The SERAPHIN Study

SERAPHIN was a global, multicenter, double-blind, randomized, placebo-controlled, event-driven, phase 3 study (ClinicalTrials.gov identification number: {"type":"clinical-trial","attrs":{"text":"NCT00660179","term_id":"NCT00660179"}}NCT00660179) [4]. The study included 742 patients with PAH who were randomized (1:1:1) to receive placebo (n = 250), macitentan 3 mg (n = 250), or macitentan 10 mg (n = 242) once daily (Fig. 1). Concomitant treatment with a stable dose of phosphodiesterase type 5 inhibitors, oral/inhaled prostanoids, calcium channel blockers, or l-arginine was allowed. Only the approved macitentan 10 mg dose arm was included for the purpose of this analysis; patients randomized to macitentan 3 mg were not included.

Schematic of the SERAPHIN study design. Time to all-cause death was evaluated up to study closure (15 March 2012), which occurred after a pre-defined number of primary endpoint events (285). Up to end of treatment (EOT), patients received their randomized double-blind treatment. Following EOT, patients could receive open-label (OL) macitentan 10 mg or any available alternative pulmonary arterial hypertension (PAH) therapy between EOT and study closure. Asterisk: 250 patients were also randomized to macitentan 3 mg, but only the approved macitentan 10 mg dose was included for the purpose of this analysis

The primary time-to-event endpoint was a composite of morbidity or mortality, whichever occurred first, up to EOT + 7 days. Events were defined as worsening of PAH, initiation of intravenous or subcutaneous prostanoid therapy, or the need for lung transplantation or atrial septostomy, or death from any cause. Worsening of PAH was defined by the occurrence of all three of the following: a decrease from baseline of ≥ 15% in 6-min walk distance (6MWD); worsening of PAH symptoms (a change from baseline to a higher World Health Organization functional class [FC] [or no change in patients who were in FC IV at baseline], and/or the appearance or worsening of signs of right heart failure that did not respond to oral diuretic therapy); and the need for additional treatment for PAH. All primary endpoint events were adjudicated by a blinded independent clinical-event committee (CEC).

Double-blind treatment continued until patients experienced a primary endpoint event or until 285 events had accrued. Patients were followed until withdrawal from the study or until study closure (March 2012). Patients who prematurely discontinued double-blind treatment and provided written informed consent were followed up to study closure. Those who experienced a nonfatal primary endpoint event and terminated double-blind treatment were eligible to receive another PAH therapy, including open-label macitentan 10 mg. In addition, all patients who completed the study as scheduled were eligible to continue in the SERAPHIN open-label study and receive open-label macitentan 10 mg once daily (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00667823","term_id":"NCT00667823"}}NCT00667823). Vital status follow-up at study closure was performed for all patients who had not prematurely discontinued from the study (i.e., died, withdrawn consent, or had been declared lost to follow-up). Patients with missing vital status at study closure were censored at date of last contact.

SERAPHIN was conducted in accordance with the amended Declaration of Helsinki and with the protocols reviewed by local institutional review boards with written informed consent obtained from all patients. This analysis is based on data from the SERAPHIN study and does not contain any new studies with human participants performed by any of the authors.