348 Absence of Withdrawal Symptoms and Rebound Insomnia Upon Discontinuation of Daridorexant in Patients with Insomnia. (3rd May 2021) - Leger, Damien
Abstract: Introduction: Abrupt discontinuation of sleep medications in patients with insomnia often causes withdrawal symptoms and rebound insomnia. In a Phase 3 program evaluating efficacy and safety of daridorexant on sleep and daytime functioning in patients with insomnia during 3 months of treatment, the risks of withdrawal symptoms and rebound insomnia were evaluated at treatment cessation. Methods: In two randomized, double-blind, 3-month trials, adult (18–64 years) and elderly (≥65) patients with insomnia were assigned (1:1:1) to receive oral daridorexant 25mg, 50mg or placebo (Trial-1, NCT03545191) or 10mg, 25mg or placebo (Trial-2, NCT03575104) every evening. Each trial included a 7-day, single-blind, placebo run-out period following double-blind treatment to evaluate withdrawal symptoms and rebound insomnia. Withdrawal effects were assessed by the change in Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) total score, from last assessment on double-blind treatment to end of placebo run-out, and occurrence of relevant adverse events (AEs). Rebound insomnia was assessed objectively by change in wake-after-sleep-onset (WASO) and latency-to-persistent sleep (LPS), from baseline to first night of placebo run-out, and by subjective total-sleep-time (sTST), from baseline to end of run-out (mean of 7-days). Analyses included all patients who received ≥1 dose of placebo run-out treatment (Trial-1: N=852; Trial-2: N=851). Results: No increase in mean BSWQ score from last assessment on double-blind treatment to end of placebo run-out was reported (Trial-1: 25mg, -0.6±2.3; 50mg, -0.6±2.3; placebo, -0.7±2.3; Trial-2: 10mg, -0.5±2.6; 25mg, -0.4±1.9; placebo, -0.4±1.4). No patients had a BWSQ score >20 at end of run-out. No AEs suggestive of withdrawal symptoms were reported. Mean WASO and LPS values (min) decreased from baseline to placebo run-out (WASO Trial-1: 25mg, -8.6±55.5; 50mg, -2.5±52.4; placebo, -20.4±45.8; Trial-2: 10mg, -11.6±58.3; 25mg, -5.1±57.9; placebo, -26.2±53.5; LPS Trial-1: 25mg, -17.2±56.7; 50mg, -15.0±55.8; placebo, -27.8±47.2; Trial-2: 10mg, -17.3±67.2; 25mg, -10.3±67.3; placebo, -18.3±63.8) while sTST values (min) increased (Trial-1: 25mg, 43.3±53.8; 50mg, 42.9±59.6; placebo, 42.3±52.7; Trial-2: 10mg, 43.3±52.9; 25mg, 46.8±55.4; placebo, 42.3±53.8) indicating absence of rebound effects. Conclusion: Treatment with daridorexant for up to 3-months was not associated with any evidence of drug withdrawal or rebound insomnia upon abrupt discontinuation, indicating no safety concerns for patients should treatment be stopped. Support (if any): Funded by Idorsia Pharmaceuticals Ltd.