BACKGROUND: In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy. OBJECTIVES: TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH. METHODS: Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26. RESULTS: Patients were assigned to initial triple (n = 123) or initial double therapy (n = 124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P = 0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died. CONCLUSIONS: In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy.
- Chin, K. M.
- Sitbon, O.
- Doelberg, M.
- Feldman, J.
- Gibbs, J. S. R.
- Grünig, E.
- Hoeper, M. M.
- Martin, N.
- Mathai, S. C.
- McLaughlin, V. V.
- Perchenet, L.
- Poch, D.
- Saggar, R.
- Simonneau, G.
- Galiè, N.
Keywords
- *macitentan
- *pulmonary arterial hypertension
- *randomized controlled trial
- *selexipag
- *triple combination therapy
- Pharmaceuticals, a Janssen Pharmaceutical Company of Johnson & Johnson. Dr Chin has
- served as a steering committee member for Janssen Pharmaceutical Companies of
- Johnson & Johnson
- has received research grants from Janssen Pharmaceutical
- Companies of Johnson & Johnson, the National Institutes of Health, Ironwood
- Pharmaceuticals, and SoniVie
- has served on advisory boards for Bayer Healthcare
- (through the University of California, San Diego) and Flowonix
- has served as an
- adjudication committee member for Arena Pharmaceuticals
- is an associate editor of
- Circulation for the American Heart Association
- and has received consultancy fees
- from Janssen Pharmaceutical Companies of Johnson & Johnson. Prof Sitbon has served
- as a steering committee member for Janssen Pharmaceutical Companies of Johnson &
- Johnson
- and has served as an advisory board member for and received research grants
- from Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Doelberg is an
- employee of Actelion Pharmaceuticals. Dr Feldman has received speaker and
- consultancy fees from Bayer and United Therapeutics
- and has received consultancy
- fees from Gilead, Gossamer, Acceleron, Altavant, Janssen Pharmaceutical Companies of
- Johnson & Johnson, and Bellerophon. Dr Gibbs has served as a steering committee
- member for Janssen Pharmaceutical Companies of Johnson & Johnson, Complexa, and
- Acceleron
- has received consultancy fees from Arena
- has received speaker fees from
- GlaxoSmithKline and Merck Sharp & Dohme
- has served as a clinical endpoints
- committee member for Pfizer, Bayer, Bellerophon, Janssen Pharmaceutical Companies of
- Johnson & Johnson, and United Therapeutics
- and has served as a data and safety
- monitoring board member for Janssen Pharmaceutical Companies of Johnson & Johnson.
- Prof Grünig has received grants and personal fees from Bayer, Janssen Pharmaceutical
- Companies of Johnson & Johnson, Merck Sharp & Dohme, and GlaxoSmithKline
- and has
- received grants from Janssen Pharmaceutical Companies of Johnson & Johnson,
- Bayer/Merck Sharp & Dohme, GlaxoSmithKline, and United Therapeutics. Prof Hoeper has
- served as a steering committee member for Janssen Pharmaceutical Companies of
- Johnson & Johnson
- has received speaker and consultancy fees from Janssen
- Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp &
- Dohme, and Pfizer
- and has received research grants from Janssen Pharmaceutical
- Companies of Johnson & Johnson. Mr Martin is an employee of Actelion
- Pharmaceuticals. Dr Mathai has served as a steering committee member for Janssen
- Pharmaceutical Companies of Johnson & Johnson
- and has served as a consultant for
- Arena, Liquidia, and United Therapeutics. Prof McLaughlin has served as a steering
- committee member for Janssen Pharmaceutical Companies of Johnson & Johnson
- has
- received grants, personal fees, and nonfinancial support from Janssen Pharmaceutical
- Companies of Johnson & Johnson and Bayer
- has received grants from Eiger and
- SoniVie
- and has received personal fees from United Therapeutics, Arena, Caremark,
- Medtronic, and Merck Sharp & Dohme. Dr Perchenet is an employee of Actelion
- Pharmaceuticals
- has previously held stock and stock options with Actelion
- Pharmaceuticals
- and currently holds stock and stock options in the parent company
- Johnson & Johnson. Dr Poch has received speaker and consultancy fees from Bayer
- Healthcare. Dr Saggar has received consultancy fees and research funding from United
- Therapeutics and Janssen Pharmaceutical Companies of Johnson & Johnson. Prof
- Simonneau has served as a steering committee member for and received research grants
- from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer
- and has
- received speaker and consultancy fees from Janssen Pharmaceutical Companies of
- Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer. Prof
- Galiè is a steering committee member for Janssen Pharmaceutical Companies of Johnson
- & Johnson
- has received grant support, personal fees, and nonfinancial support from
- Janssen Pharmaceutical Companies of Johnson & Johnson
- and has received grant
- support and personal fees from Bayer Healthcare, Pfizer, and GlaxoSmithKline.
