) 40 percentage (%). Exclusion criterion 2 was changed: Subjects who changed the dose or discontinued calcium channel blockers within 1 week prior to Day 1. Exclusion criterion 9 was clarified: Significant aortic and mitral valve disease treated with a specific treatment. Exclusion criterion 11 (Significant left ventricular dysfunction in the opinion of the investigator) was deleted. Exclusion criterion 20 was created [DLCO < 40% of predicted value (eligible only if no sign of
enoocclusive disease according to adjudication committee]. DLCO < 40% of predicted value was deleted from Exclusion criteria 21. Calcium channel blocker were authorized if present at a stable dose for at least 1 week before Day 1 instead of 3 months. Assessment of NT-proBNP were changed: Laboratory assessment were done on blood samples collected at inclusion visit and at Week 16. Finally, laboratory tests for screening and Day 1 can be
performed on the same day. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The study was stopped early due to a slow recruitment rate. | |||
