Efficacy and safety of selexipag in patients with inoperable or persistent/recurrent CTEPH (SELECT randomised trial)

Abstract

Background: SELECT was the first global randomised controlled trial of selexipag with standard of care in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension.

Methods: SELECT was a multicentre, randomised, double-blind, placebo-controlled, parallel-group, group-sequential, phase 3 study (ClinicalTrials.gov: NCT03689244). Adults aged ≤85 years in World Health Organization Functional Class I-IV, with a 6-min walk distance of 100-450 m, were randomised (1:1) to receive selexipag (200-1600 µg twice daily titration until individual maximum tolerated dose)+standard of care or placebo+standard of care. Patients were recruited into the haemodynamic set (first 91 randomised patients to undergo right heart catheterisation (RHC); week 20) or non-haemodynamic cohort (remaining patients, no RHC required). The primary end-point was percent of baseline pulmonary vascular resistance (PVR; week 20). Safety was also assessed.

Results: Of 321 patients screened, 128 were randomised (haemodynamic set n=91 (selexipag n=47; placebo n=44)). In the haemodynamic set, 29 (31.9%) patients had previous pulmonary endarterectomy (PEA), 20 (22.0%) balloon pulmonary angioplasty (BPA), and 14 (15.4%) both PEA and BPA; 28 (30.8%) were inoperable. The independent data monitoring committee recommended to stop the study for futility as no statistically significant difference was observed for the primary end-point (between-treatment geometric least squares mean ratio of PVR: 0.95, 95% CI 0.84-1.07; p=0.412). Adverse events were reported in 63 (98.4%) and 53 (82.8%) patients for selexipag and placebo, respectively.

Conclusions: SELECT was discontinued for futility, as no treatment effect on the primary end-point (PVR) was observed. Safety data were consistent with the established safety profile of selexipag, with no new safety signals identified.

Overview of the study. ^#: patients were stratified by baseline treatment with pulmonary hypertension (PH)-specific therapies (endothelin receptor antagonists, phosphodiesterase-5 inhibitors or soluble guanylyl cyclase stimulators; stratified as one therapy versus two therapies versus treatment-naïve) and chronic thromboembolic pulmonary hypertension (CTEPH) subpopulation (inoperable (with/without balloon pulmonary angioplasty (BPA)) versus persistent/recurrent after pulmonary endarterectomy (PEA) (including PEA followed by BPA)). ^¶: the haemodynamic set comprised the first 91 patients randomised, who were planned to undergo right heart catheterisation (RHC) at week 20; the non-haemodynamic cohort comprised the remaining patients for which no week 20 RHC was required. ⁺: secondary and exploratory end-points: time to death or PH-related hospitalisation, improvement in World Health Organization Functional Class (WHO FC) at week 26, change from baseline to week 26 in PAH-SYMPACT questionnaire cardiopulmonary and cardiovascular symptoms domains, and change from baseline to week 26 in Borg Dyspnoea Index or Borg Category-Ratio 10 scale. 6MWD: 6-min walk distance; SoC: standard of care; PVR: pulmonary vascular resistance; TTCW: time to clinical worsening; GMR: between-treatment geometric least squares mean ratio.

FIGURE 1

a) Overall study design of SELECT and b) design flow of decision making for analysis conducted at sequential time-points. The double-blind treatment period started on the day of randomisation when patients received their first dose. The double-blind period ended on the day of the last dose with the end of double-blind treatment (EDBT) visit. The EDBT visit was planned to occur within 4 weeks after the announcement of the end of the double-blind period, for all subjects who had not discontinued treatment early. As per protocol, the end of the double-blind period could have been announced either when the overall target number of clinical worsening events had been reached, or earlier following recommendation of the independent data monitoring committee (IDMC) or sponsor's decision. It was announced following the recommendation of the IDMC to stop the study for futility. The open-label period started with the first dose of the open-label study intervention in the evening of the day of the last dose of double-blind study intervention; this period was only applicable to a small number of patients due to change in study design. ^#: patients were required to have pulmonary vascular resistance (PVR) at rest ≥5 WU for the haemodynamic set and ≥3.75 WU for the non-haemodynamic cohort; diagnosis and inoperability confirmed by an independent adjudication committee. ^¶: the 12-week titration phase involved an incremental increase in study treatment from 200 μg twice daily to the individual maximum tolerated dose, up to 1600 μg twice daily (if well tolerated, incremental increase was 200 μg twice daily per week from week 0 to week 7). ⁺: only patients who completed the 52-week period according to the initial study protocol were enrolled into the open-label extension. PH: pulmonary hypertension; 6MWD: 6-min walk distance; TTCW: time to clinical worsening; QoL: quality of life; EOLT: end of open-label treatment; EOS: end of study; CTEPH: chronic thromboembolic pulmonary hypertension; PEA: pulmonary endarterectomy; BPA: balloon angioplasty; WHO FC: World Health Organization Functional Class; ERA: endothelin receptor antagonist; PDE5: phosphodiesterase-5.

FIGURE 2

Disposition of patients in SELECT. EDBT: end of double-blind treatment. ^#: patients were screened at 117 study centres across 31 countries; ^¶: patients were randomised in 65 study centres.

FIGURE 3

Primary end-point in SELECT study: pulmonary vascular resistance (PVR) at week 20, assessed at rest, within 2–5 h post-dose, expressed as ratio of week 20 to baseline PVR. Data presented as geometric least squares mean ratio with 95% confidence interval. An ANCOVA model was applied on the log_e-transformed PVR pre–post percent. Model covariates included randomised treatment, stratification factors per informative response technology (pulmonary hypertension-specific therapies and chronic thromboembolic pulmonary hypertension population) and the log_e-transformed baseline PVR value.