TRITON: The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension
Sponsor
Actelion (Industry)
Overall Status
Completed
CT.gov ID
NCT02558231
Collaborator
(none)
247
58
2
47.6
4.3
0.1
Study Details
Study Description
Brief Summary
The objective of this clinical trial is to compare the efficacy and safety of an initial triple oral treatment regimen (macitentan, tadalafil, selexipag) versus an initial dual oral treatment regimen (macitentan, tadalafil, placebo) in newly diagnosed, treatment-naïve patients with pulmonary arterial hypertension.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
247 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension: A Multi-center, Double-blind, Placebo-controlled, Phase 3b Study
Actual Study Start Date
:
May 1, 2016
Actual Primary Completion Date
:
Aug 29, 2019
Actual Study Completion Date
:
Apr 20, 2020
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Triple oral combination treatment Macitentan, tadalafil, and selexipag |
Drug: Macitentan
Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.
Drug: Tadalafil
Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d.
Drug: Selexipag
Used double-blind in the triple oral treatment arm, 200 microgram tablet, 1-8 tablets b.i.d.
|
| Placebo Comparator: Dual oral combination treatment Macitentan, tadalafil, and placebo |
Drug: Macitentan
Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.
Drug: Tadalafil
Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d.
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR) [Baseline, Week 26]
Change from baseline to Week 26 in PVR was expressed as the ratio of Week 26 to baseline PVR value (Week 26 divided by baseline) using re-calculated PVR. PVR was determined by right heart catheterization (RHC). A geometric least square mean ratio of Week 26 to baseline PVR less than (<) 1 corresponds to a reduction in PVR from baseline. Missing values were imputed using a last observation carried forward (LOCF) approach.
Secondary Outcome Measures
- Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) [Baseline, Week 26]
The change from baseline to Week 26 in 6MWD was calculated as Week 26 minus baseline. 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. Missing values were imputed using a LOCF approach.
- Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels [Baseline, Week 26]
The change from baseline to Week 26 in NT-proBNP was expressed as the ratio of Week 26 to baseline NT-proBNP (Week 26 divided by baseline). A geometric least square mean ratio of Week 26 to baseline NT-proBNP <1 corresponds to a reduction in NT-proBNP from baseline. Missing values were imputed using a LOCF approach.
- Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC) [Week 26]
WHO FC is a classification graded from Class I to IV which reflects disease severity based on symptoms. Worsening was defined as death or hospitalization due to PAH. Class I: No limitation of activity; Class II: slight limitation with ordinary activities; Class III: may not have symptoms at rest but greatly limited activities; Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Missing values were imputed using a LOCF approach.
- Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP) [Baseline, Week 26]
Change from baseline to Week 26 in mean Pulmonary Arterial Pressure (mPAP) was measured. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Missing values were imputed using a LOCF approach.
- Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP) [Baseline, Week 26]
Change from baseline to Week 26 in mean Right Atrial Pressure (mRAP) was measured. Missing values were imputed using a LOCF approach.
- Change From Baseline to Week 26 in Total Pulmonary Resistance [Baseline, Week 26]
Change from baseline to Week 26 in total pulmonary resistance was measured. Total pulmonary resistance was calculated as mPAP/CO*80, where CO is cardiac output. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach.
- Change From Baseline to Week 26 in Cardiac Index [Baseline, Week 26]
Change from baseline to Week 26 in cardiac index was measured. Cardiac index is the amount of blood pumped by the heart, per minute, per meter square of body surface area. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach.
- Change From Baseline to Week 26 in Venous Oxygen Saturation (%) [Baseline, Week 26]
Change from baseline to Week 26 in venous oxygen saturation was measured. Missing values were imputed using a LOCF approach.
- Number of Participants With Disease Progression Event [Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)]
Number of participants with disease progression event were reported. Disease progression event as adjudicated by the CEC, defined as any of the following: a. Death (all causes; adjudicated for PAH relationship); b. Hospitalization for worsening PAH; c. Initiation of prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist for worsening PAH; d. Clinical worsening defined as a post-baseline decrease in 6MWD by more than (>) 15 percent (%) from the highest 6MWD obtained at or after baseline, accompanied by WHO FC III or IV (both conditions confirmed at two consecutive post-baseline visits separated by 1-21 days).
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 75 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Signed informed consent prior to any study-mandated procedure.
-
Male or female ≥ 18 and ≤ 75 years of age at screening.
-
Initial PAH diagnosis < 6 months prior to enrollment.
-
RHC performed between Day -28 and Day 1, meeting all the following criteria:
-
Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg.
-
Pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg.
-
PVR ≥ 480 dyn•sec/cm5 (≥ 6 Wood Units).
-
Negative vasoreactivity test mandatory in idiopathic, heritable, and drug/toxin induced PAH (at this or a previous RHC).
- Symptomatic PAH belonging to one of the following subgroups:
-
Idiopathic.
-
Heritable.
-
Drug or toxin induced.
-
Associated with one of the following: connective tissue disease; HIV infection; congenital heart disease.
-
6-minute walk distance (6MWD) ≥ 50 m at screening.
-
Women of childbearing potential must not be pregnant, must perform regular pregnancy tests, and use reliable contraception.
Exclusion Criteria:
-
Any PAH-specific drug therapy at any time.
-
Cardio pulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Day 1).
-
Body mass index (BMI) > 40 kg/m2 at screening.
-
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.
-
Coronary artery disease, i.e., any of the following:
-
History of stable angina or
-
More than 50% stenosis in a coronary artery (by coronary angiography) or
-
History of myocardial infarction or
-
History of or planned coronary artery bypass grafting and/or coronary artery stenting.
-
Acute myocardial infarction ≤ 12 weeks prior to screening.
-
Stroke ≤ 12 weeks prior to screening.
-
Known permanent atrial fibrillation.
-
SBP < 90 mmHg at screening or Day 1.
-
Ongoing or planned treatment with organic nitrates and/or doxazosin.
-
Presence of one or more of the following signs of relevant lung disease at any time up to screening:
-
Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
-
Forced vital capacity (FVC) < 60% of predicted.
-
Forced expiratory volume in one second (FEV1) < 60% of predicted.
-
Known or suspected pulmonary veno-occlusive disease (PVOD).
-
Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin
3 × upper limit of the normal range (ULN) accompanied by aspartate aminotransferase (AST) > ULN (assessed by central laboratory at screening); and/or Child-Pugh Class C.
-
Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN (assessed by central laboratory at screening).
-
Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m2) assessed by central laboratory at screening.
-
Ongoing or planned dialysis.
-
Hemoglobin < 100 g/L assessed by central laboratory at screening.
-
Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
-
Loss of vision in one or both eyes because of non-arteritic ischemic optic neuropathy (NAION).
-
Treatment with strong inducers of cytochrome P450 3A4 (CYP3A4; e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤ 28 days prior to Day 1.
-
Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) and/or strong inhibitors of CYP2C8 (e.g., gemfibrozil) ≤ 28 days prior to Day 1.
-
Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to Day 1).
-
Hypersensitivity to any of the 3 study treatments or any excipient of their formulations.
-
Pregnancy, breastfeeding, or intention to become pregnant during the study.
-
Concomitant life-threatening disease with a life expectancy < 12 months.
-
Alcohol abuse.
-
Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Arizona Pulmonary Specialists, LTD | Phoenix | Arizona | United States | 85012 |
| 2 | UCSD Health Sciences | La Jolla | California | United States | 92093 |
| 3 | UCLA Medical Center | Los Angeles | California | United States | 90095 |
| 4 | Mayo Clinic Jacksonville | Jacksonville | Florida | United States | 32224 |
| 5 | Cleveland Clinic Florida | Weston | Florida | United States | 33331 |
| 6 | Piedmont Pulmonary and Critical Care Research | Atlanta | Georgia | United States | 30309 |
| 7 | Northwestern University | Chicago | Illinois | United States | 60611 |
| 8 | University of Iowa Hospitals & Clinics | Iowa City | Iowa | United States | 52242 |
| 9 | Kentuckiana Pulmonary Associates | Louisville | Kentucky | United States | 40202 |
| 10 | LSU Health Sciences Center | New Orleans | Louisiana | United States | 70112 |
| 11 | Johns Hopkins School of Medicine | Baltimore | Maryland | United States | 21205 |
| 12 | Tufts Medical Center | Boston | Massachusetts | United States | 02111-1552 |
| 13 | Boston University Medical Center | Boston | Massachusetts | United States | 02118-2526 |
| 14 | Washington University School of Medicine | Saint Louis | Michigan | United States | 63110 |
| 15 | University of New Mexico Hospital | Albuquerque | New Mexico | United States | 87106 |
| 16 | The Christ Hospital | Cincinnati | Ohio | United States | 45219-2906 |
| 17 | Allegheny General Hospital of Research | Pittsburgh | Pennsylvania | United States | 15212 |
| 18 | UPMC Presbyterian | Pittsburgh | Pennsylvania | United States | 15213 |
| 19 | University of Texas Southwestern Medical Center | Dallas | Texas | United States | 75390-8550 |
| 20 | Houston Methodist Hospital | Houston | Texas | United States | 77030 |
| 21 | Royal Prince Albert Hospital | Camperdown | New South Wales | Australia | 2050 |
| 22 | St. Vincents Hospital Sydney | Darlinghurst | New South Wales | Australia | 2010 |
| 23 | LKH -Universität Klinkum Graz | Graz | Austria | 8036 | |
| 24 | Krankenhaus der Elisabethinen Linz | Linz | Austria | 4020 | |
| 25 | AKH Wien | Wien | Austria | 1090 | |
| 26 | Hôpital Erasme | Brussels | Belgium | 1070 | |
| 27 | UZ Leuven - Campus Gasthuisberg | Leuven | Belgium | 3000 | |
| 28 | Vancouver General Hospital | Vancouver | British Columbia | Canada | V5Z 1M9 |
| 29 | London Health Sciences Centre - Victoria Hospital | London | Ontario | Canada | N6A 5W9 |
| 30 | University of Toronto | Toronto | Ontario | Canada | M5G 2N2 |
| 31 | Jewish General Hospital | Montreal | Quebec | Canada | H3T 1E2 |
| 32 | Institut Universitaire de Cardiologie et de Pneumologie de Québec | Quebec City | Quebec | Canada | G1V 4G5 |
| 33 | University of Calgary | Calgary | Canada | T1Y 6J4 | |
| 34 | University of Ottawa Heart Institute | Ottawa | Canada | K1Y 4W7 | |
| 35 | Aarhus University Hospital Skejby | Aarhus | Denmark | 8200 | |
| 36 | Rigshospitalet Copenhagen | Copenhagen | Denmark | 2100 | |
| 37 | CHU de Bicêtre | Le Kremlin-Bicêtre | France | 94270 | |
| 38 | Unversitätsklinikum Carl Gustav Carus | Dresden | Germany | 01307 | |
| 39 | Universitätsklinikum Giessen | Giessen | Germany | 35392 | |
| 40 | Universitätsklinikum Hamburg-Eppendorf | Hamburg | Germany | 20246 | |
| 41 | Medizinische Hochschule Hannover | Hannover | Germany | 30625 | |
| 42 | Universitätsklinikum Heidelberg | Heidelberg | Germany | 69126 | |
| 43 | Universitätsklinikum Köln | Köln | Germany | 50924 | |
| 44 | Universitätsklinikum Regensburg | Regensburg | Germany | 93053 | |
| 45 | Mater Misericordiae University Hospital | Dublin | Ireland | D07 R2WY | |
| 46 | Ospedale Sant'Orsola | Bologna | Italy | 40138 | |
| 47 | VUmc Amsterdam | Amsterdam | Netherlands | 1081 HV | |
| 48 | Maastricht University Medical Center | Maastricht | Netherlands | 6229 HX | |
| 49 | Hospital Clinic de Barcelona | Barcelona | Spain | 08036 | |
| 50 | Hospital 12 de Octubre | Madrid | Spain | 28041 | |
| 51 | Skånes universitetssjukhus Lund | Lund | Sweden | 221 85 | |
| 52 | Norrlands universitetssjukhus | Umeå | Sweden | 901 85 | |
| 53 | Kardiologkliniken | Uppsala | Sweden | 751 85 | |
| 54 | Universiätsspital Zürich | Zürich | Switzerland | 8091 | |
| 55 | Golden Jubilee National Hospital | Clydebank | United Kingdom | G81 4DY | |
| 56 | The Royal Free Hospital | London | United Kingdom | NW3 2QG | |
| 57 | Royal Brompton Hospital | London | United Kingdom | SW3 6NP | |
| 58 | Hammersmith Hospital | London | United Kingdom | W12 0HS |
Sponsors and Collaborators
- Actelion
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Actelion
ClinicalTrials.gov Identifier:
NCT02558231
Other Study ID Numbers:
- AC-065A308
First Posted:
Sep 23, 2015
Last Update Posted:
Apr 13, 2021
Last Verified:
Mar 1, 2021
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Period Title: Overall Study | ||
| STARTED | 123 | 124 |
| Treated | 123 | 123 |
| COMPLETED | 98 | 98 |
| NOT COMPLETED | 25 | 26 |
Baseline Characteristics
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | Total |
|---|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Total of all reporting groups |
| Overall Participants | 123 | 124 | 247 |
| Overall Number | 123 | 124 | 247 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
52.2
(13.48)
|
51.6
(13.92)
|
51.9
(13.67)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
93
75.6%
|
94
75.8%
|
187
75.7%
|
| Male |
30
24.4%
|
30
24.2%
|
60
24.3%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
10
8.1%
|
10
8.1%
|
20
8.1%
|
| Not Hispanic or Latino |
106
86.2%
|
108
87.1%
|
214
86.6%
|
| Unknown or Not Reported |
7
5.7%
|
6
4.8%
|
13
5.3%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| Black or African American |
5
4.1%
|
5
4%
|
10
4%
|
| American Indian or Alaska Native |
1
0.8%
|
0
0%
|
1
0.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Asian |
7
5.7%
|
3
2.4%
|
10
4%
|
| White |
102
82.9%
|
108
87.1%
|
210
85%
|
| Other |
3
2.4%
|
3
2.4%
|
6
2.4%
|
| Unknown or Not Reported |
5
4.1%
|
5
4%
|
10
4%
|
| Region of Enrollment (participants) [Number] | |||
| AUSTRALIA |
2
1.6%
|
2
1.6%
|
4
1.6%
|
| AUSTRIA |
9
7.3%
|
5
4%
|
14
5.7%
|
| BELGIUM |
2
1.6%
|
5
4%
|
7
2.8%
|
| CANADA |
11
8.9%
|
14
11.3%
|
25
10.1%
|
| DENMARK |
3
2.4%
|
2
1.6%
|
5
2%
|
| FRANCE |
4
3.3%
|
5
4%
|
9
3.6%
|
| GERMANY |
13
10.6%
|
23
18.5%
|
36
14.6%
|
| IRELAND |
1
0.8%
|
0
0%
|
1
0.4%
|
| ITALY |
5
4.1%
|
6
4.8%
|
11
4.5%
|
| NETHERLANDS |
2
1.6%
|
2
1.6%
|
4
1.6%
|
| SPAIN |
2
1.6%
|
1
0.8%
|
3
1.2%
|
| SWEDEN |
7
5.7%
|
0
0%
|
7
2.8%
|
| SWITZERLAND |
1
0.8%
|
1
0.8%
|
2
0.8%
|
| UNITED KINGDOM |
3
2.4%
|
2
1.6%
|
5
2%
|
| UNITED STATES |
58
47.2%
|
56
45.2%
|
114
46.2%
|
Outcome Measures
| Title | Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR) |
|---|---|
| Description | Change from baseline to Week 26 in PVR was expressed as the ratio of Week 26 to baseline PVR value (Week 26 divided by baseline) using re-calculated PVR. PVR was determined by right heart catheterization (RHC). A geometric least square mean ratio of Week 26 to baseline PVR less than (<) 1 corresponds to a reduction in PVR from baseline. Missing values were imputed using a last observation carried forward (LOCF) approach. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set (FAS) included all randomized participants. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 123 | 124 |
| Geometric Least Squares Mean (95% Confidence Interval) [ratio] |
0.46
|
0.48
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4239 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of geometric Least Square mean |
| Estimated Value | 0.96 | |
| Confidence Interval |
(2-Sided) 95% 0.86 to 1.07 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) |
|---|---|
| Description | The change from baseline to Week 26 in 6MWD was calculated as Week 26 minus baseline. 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. Missing values were imputed using a LOCF approach. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 123 | 121 |
| Least Squares Mean (95% Confidence Interval) [meter] |
54.96
|
56.39
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8758 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Square (LS) Mean difference |
| Estimated Value | -1.43 | |
| Confidence Interval |
(2-Sided) 95% -19.393 to 16.538 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels |
|---|---|
| Description | The change from baseline to Week 26 in NT-proBNP was expressed as the ratio of Week 26 to baseline NT-proBNP (Week 26 divided by baseline). A geometric least square mean ratio of Week 26 to baseline NT-proBNP <1 corresponds to a reduction in NT-proBNP from baseline. Missing values were imputed using a LOCF approach. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 121 | 122 |
| Geometric Least Squares Mean (95% Confidence Interval) [ratio] |
0.26
|
0.25
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8529 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of geometric LS mean |
| Estimated Value | 1.03 | |
| Confidence Interval |
(2-Sided) 95% 0.770 to 1.371 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC) |
|---|---|
| Description | WHO FC is a classification graded from Class I to IV which reflects disease severity based on symptoms. Worsening was defined as death or hospitalization due to PAH. Class I: No limitation of activity; Class II: slight limitation with ordinary activities; Class III: may not have symptoms at rest but greatly limited activities; Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Missing values were imputed using a LOCF approach. |
| Time Frame | Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS included all randomized participants. Here, N (number of participants analyzed) signifies number of participants analyzed for this outcome measure. Participants with WHO FC IV at baseline were excluded from this analysis as they could not shift to a worse category. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 122 | 119 |
| Number [percentage of participants] |
99.2
80.7%
|
97.5
78.6%
|
| Title | Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP) |
|---|---|
| Description | Change from baseline to Week 26 in mean Pulmonary Arterial Pressure (mPAP) was measured. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Missing values were imputed using a LOCF approach. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set included all randomized participants. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 123 | 124 |
| Least Squares Mean (95% Confidence Interval) [millimeters of mercury (mmHg)] |
-12.92
|
-12.20
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4998 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -0.72 | |
| Confidence Interval |
(2-Sided) 95% -2.834 to 1.386 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP) |
|---|---|
| Description | Change from baseline to Week 26 in mean Right Atrial Pressure (mRAP) was measured. Missing values were imputed using a LOCF approach. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 123 | 123 |
| Least Squares Mean (95% Confidence Interval) [mmHg] |
-1.78
|
-1.69
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8528 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -0.09 | |
| Confidence Interval |
(2-Sided) 95% -1.003 to 0.830 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 26 in Total Pulmonary Resistance |
|---|---|
| Description | Change from baseline to Week 26 in total pulmonary resistance was measured. Total pulmonary resistance was calculated as mPAP/CO*80, where CO is cardiac output. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set included all randomized participants. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 123 | 124 |
| Least Squares Mean (95% Confidence Interval) [dynes*second per centimeter^5] |
-511.88
|
-514.28
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9474 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 2.40 | |
| Confidence Interval |
(2-Sided) 95% -69.368 to 74.178 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 26 in Cardiac Index |
|---|---|
| Description | Change from baseline to Week 26 in cardiac index was measured. Cardiac index is the amount of blood pumped by the heart, per minute, per meter square of body surface area. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set included all randomized participants. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 123 | 124 |
| Least Squares Mean (95% Confidence Interval) [liters per minute per meter square] |
0.97
|
0.84
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1902 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 0.13 | |
| Confidence Interval |
(2-Sided) 95% -0.066 to 0.328 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 26 in Venous Oxygen Saturation (%) |
|---|---|
| Description | Change from baseline to Week 26 in venous oxygen saturation was measured. Missing values were imputed using a LOCF approach. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 120 | 118 |
| Least Squares Mean (95% Confidence Interval) [percentage of oxygen saturation] |
5.59
|
6.79
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1227 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -1.20 | |
| Confidence Interval |
(2-Sided) 95% -2.737 to 0.327 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants With Disease Progression Event |
|---|---|
| Description | Number of participants with disease progression event were reported. Disease progression event as adjudicated by the CEC, defined as any of the following: a. Death (all causes; adjudicated for PAH relationship); b. Hospitalization for worsening PAH; c. Initiation of prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist for worsening PAH; d. Clinical worsening defined as a post-baseline decrease in 6MWD by more than (>) 15 percent (%) from the highest 6MWD obtained at or after baseline, accompanied by WHO FC III or IV (both conditions confirmed at two consecutive post-baseline visits separated by 1-21 days). |
| Time Frame | Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set included all randomized participants. |
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). |
| Measure Participants | 123 | 124 |
| Week 26 |
8
6.5%
|
13
10.5%
|
| Month 12 |
13
10.6%
|
20
16.1%
|
| Month 18 |
15
12.2%
|
23
18.5%
|
| Month 24 |
15
12.2%
|
25
20.2%
|
| Month 30 |
16
13%
|
27
21.8%
|
| End of Analysis Period (up to 40 months) |
16
13%
|
27
21.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag), Double Oral Therapy (Macitentan, Tadalafil, and Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0867 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.59 | |
| Confidence Interval |
(2-Sided) 95% 0.32 to 1.09 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | Up to 42 Months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses. | |||
| Arm/Group Title | Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | ||
| Arm/Group Description | Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled). | ||
All Cause Mortality |
||||
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/119 (3.4%) | 12/127 (9.4%) | ||
Serious Adverse Events |
||||
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 58/119 (48.7%) | 48/127 (37.8%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 3/119 (2.5%) | 2/127 (1.6%) | ||
| Blood Loss Anaemia | 1/119 (0.8%) | 0/127 (0%) | ||
| Febrile Neutropenia | 0/119 (0%) | 1/127 (0.8%) | ||
| Iron Deficiency Anaemia | 3/119 (2.5%) | 1/127 (0.8%) | ||
| Leukopenia | 0/119 (0%) | 1/127 (0.8%) | ||
| Microcytic Anaemia | 1/119 (0.8%) | 0/127 (0%) | ||
| Cardiac disorders | ||||
| Arrhythmia | 1/119 (0.8%) | 0/127 (0%) | ||
| Atrial Fibrillation | 1/119 (0.8%) | 2/127 (1.6%) | ||
| Atrial Flutter | 0/119 (0%) | 2/127 (1.6%) | ||
| Cardiac Arrest | 0/119 (0%) | 2/127 (1.6%) | ||
| Cardiac Failure Chronic | 1/119 (0.8%) | 0/127 (0%) | ||
| Ischaemic Cardiomyopathy | 0/119 (0%) | 1/127 (0.8%) | ||
| Left Ventricular Failure | 2/119 (1.7%) | 1/127 (0.8%) | ||
| Palpitations | 0/119 (0%) | 1/127 (0.8%) | ||
| Pericardial Effusion | 2/119 (1.7%) | 3/127 (2.4%) | ||
| Right Ventricular Failure | 6/119 (5%) | 8/127 (6.3%) | ||
| Supraventricular Tachycardia | 1/119 (0.8%) | 0/127 (0%) | ||
| Ventricular Tachycardia | 0/119 (0%) | 1/127 (0.8%) | ||
| Acute Left Ventricular Failure | 1/119 (0.8%) | 0/127 (0%) | ||
| Acute Right Ventricular Failure | 1/119 (0.8%) | 0/127 (0%) | ||
| Atrial Tachycardia | 1/119 (0.8%) | 0/127 (0%) | ||
| Cardiac Failure | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Cardiac Failure Acute | 0/119 (0%) | 1/127 (0.8%) | ||
| Cardiac Failure Congestive | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Cardiac Failure High Output | 1/119 (0.8%) | 0/127 (0%) | ||
| Cardiogenic Shock | 1/119 (0.8%) | 0/127 (0%) | ||
| Coronary Artery Disease | 0/119 (0%) | 2/127 (1.6%) | ||
| Sinus Tachycardia | 1/119 (0.8%) | 0/127 (0%) | ||
| Congenital, familial and genetic disorders | ||||
| Gastrointestinal Arteriovenous Malformation | 1/119 (0.8%) | 0/127 (0%) | ||
| Ear and labyrinth disorders | ||||
| Deafness Neurosensory | 0/119 (0%) | 1/127 (0.8%) | ||
| Eye disorders | ||||
| Blindness | 1/119 (0.8%) | 0/127 (0%) | ||
| Gastrointestinal disorders | ||||
| Abdominal Pain | 1/119 (0.8%) | 0/127 (0%) | ||
| Anal Haemorrhage | 0/119 (0%) | 1/127 (0.8%) | ||
| Constipation | 1/119 (0.8%) | 0/127 (0%) | ||
| Gastrointestinal Amyloidosis | 1/119 (0.8%) | 0/127 (0%) | ||
| Gastrointestinal Haemorrhage | 3/119 (2.5%) | 2/127 (1.6%) | ||
| Gastrointestinal Polyp Haemorrhage | 1/119 (0.8%) | 0/127 (0%) | ||
| Incarcerated Umbilical Hernia | 1/119 (0.8%) | 0/127 (0%) | ||
| Large Intestinal Haemorrhage | 1/119 (0.8%) | 0/127 (0%) | ||
| Nausea | 2/119 (1.7%) | 1/127 (0.8%) | ||
| Pancreatitis | 1/119 (0.8%) | 0/127 (0%) | ||
| Rectal Prolapse | 0/119 (0%) | 1/127 (0.8%) | ||
| Small Intestinal Obstruction | 1/119 (0.8%) | 0/127 (0%) | ||
| Upper Gastrointestinal Haemorrhage | 2/119 (1.7%) | 0/127 (0%) | ||
| Vomiting | 1/119 (0.8%) | 2/127 (1.6%) | ||
| Intestinal Ischaemia | 1/119 (0.8%) | 0/127 (0%) | ||
| Oesophageal Haemorrhage | 1/119 (0.8%) | 0/127 (0%) | ||
| Retroperitoneal Haemorrhage | 1/119 (0.8%) | 0/127 (0%) | ||
| General disorders | ||||
| Accidental Death | 0/119 (0%) | 1/127 (0.8%) | ||
| Non-Cardiac Chest Pain | 2/119 (1.7%) | 3/127 (2.4%) | ||
| Oedema Peripheral | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Pyrexia | 0/119 (0%) | 1/127 (0.8%) | ||
| Sudden Cardiac Death | 0/119 (0%) | 1/127 (0.8%) | ||
| Sudden Death | 0/119 (0%) | 1/127 (0.8%) | ||
| Hepatobiliary disorders | ||||
| Autoimmune Hepatitis | 1/119 (0.8%) | 0/127 (0%) | ||
| Drug-Induced Liver Injury | 1/119 (0.8%) | 0/127 (0%) | ||
| Hepatic Cirrhosis | 1/119 (0.8%) | 0/127 (0%) | ||
| Hepatic Failure | 1/119 (0.8%) | 0/127 (0%) | ||
| Liver Disorder | 1/119 (0.8%) | 0/127 (0%) | ||
| Immune system disorders | ||||
| Allergy to Arthropod Sting | 1/119 (0.8%) | 0/127 (0%) | ||
| Infections and infestations | ||||
| Bronchitis | 1/119 (0.8%) | 2/127 (1.6%) | ||
| Device Related Infection | 1/119 (0.8%) | 0/127 (0%) | ||
| Escherichia Sepsis | 0/119 (0%) | 1/127 (0.8%) | ||
| Gastroenteritis Viral | 1/119 (0.8%) | 0/127 (0%) | ||
| Gastrointestinal Infection | 0/119 (0%) | 1/127 (0.8%) | ||
| Hepatitis C | 0/119 (0%) | 1/127 (0.8%) | ||
| Influenza | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Lower Respiratory Tract Infection | 1/119 (0.8%) | 0/127 (0%) | ||
| Osteomyelitis Chronic | 1/119 (0.8%) | 0/127 (0%) | ||
| Pneumonia | 8/119 (6.7%) | 4/127 (3.1%) | ||
| Pneumonia Legionella | 1/119 (0.8%) | 0/127 (0%) | ||
| Pneumonia Pseudomonal | 1/119 (0.8%) | 0/127 (0%) | ||
| Pyelonephritis Acute | 1/119 (0.8%) | 0/127 (0%) | ||
| Sepsis | 4/119 (3.4%) | 3/127 (2.4%) | ||
| Septic Shock | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Staphylococcal Bacteraemia | 1/119 (0.8%) | 0/127 (0%) | ||
| Upper Respiratory Tract Infection | 0/119 (0%) | 2/127 (1.6%) | ||
| Urinary Tract Infection | 1/119 (0.8%) | 2/127 (1.6%) | ||
| Urosepsis | 1/119 (0.8%) | 0/127 (0%) | ||
| Vascular Device Infection | 1/119 (0.8%) | 0/127 (0%) | ||
| Appendicitis | 1/119 (0.8%) | 0/127 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Chest Injury | 0/119 (0%) | 1/127 (0.8%) | ||
| Deep Vein Thrombosis Postoperative | 0/119 (0%) | 1/127 (0.8%) | ||
| Fall | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Intentional Overdose | 1/119 (0.8%) | 0/127 (0%) | ||
| Overdose | 0/119 (0%) | 1/127 (0.8%) | ||
| Procedural Haemorrhage | 0/119 (0%) | 1/127 (0.8%) | ||
| Rib Fracture | 0/119 (0%) | 1/127 (0.8%) | ||
| Road Traffic Accident | 1/119 (0.8%) | 0/127 (0%) | ||
| Spinal Compression Fracture | 1/119 (0.8%) | 0/127 (0%) | ||
| Thoracic Vertebral Fracture | 0/119 (0%) | 1/127 (0.8%) | ||
| Toxicity to Various Agents | 0/119 (0%) | 1/127 (0.8%) | ||
| Vascular Pseudoaneurysm | 1/119 (0.8%) | 0/127 (0%) | ||
| Wrist Fracture | 1/119 (0.8%) | 0/127 (0%) | ||
| Hip Fracture | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Investigations | ||||
| Alanine Aminotransferase Increased | 1/119 (0.8%) | 0/127 (0%) | ||
| Aspartate Aminotransferase Increased | 1/119 (0.8%) | 0/127 (0%) | ||
| Blood Pressure Increased | 0/119 (0%) | 1/127 (0.8%) | ||
| Catheterisation Cardiac | 1/119 (0.8%) | 0/127 (0%) | ||
| Haemoglobin Decreased | 0/119 (0%) | 1/127 (0.8%) | ||
| Hepatic Enzyme Increased | 0/119 (0%) | 1/127 (0.8%) | ||
| Influenza A Virus Test Positive | 0/119 (0%) | 1/127 (0.8%) | ||
| Liver Function Test Increased | 1/119 (0.8%) | 0/127 (0%) | ||
| Rotavirus Test Positive | 1/119 (0.8%) | 0/127 (0%) | ||
| Sleep Study | 1/119 (0.8%) | 0/127 (0%) | ||
| Transaminases Increased | 1/119 (0.8%) | 0/127 (0%) | ||
| Waist Circumference Increased | 0/119 (0%) | 1/127 (0.8%) | ||
| Cardiac Electrophysiologic Study | 1/119 (0.8%) | 0/127 (0%) | ||
| Transplant Evaluation | 0/119 (0%) | 1/127 (0.8%) | ||
| Metabolism and nutrition disorders | ||||
| Dehydration | 0/119 (0%) | 2/127 (1.6%) | ||
| Hypokalaemia | 2/119 (1.7%) | 1/127 (0.8%) | ||
| Failure to Thrive | 1/119 (0.8%) | 0/127 (0%) | ||
| Fluid Overload | 1/119 (0.8%) | 0/127 (0%) | ||
| Hypertriglyceridaemia | 0/119 (0%) | 1/127 (0.8%) | ||
| Malnutrition | 0/119 (0%) | 1/127 (0.8%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back Pain | 0/119 (0%) | 1/127 (0.8%) | ||
| Chest Wall Haematoma | 0/119 (0%) | 1/127 (0.8%) | ||
| Costochondritis | 1/119 (0.8%) | 0/127 (0%) | ||
| Muscular Weakness | 0/119 (0%) | 1/127 (0.8%) | ||
| Musculoskeletal Chest Pain | 2/119 (1.7%) | 0/127 (0%) | ||
| Systemic Scleroderma | 1/119 (0.8%) | 0/127 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Invasive Ductal Breast Carcinoma | 0/119 (0%) | 1/127 (0.8%) | ||
| Lung Neoplasm Malignant | 0/119 (0%) | 1/127 (0.8%) | ||
| Malignant Melanoma | 1/119 (0.8%) | 0/127 (0%) | ||
| Plasma Cell Myeloma | 1/119 (0.8%) | 0/127 (0%) | ||
| Squamous Cell Carcinoma of the Tongue | 1/119 (0.8%) | 0/127 (0%) | ||
| Breast Cancer | 1/119 (0.8%) | 0/127 (0%) | ||
| Lung Carcinoma Cell Type Unspecified Stage I | 0/119 (0%) | 1/127 (0.8%) | ||
| Nervous system disorders | ||||
| Cerebral Infarction | 0/119 (0%) | 1/127 (0.8%) | ||
| Dizziness | 0/119 (0%) | 1/127 (0.8%) | ||
| Embolic Stroke | 0/119 (0%) | 1/127 (0.8%) | ||
| Haemorrhagic Stroke | 0/119 (0%) | 1/127 (0.8%) | ||
| Ischaemic Stroke | 0/119 (0%) | 1/127 (0.8%) | ||
| Seizure | 0/119 (0%) | 1/127 (0.8%) | ||
| Syncope | 0/119 (0%) | 6/127 (4.7%) | ||
| Product Issues | ||||
| Device Dislocation | 2/119 (1.7%) | 0/127 (0%) | ||
| Psychiatric disorders | ||||
| Confusional State | 0/119 (0%) | 1/127 (0.8%) | ||
| Psychotic Disorder | 1/119 (0.8%) | 0/127 (0%) | ||
| Schizophrenia | 1/119 (0.8%) | 0/127 (0%) | ||
| Renal and urinary disorders | ||||
| Acute Kidney Injury | 3/119 (2.5%) | 1/127 (0.8%) | ||
| Nephropathy Toxic | 0/119 (0%) | 1/127 (0.8%) | ||
| Prerenal Failure | 0/119 (0%) | 1/127 (0.8%) | ||
| Renal Amyloidosis | 1/119 (0.8%) | 0/127 (0%) | ||
| Renal Failure | 1/119 (0.8%) | 0/127 (0%) | ||
| Renal Impairment | 1/119 (0.8%) | 0/127 (0%) | ||
| Scleroderma Renal Crisis | 1/119 (0.8%) | 0/127 (0%) | ||
| Reproductive system and breast disorders | ||||
| Menorrhagia | 0/119 (0%) | 1/127 (0.8%) | ||
| Priapism | 1/119 (0.8%) | 0/127 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute Respiratory Failure | 6/119 (5%) | 5/127 (3.9%) | ||
| Choking | 1/119 (0.8%) | 0/127 (0%) | ||
| Dyspnoea | 5/119 (4.2%) | 0/127 (0%) | ||
| Epistaxis | 0/119 (0%) | 1/127 (0.8%) | ||
| Haemoptysis | 0/119 (0%) | 1/127 (0.8%) | ||
| Hypoxia | 1/119 (0.8%) | 2/127 (1.6%) | ||
| Interstitial Lung Disease | 2/119 (1.7%) | 0/127 (0%) | ||
| Pleural Effusion | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Pleurisy | 0/119 (0%) | 1/127 (0.8%) | ||
| Pneumonia Aspiration | 0/119 (0%) | 2/127 (1.6%) | ||
| Pulmonary Arterial Hypertension | 8/119 (6.7%) | 8/127 (6.3%) | ||
| Pulmonary Embolism | 2/119 (1.7%) | 1/127 (0.8%) | ||
| Pulmonary Mass | 1/119 (0.8%) | 0/127 (0%) | ||
| Pulmonary Oedema | 1/119 (0.8%) | 0/127 (0%) | ||
| Pulmonary Veno-Occlusive Disease | 0/119 (0%) | 3/127 (2.4%) | ||
| Respiratory Arrest | 0/119 (0%) | 1/127 (0.8%) | ||
| Respiratory Distress | 0/119 (0%) | 2/127 (1.6%) | ||
| Respiratory Failure | 6/119 (5%) | 1/127 (0.8%) | ||
| Pulmonary Hypertension | 0/119 (0%) | 1/127 (0.8%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Skin Ulcer | 1/119 (0.8%) | 0/127 (0%) | ||
| Surgical and medical procedures | ||||
| Drug Delivery Device Implantation | 1/119 (0.8%) | 1/127 (0.8%) | ||
| Hip Arthroplasty | 1/119 (0.8%) | 2/127 (1.6%) | ||
| Knee Arthroplasty | 0/119 (0%) | 1/127 (0.8%) | ||
| Lung Transplant | 0/119 (0%) | 1/127 (0.8%) | ||
| Open Reduction of Fracture | 1/119 (0.8%) | 0/127 (0%) | ||
| Penile Operation | 1/119 (0.8%) | 0/127 (0%) | ||
| Pericardial Drainage | 0/119 (0%) | 1/127 (0.8%) | ||
| Therapy Change | 1/119 (0.8%) | 0/127 (0%) | ||
| Toe Amputation | 0/119 (0%) | 1/127 (0.8%) | ||
| Vascular disorders | ||||
| Deep Vein Thrombosis | 0/119 (0%) | 2/127 (1.6%) | ||
| Hypertensive Crisis | 1/119 (0.8%) | 0/127 (0%) | ||
| Hypotension | 2/119 (1.7%) | 2/127 (1.6%) | ||
| Paradoxical Embolism | 0/119 (0%) | 1/127 (0.8%) | ||
| Shock | 1/119 (0.8%) | 0/127 (0%) | ||
| Hypertension | 0/119 (0%) | 1/127 (0.8%) | ||
| Shock Haemorrhagic | 1/119 (0.8%) | 0/127 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 118/119 (99.2%) | 119/127 (93.7%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 14/119 (11.8%) | 11/127 (8.7%) | ||
| Iron Deficiency Anaemia | 6/119 (5%) | 5/127 (3.9%) | ||
| Cardiac disorders | ||||
| Palpitations | 14/119 (11.8%) | 11/127 (8.7%) | ||
| Gastrointestinal disorders | ||||
| Abdominal Distension | 6/119 (5%) | 4/127 (3.1%) | ||
| Abdominal Pain | 7/119 (5.9%) | 6/127 (4.7%) | ||
| Abdominal Pain Upper | 8/119 (6.7%) | 7/127 (5.5%) | ||
| Constipation | 7/119 (5.9%) | 9/127 (7.1%) | ||
| Diarrhoea | 66/119 (55.5%) | 41/127 (32.3%) | ||
| Dyspepsia | 27/119 (22.7%) | 17/127 (13.4%) | ||
| Gastrooesophageal Reflux Disease | 11/119 (9.2%) | 18/127 (14.2%) | ||
| Nausea | 56/119 (47.1%) | 33/127 (26%) | ||
| Vomiting | 30/119 (25.2%) | 14/127 (11%) | ||
| General disorders | ||||
| Chest Discomfort | 7/119 (5.9%) | 10/127 (7.9%) | ||
| Chest Pain | 6/119 (5%) | 4/127 (3.1%) | ||
| Chills | 7/119 (5.9%) | 2/127 (1.6%) | ||
| Fatigue | 24/119 (20.2%) | 22/127 (17.3%) | ||
| Non-Cardiac Chest Pain | 10/119 (8.4%) | 6/127 (4.7%) | ||
| Oedema Peripheral | 45/119 (37.8%) | 46/127 (36.2%) | ||
| Pain | 11/119 (9.2%) | 9/127 (7.1%) | ||
| Peripheral Swelling | 11/119 (9.2%) | 4/127 (3.1%) | ||
| Pyrexia | 11/119 (9.2%) | 11/127 (8.7%) | ||
| Influenza Like Illness | 6/119 (5%) | 7/127 (5.5%) | ||
| Infections and infestations | ||||
| Bronchitis | 6/119 (5%) | 6/127 (4.7%) | ||
| Influenza | 6/119 (5%) | 7/127 (5.5%) | ||
| Nasopharyngitis | 20/119 (16.8%) | 23/127 (18.1%) | ||
| Upper Respiratory Tract Infection | 14/119 (11.8%) | 21/127 (16.5%) | ||
| Urinary Tract Infection | 9/119 (7.6%) | 11/127 (8.7%) | ||
| Sinusitis | 5/119 (4.2%) | 8/127 (6.3%) | ||
| Investigations | ||||
| Alanine Aminotransferase Increased | 8/119 (6.7%) | 4/127 (3.1%) | ||
| Aspartate Aminotransferase Increased | 10/119 (8.4%) | 4/127 (3.1%) | ||
| Haemoglobin Decreased | 10/119 (8.4%) | 6/127 (4.7%) | ||
| Weight Increased | 5/119 (4.2%) | 8/127 (6.3%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased Appetite | 14/119 (11.8%) | 4/127 (3.1%) | ||
| Fluid Retention | 6/119 (5%) | 8/127 (6.3%) | ||
| Hypokalaemia | 17/119 (14.3%) | 15/127 (11.8%) | ||
| Iron Deficiency | 3/119 (2.5%) | 7/127 (5.5%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 19/119 (16%) | 19/127 (15%) | ||
| Back Pain | 13/119 (10.9%) | 19/127 (15%) | ||
| Muscle Spasms | 9/119 (7.6%) | 7/127 (5.5%) | ||
| Musculoskeletal Pain | 8/119 (6.7%) | 1/127 (0.8%) | ||
| Myalgia | 21/119 (17.6%) | 19/127 (15%) | ||
| Pain in Extremity | 37/119 (31.1%) | 24/127 (18.9%) | ||
| Pain in Jaw | 35/119 (29.4%) | 15/127 (11.8%) | ||
| Nervous system disorders | ||||
| Dizziness | 17/119 (14.3%) | 27/127 (21.3%) | ||
| Headache | 83/119 (69.7%) | 78/127 (61.4%) | ||
| Hypoaesthesia | 6/119 (5%) | 1/127 (0.8%) | ||
| Paraesthesia | 8/119 (6.7%) | 2/127 (1.6%) | ||
| Psychiatric disorders | ||||
| Anxiety | 9/119 (7.6%) | 5/127 (3.9%) | ||
| Insomnia | 8/119 (6.7%) | 6/127 (4.7%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 19/119 (16%) | 23/127 (18.1%) | ||
| Dyspnoea | 20/119 (16.8%) | 25/127 (19.7%) | ||
| Epistaxis | 13/119 (10.9%) | 13/127 (10.2%) | ||
| Hypoxia | 6/119 (5%) | 7/127 (5.5%) | ||
| Nasal Congestion | 22/119 (18.5%) | 23/127 (18.1%) | ||
| Oropharyngeal Pain | 9/119 (7.6%) | 2/127 (1.6%) | ||
| Pulmonary Arterial Hypertension | 8/119 (6.7%) | 3/127 (2.4%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Rash | 6/119 (5%) | 9/127 (7.1%) | ||
| Swelling Face | 8/119 (6.7%) | 2/127 (1.6%) | ||
| Vascular disorders | ||||
| Flushing | 21/119 (17.6%) | 22/127 (17.3%) | ||
| Hypotension | 10/119 (8.4%) | 8/127 (6.3%) | ||
Limitations/Caveats
The main limitation of the sponsor's findings was that analyses of disease progression and mortality were exploratory due to the testing hierarchy and the post hoc nature of the analyses. The study was not powered to show significant differences for the disease progression related endpoint. Another limitation was the availability of hemodynamic assessments only for Week 26 timepoint.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Any study-related publication written independently by investigators must be submitted to Actelion for review at least 30 days prior to submission for publication or presentation. Upon review, Actelion may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights.
Results Point of Contact
| Name/Title | Principal Clinical Scientist |
|---|---|
| Organization | Actelion Pharmaceuticals Ltd. |
| Phone | 844-434-4210 |
| ClinicalTrialDisclosure@its.jnj.com |
Responsible Party:
Actelion
ClinicalTrials.gov Identifier:
NCT02558231
Other Study ID Numbers:
- AC-065A308
First Posted:
Sep 23, 2015
Last Update Posted:
Apr 13, 2021
Last Verified:
Mar 1, 2021