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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02558231




Registration number
NCT02558231
Ethics application status
Date submitted
22/09/2015
Date registered
23/09/2015
Date last updated
11/09/2020

Titles & IDs
Public title
The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension
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
Secondary ID [1] 0 0
AC-065A308
Universal Trial Number (UTN)
Trial acronym
TRITON
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Macitentan
Treatment: Drugs - Tadalafil
Treatment: Drugs - Selexipag

Experimental: Triple oral combination treatment - Macitentan, tadalafil, and selexipag

Placebo Comparator: Dual oral combination treatment - Macitentan, tadalafil, and placebo


Treatment: Drugs: Macitentan
Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.

Treatment: Drugs: Tadalafil
Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d.

Treatment: Drugs: Selexipag
Used double-blind in the triple oral treatment arm, 200 microgram tablet, 1-8 tablets b.i.d.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Baseline, Week 26
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Baseline, Week 26
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
Baseline, Week 26
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
Week 26
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Baseline, Week 26
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Baseline, Week 26
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
Baseline, Week 26
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
Baseline, Week 26
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
Baseline, Week 26
Secondary outcome [9] 0 0
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).
Timepoint [9] 0 0
Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Royal Prince Albert Hospital - Camperdown
Recruitment hospital [2] 0 0
St. Vincents Hospital Sydney - Darlinghurst
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2010 - Darlinghurst
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Iowa
Country [7] 0 0
United States of America
State/province [7] 0 0
Kentucky
Country [8] 0 0
United States of America
State/province [8] 0 0
Louisiana
Country [9] 0 0
United States of America
State/province [9] 0 0
Maryland
Country [10] 0 0
United States of America
State/province [10] 0 0
Massachusetts
Country [11] 0 0
United States of America
State/province [11] 0 0
Michigan
Country [12] 0 0
United States of America
State/province [12] 0 0
New Mexico
Country [13] 0 0
United States of America
State/province [13] 0 0
Ohio
Country [14] 0 0
United States of America
State/province [14] 0 0
Pennsylvania
Country [15] 0 0
United States of America
State/province [15] 0 0
Texas
Country [16] 0 0
Austria
State/province [16] 0 0
Graz
Country [17] 0 0
Austria
State/province [17] 0 0
Linz
Country [18] 0 0
Austria
State/province [18] 0 0
Wien
Country [19] 0 0
Belgium
State/province [19] 0 0
Brussels
Country [20] 0 0
Belgium
State/province [20] 0 0
Leuven
Country [21] 0 0
Canada
State/province [21] 0 0
British Columbia
Country [22] 0 0
Canada
State/province [22] 0 0
Ontario
Country [23] 0 0
Canada
State/province [23] 0 0
Quebec
Country [24] 0 0
Canada
State/province [24] 0 0
Calgary
Country [25] 0 0
Canada
State/province [25] 0 0
Ottawa
Country [26] 0 0
Denmark
State/province [26] 0 0
Aarhus
Country [27] 0 0
Denmark
State/province [27] 0 0
Copenhagen
Country [28] 0 0
France
State/province [28] 0 0
Le Kremlin-Bicêtre
Country [29] 0 0
Germany
State/province [29] 0 0
Dresden
Country [30] 0 0
Germany
State/province [30] 0 0
Giessen
Country [31] 0 0
Germany
State/province [31] 0 0
Hamburg
Country [32] 0 0
Germany
State/province [32] 0 0
Hannover
Country [33] 0 0
Germany
State/province [33] 0 0
Heidelberg
Country [34] 0 0
Germany
State/province [34] 0 0
Köln
Country [35] 0 0
Germany
State/province [35] 0 0
Regensburg
Country [36] 0 0
Ireland
State/province [36] 0 0
Dublin
Country [37] 0 0
Italy
State/province [37] 0 0
Bologna
Country [38] 0 0
Netherlands
State/province [38] 0 0
Amsterdam
Country [39] 0 0
Netherlands
State/province [39] 0 0
Maastricht
Country [40] 0 0
Spain
State/province [40] 0 0
Barcelona
Country [41] 0 0
Spain
State/province [41] 0 0
Madrid
Country [42] 0 0
Sweden
State/province [42] 0 0
Lund
Country [43] 0 0
Sweden
State/province [43] 0 0
Umeå
Country [44] 0 0
Sweden
State/province [44] 0 0
Uppsala
Country [45] 0 0
Switzerland
State/province [45] 0 0
Zürich
Country [46] 0 0
United Kingdom
State/province [46] 0 0
Clydebank
Country [47] 0 0
United Kingdom
State/province [47] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Actelion
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02558231
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications