GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus

\ua9 2023 The Authors. Background & Aims: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). Methods: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0–10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. Results: One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. Conclusions: Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. ClinicalTrials.gov ID: NCT02966834

The Responsiveness of Exercise Tests in COPD

BackgroundCOPD is characterized by reduced exercise tolerance, and improving physical performance is an important therapeutic goal. A variety of exercise tests commonly are used to assess exercise tolerance, including laboratory and field-based tests. The responsiveness of these tests to common COPD interventions is yet to be compared, but the results may inform test selection in clinical and research settings.Research questionWhat exercise test possesses the greatest sensitivity to change from before to after intervention in patients with COPD?Study design and methodsOne hundred fifty-four patients with symptomatic COPD were recruited and randomized (2:1:1) to 6 weeks of long-acting muscarinic antagonist (LAMA), pulmonary rehabilitation (PR), or usual care. Before and after intervention, participants performed a ramp-incremental cycle exercise test (ICET) and constant work rate cycle test (CWRCT), incremental shuttle walk test (ISWT) and endurance shuttle walk test (ESWT), 6-min walk test (6MWT), and 4-m gait speed test.ResultsOne hundred three participants (mean ± SD age, 67 ± 8 years; 75 male participants [73%]; FEV1, 50.6 ± 16.8% predicted) completed the study. Significant improvements in the ICET, CWRCT, ISWT, ESWT, and 6MWT results were observed after PR (P InterpretationThe ESWT and CWRCT seemed to be the most responsive exercise test protocols to LAMA and PR therapy. The magnitude of change was much greater after a program of rehabilitation compared with bronchodilator therapy.Trial registryISRCTN; No. 64759523