The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension Clinical Trial

— TRITON  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02558231
• Other study ID #: AC-065A308
• Status: Completed
• Phase: Phase 3
• Start date: May 1, 2016
• Est. completion date: April 20, 2020

Study information

• Verified date: March 2021
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 247
• Est. completion date: April 20, 2020
• Est. primary completion date: August 29, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure.

2. Male or female = 18 and = 75 years of age at screening.

3. Initial PAH diagnosis < 6 months prior to enrollment.

4. 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).

5. 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. 6-minute walk distance (6MWD) = 50 m at screening.

7. Women of childbearing potential must not be pregnant, must perform regular pregnancy tests, and use reliable contraception.

Exclusion Criteria:

1. Any PAH-specific drug therapy at any time.

2. Cardio pulmonary rehabilitation program based on exercise (planned, or started = 12 weeks prior to Day 1).

3. Body mass index (BMI) > 40 kg/m2 at screening.

4. 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.

5. Acute myocardial infarction = 12 weeks prior to screening.

6. Stroke = 12 weeks prior to screening.

7. Known permanent atrial fibrillation.

8. SBP < 90 mmHg at screening or Day 1.

9. Ongoing or planned treatment with organic nitrates and/or doxazosin.

10. 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.

11. Known or suspected pulmonary veno-occlusive disease (PVOD).

12. 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.

13. Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN (assessed by central laboratory at screening).

14. Severe renal impairment (estimated creatinine clearance = 30 mL/min/1.73 m2) assessed by central laboratory at screening.

15. Ongoing or planned dialysis.

16. Hemoglobin < 100 g/L assessed by central laboratory at screening.

17. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).

18. Loss of vision in one or both eyes because of non-arteritic ischemic optic neuropathy (NAION).

19. 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.

20. 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.

21. Treatment with another investigational drug (planned, or taken = 12 weeks prior to Day 1).

22. Hypersensitivity to any of the 3 study treatments or any excipient of their formulations.

23. Pregnancy, breastfeeding, or intention to become pregnant during the study.

24. Concomitant life-threatening disease with a life expectancy < 12 months.

25. Alcohol abuse.

26. Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Macitentan
Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.
• Tadalafil
Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d.
• Selexipag
Used double-blind in the triple oral treatment arm, 200 microgram tablet, 1-8 tablets b.i.d.

Locations

Country	Name	City	State
Australia	Royal Prince Albert Hospital	Camperdown	New South Wales
Australia	St. Vincents Hospital Sydney	Darlinghurst	New South Wales
Austria	LKH -Universität Klinkum Graz	Graz
Austria	Krankenhaus der Elisabethinen Linz	Linz
Austria	AKH Wien	Wien
Belgium	Hôpital Erasme	Brussels
Belgium	UZ Leuven - Campus Gasthuisberg	Leuven
Canada	University of Calgary	Calgary
Canada	London Health Sciences Centre - Victoria Hospital	London	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	University of Ottawa Heart Institute	Ottawa
Canada	Institut Universitaire de Cardiologie et de Pneumologie de Québec	Quebec City	Quebec
Canada	University of Toronto	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Denmark	Aarhus University Hospital Skejby	Aarhus
Denmark	Rigshospitalet Copenhagen	Copenhagen
France	CHU de Bicêtre	Le Kremlin-Bicêtre
Germany	Unversitätsklinikum Carl Gustav Carus	Dresden
Germany	Universitätsklinikum Giessen	Giessen
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Köln	Köln
Germany	Universitätsklinikum Regensburg	Regensburg
Ireland	Mater Misericordiae University Hospital	Dublin
Italy	Ospedale Sant'Orsola	Bologna
Netherlands	VUmc Amsterdam	Amsterdam
Netherlands	Maastricht University Medical Center	Maastricht
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital 12 de Octubre	Madrid
Sweden	Skånes universitetssjukhus Lund	Lund
Sweden	Norrlands universitetssjukhus	Umeå
Sweden	Kardiologkliniken	Uppsala
Switzerland	Universiätsspital Zürich	Zürich
United Kingdom	Golden Jubilee National Hospital	Clydebank
United Kingdom	Hammersmith Hospital	London
United Kingdom	Royal Brompton Hospital	London
United Kingdom	The Royal Free Hospital	London
United States	University of New Mexico Hospital	Albuquerque	New Mexico
United States	Piedmont Pulmonary and Critical Care Research	Atlanta	Georgia
United States	Johns Hopkins School of Medicine	Baltimore	Maryland
United States	Boston University Medical Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	The Christ Hospital	Cincinnati	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Houston Methodist Hospital	Houston	Texas
United States	University of Iowa Hospitals & Clinics	Iowa City	Iowa
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	UCSD Health Sciences	La Jolla	California
United States	UCLA Medical Center	Los Angeles	California
United States	Kentuckiana Pulmonary Associates	Louisville	Kentucky
United States	LSU Health Sciences Center	New Orleans	Louisiana
United States	Arizona Pulmonary Specialists, LTD	Phoenix	Arizona
United States	Allegheny General Hospital of Research	Pittsburgh	Pennsylvania
United States	UPMC Presbyterian	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Michigan
United States	Cleveland Clinic Florida	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Denmark,  France,  Germany,  Ireland,  Italy,  Netherlands,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)	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.	Baseline, Week 26
Secondary	Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD)	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.	Baseline, Week 26
Secondary	Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels	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.	Baseline, Week 26
Secondary	Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC)	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.	Week 26
Secondary	Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP)	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.	Baseline, Week 26
Secondary	Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP)	Change from baseline to Week 26 in mean Right Atrial Pressure (mRAP) was measured. Missing values were imputed using a LOCF approach.	Baseline, Week 26
Secondary	Change From Baseline to Week 26 in Total Pulmonary Resistance	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.	Baseline, Week 26
Secondary	Change From Baseline to Week 26 in Cardiac Index	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.	Baseline, Week 26
Secondary	Change From Baseline to Week 26 in Venous Oxygen Saturation (%)	Change from baseline to Week 26 in venous oxygen saturation was measured. Missing values were imputed using a LOCF approach.	Baseline, Week 26
Secondary	Number of Participants With Disease Progression Event	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).	Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)