Long-Term Treatment with Single-Tablet Combination of Macitentan and Tadalafil in Pulmonary Arterial Hypertension: Results from A DUE and Its Open-Label Period.

INTRODUCTION

In the A DUE study, a fixed-dose combination of macitentan 10 mg and tadalafil 40 mg (M/T FDC) as a single tablet significantly improved pulmonary vascular resistance at Week 16 versus corresponding monotherapies in patients with pulmonary arterial hypertension (PAH). Safety was consistent with known profiles of macitentan and tadalafil. The open-label (OL) period of A DUE provides long-term safety/efficacy data for M/T FDC.

METHODS

In A DUE (NCT03904693), patients were randomized (2:1:1) to double-blind M/T FDC, macitentan 10 mg or tadalafil 40 mg and followed for 16 weeks. They then transitioned to OL M/T FDC and were followed for up to 2 years to end of study (EOS). Efficacy analyses, including survival, changes in six-minute walk distance (6MWD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline, are reported in patients randomized to M/T FDC at start of A DUE (efficacy set). Safety is reported for all patients receiving M/T FDC at any time during the double-blind (DB) and/or OL (safety set).

RESULTS

In A DUE, 185 patients received M/T FDC for median (range) of 105.1 (0.6, 182.6) weeks. In the efficacy set, 91% of patients were alive at EOS. Mean (SD) change in 6MWD from M/T FDC initiation to OL Week 120 was 60.5 m (84.2). For NT-proBNP, geometric mean percent of baseline was 50.2% at OL Week 120. In the safety set, adverse events (AEs) occurred in 94.1% and serious AEs in 33.5% of patients; 10.3% discontinued study treatment due to an AE. Seven on-treatment deaths occurred in those receiving M/T FDC; all were evaluated as unrelated to treatment.

CONCLUSIONS

Long-term treatment with single-tablet combination of macitentan/tadalafil was well tolerated, with no new safety findings identified. Most patients were alive at EOS. Incremental improvements in 6MWD and NT-proBNP observed in the DB with M/T FDC were sustained over 2 years.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03904693. A graphical abstract is also available for this article.