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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02558231
• Date of registration: 22/09/2015
• Prospective Registration: Yes
• Primary sponsor: Actelion
• Public title: The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension TRITON
• Scientific 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
• Date of first enrolment: May 1, 2016
• Target sample size: 247
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02558231
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 3

Countries of recruitment

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

Key inclusion & exclusion criteria

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.



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension

Intervention(s)

Drug: Selexipag

Drug: Tadalafil

Drug: Macitentan

Primary Outcome(s)

Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR) [Time Frame: Baseline, Week 26]

Secondary Outcome(s)

Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels [Time Frame: Baseline, Week 26]

Change From Baseline to Week 26 in Total Pulmonary Resistance [Time Frame: Baseline, Week 26]

Change From Baseline to Week 26 in Cardiac Index [Time Frame: Baseline, Week 26]

Change From Baseline to Week 26 in Venous Oxygen Saturation (%) [Time Frame: Baseline, Week 26]

Number of Participants With Disease Progression Event [Time Frame: Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)]

Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC) [Time Frame: Week 26]

Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) [Time Frame: Baseline, Week 26]

Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP) [Time Frame: Baseline, Week 26]

Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP) [Time Frame: Baseline, Week 26]

Secondary ID(s)

AC-065A308

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 11/09/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02558231