Objective
The objective of this section is to summarize the results of CHEST-2, the open-label extension study to CHEST-1.8 The following summary is based on unpublished data provided by the manufacturer on the open-label extension phase.
Findings
Study Design
After completion of the 16-week double-blind CHEST-1 trial, a multi-centre, multinational open-label long-term extension study was initiated to evaluate the safety and tolerability of riociguat (1 mg, 1.5 mg, 2 mg, or 2.5 mg three times a day) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The aim was to collect additional information to evaluate safety and tolerability. The trial recruited 237 patients and these patients were treated with their individual optimal dose (between 0.5 mg and 2.5 mg three times a day) of open-label riociguat.
Patients who received riociguat during CHEST-1 were continued on the same dose they received on their last day of follow-up in CHEST-1, while patients who had received placebo during CHEST-1 were initiated on riociguat using the same, eight-week dose titration protocol used in CHEST-1. Efficacy outcomes evaluated in the open-label extension stage included the change from baseline (week 0 in CHEST-1) for the following: six-minute walk distance (6MWD), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), World Health Organization functional class (WHO FC), Borg CR10 score, EuroQoL 5-Dimensions Questionnaire (EQ-5D) score, Living With Hypertension Questionnaire (LPH) score, use of health care resources, and time to clinical worsening. Safety outcomes evaluated included adverse events, mortality, laboratory parameters, vital signs, electrocardiogram parameters, and blood-gas analysis.
At the time of the March 2013 safety update, 237 participants were enrolled in CHEST-2: 155 from the former riociguat treatment group and 82 from placebo. The majority of the patients were female (153 [64.6%]). The mean age of patients was 59.1 years. The majority of patients were white (165 [69.6%]).53
Results
The mean duration of treatment was 582.2 days (590.4 in the former riociguat group and 566.6 in the former placebo group). Adverse event results are presented in . There were eight treatment discontinuations due to treatment-emergent adverse events. Four discontinuations were determined to be related to riociguat and one event resulted in death. Eight deaths were reported between May 2012 and March 2013 (safety cut-offs 1 and 2). The causes of death were cardiac arrest (n = 2), cardiac failure (n = 1), sudden death (n = 1), unspecified cause of death (n = 1), thyroid cancer (n = 1), multi-organ failure (n = 1), and pneumonia and neoplasm (n = 1).
Results Summary for Open-Label Extension.
Most Frequently Reported Treatment-Emergent Serious Adverse Events.
Summary
The goal of the study was to evaluate the long-term safety and efficacy of riociguat. Design limitations (open-label, no control group) limit its usefulness for providing any further information on the risk of harm for riociguat. No new safety concerns were identified in the open-label extension phase.
