Efficacy and Safety of Daridorexant in Adult and Elderly Patients with Insomnia Dr Tom Roth Division of Sleep Medicine and Research Center, Henry Ford Health System, Detroit, USA
Type of Potential Conflict Details of Potential Conflict Grant/Research Support n Consultant Eisai, Idorsia, jazz, Merck, Takeda, Philips, Novartis ,seq Speakers’ Bureaus Financial support Other 1. Consultancy agreement between the speaker and Idorsia Pharmaceuticals Ltd 2. 3.
Rationale • Daridorexant, a new dual orexin receptor antagonist optimized for onset and duration of action at optimally effective doses, dose-dependently (5–50 mg) improved night- time efficacy, without residual effects, in adult and elderly patients with insomnia in phase 2 1,2 • These pharmacological properties lead us to hypothesize that daridorexant could also improve the impaired daytime functioning frequently observed in insomnia • We therefore developed and validated a new patient-reported outcome instrument to specifically assess daytime functioning in patients with insomnia 1. Dauvilliers et al. Ann Neurol. 2020;87(3):347-56 2. Zammit et al. Neurology 2020;94(21):e2222-32
Objective • This phase 3 trial was designed to measure the impact of daridorexant on objective and subjective sleep parameters as well as on daytime functioning, and to evaluate safety, in patients with moderate to severe insomnia o Sleep variables were assessed using PSG (WASO, LPS) and a sleep diary questionnaire (sTST) o Daytime functioning was assessed using a newly developed and validated patient-reported outcome instrument, the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) LPS, latency to persistent sleep; PSG, polysomnography; sTST, subjective total sleep time; WASO, wake after sleep onset
IDSIQ - Insomnia Daytime Symptoms and Impacts Questionnaire Patient-reported outcome instrument validated according to FDA guidance 1 Measures • Items are ranked on a NRS scale from 0-10 1 Clear-Headed “Alert/cognition” 19:30 2 Concentrate domain score 3 Forgetful (0-60) 4 Worried 11. How mentally tired did you feel today ? 5 Frustrated 6 Irritable “Mood” 7 Stressed domain score Very Not at all 8 Energetic (0-40) mentally mentally tired tired 9 Effort 10 Refreshed 11 Mentally Tired “Sleepiness/Tiredness” 12 Physically Tired • Lower scores indicate improvements in domain score 13 Sleepy patient-perceived daytime functioning (0-40) 14 Awake 1. FDA. 2009. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Available at: NRS, numeric rating scale https://www.fda.gov/media/77832/download (Accessed: 06 July 2020)
Study Design Phase 3, multi-center, double-blind, randomized, placebo-controlled, PSG study Screening 20-31days Treatment Period 84 days Safety Follow-up 30 days Nightly oral DB treatment with placebo or daridorexant 25 mg or 50 mg Daily assessment of sleep and daytime functioning EODBT 1 st month 2 nd month 3 rd month EOS EOT V1 V8 V9 V2 V3 V5 V6 V7 V4 V10 V11 V9 SB SB placebo placebo run-in Placebo run-out (13-24 days) (7 days) Daridorexant 25 mg Daridorexant 50 mg Extension study Randomization (1:1:1) Stratified by age (<65; ≥65 years) Single PSG night Two consecutive PSG nights DB, double-blind; EODBT, end of double-blind treatment; M, month; SB, single-blind; V, visit
Endpoints • Primary efficacy WASO • LPS Type I error rate (5%) was controlled across the primary and secondary endpoints • Secondary efficacy sTST assessed at Month 1 and Month 3 for each active dose (25 and 50 mg) comparison vs • IDSIQ sleepiness domain placebo ( 16 comparisons ) • IDSIQ alert/cognition domain score Other efficacy • IDSIQ mood domain score • Total IDSIQ score • AEs Key safety • AESIs (Adjudicated by ISB), • Next-morning sleepiness (VAS) • Withdrawal (BWSQ) • Rebound insomnia AESI, adverse event of special interest; BWSQ; benzodiazepine withdrawal symptoms questionnaire; ISB, independent safety board; VAS, visual analog scale
Patient Disposition Key entry criteria History of sleep-related breathing disorder Adults (18-64 yr ) and elderly (≥65 yr) Insomnia disorder (DSM-5) History of suicidal ideation/attempt ISI score ≥15 Acute/unstable psychiatric conditions (inc. No other sleep disorder 3326 screened depression) PSG criteria (two consecutive nights) Sleep diary criteria For ≥3 of 7 consecutive nights: Mean LPS ≥20 min (neither night <15 min) ≥30 min to fall asleep Mean WASO ≥30 min (neither night <20 min) 2022 entered run-in Wake time during sleep ≥30 min Mean TST < 7 h Total sleep time ≤6.5 h PLMAI ≥15/h Usual bedtime 21:30–00:30 AHI ≥15/h Time in bed 6–9 h 930 randomized Discontinuation of DB treatment • AE, n=20 • Lost to follow-up, n=5 853* completed • Withdrawal by subject, n=25 • Other, n=8 DB treatment • Lack of efficacy, n=15 • Death, n=1 Discontinuation of SB treatment 847 § completed • AE, n=1 • Other, n=1 run-out • Withdrawal by subject, n=3 * One patient in placebo group and two patients in daridorexant 50 mg group were randomized in error and discontinued from study before receiving DB treatment § One patient did not start run-out treatment AHI, Apnea/hypopnea index; PLMAI, Periodic limb movement disorder with arousal index
Patient Population Daridorexant Daridorexant Placebo 25 mg 50 mg (N=310) (N=310) (N=310) Demographics Female Sex – % 68 69 64 Age – mean ±SD, years 55 ± 15 56 ± 15 56 ± 15 ≥65 – % 39 39 39 Race– % Black or African American 9 6 10 Asian 0 1 1 US region - % 34 32 31 Baseline sleep characteristics, mean ±SD WASO – min 103 ± 41 98 ± 39 96 ± 38 LPS – min 67 ± 40 67 ± 39 64 ± 37 sTST – min 316 ± 53 310 ± 60 313 ± 58 ISI 19 ± 4 19 ± 4 19 ± 4 Baseline daytime characteristics (IDSIQ) , mean ±SD IDSIQ sleepiness domain score (0-40) 22 ± 7 22 ± 7 23 ± 7 IDSIQ alert/cognition domain score (0-60) 32 ± 10 32 ± 10 32 ± 11 IDSIQ mood domain score (0-40) 19 ± 9 19 ± 9 20 ± 9 IDSIQ total score (0-140) 74 ± 25 73 ± 25 75 ± 25
Improvement in WASO Placebo Daridorexant 25 mg Daridorexant 50 mg Two-sided p-values are versus placebo and statistically significant under the control of type I error Mixed effects model for repeated measures adjusted for: baseline value, age group (< 65; ≥ 65 years), treatment, time point, interaction of treatment by visit, and baseline by visit. LSM, least squares mean Analysis set: Full analysis set
Improvement in LPS Placebo Daridorexant 25 mg Daridorexant 50 mg Two-sided p-values are versus placebo and statistically significant under the control of type I error Mixed effects model for repeated measures adjusted for: baseline value, age group (< 65; ≥ 65 years), treatment, time point, interaction of treatment by visit, and baseline by visit. LSM, least squares mean Analysis set: Full analysis set
Improvement in sTST Placebo Daridorexant 25 mg Daridorexant 50 mg Two-sided p-values are versus placebo and statistically significant under the control of type I error Mixed effects model for repeated measures adjusted for: baseline value, age group (< 65; ≥ 65 years), treatment, time point, interaction of treatment by visit, and baseline by visit. LSM, least squares mean Analysis set: Full analysis set
Improvement in IDSIQ Sleepiness/Tiredness Domain Score Placebo Daridorexant 25 mg Daridorexant 50 mg Two-sided p-values are versus placebo and for 50 mg (but not 25 mg), are statistically significant under the control of type I error Mixed effects model for repeated measures adjusted for: baseline value, age group (< 65; ≥ 65 years), treatment, time point, interaction of treatment by visit, and baseline by visit. LSM, least squares mean; NS, non-significant Analysis set: Full analysis set
Improvement in Daytime Function IDSIQ total score, mood domain, and alert/cognition domain Mood domain Total IDSIQ score Alert/cognition domain Placebo Daridorexant 25 mg Daridorexant 50 mg Nominal two-sided p-values (versus placebo) are not under type 1 error rate control (not adjusted for multiplicity) Analysis set: Full analysis set
Overall Safety Adverse events Daridorexant Daridorexant Placebo 25 mg 50 mg No. of patients (%) (N=309) (N=310) (N=308) Patients with ≥1 adverse event 105 (34.0) 117 (37.7) 116 (37.7) Patients with a given adverse event (≥2% in any group) Nasopharyngitis 20 (6.5) 21 (6.8) 20 (6.5) Headache 12 (3.9) 16 (5.2) 19 (6.2) Accidental overdose 5 (1.6) 4 (1.3) 8 (2.6) Fatigue 2 (0.6) 7 (2.3) 7 (2.3) Dizziness 2 (0.6) 6 (1.9) 7 (2.3) Nausea 3 (1.0) 1 (0.3) 7 (2.3) Somnolence 6 (1.9) 11 (3.5) 5 (1.6) Fall 8 (2.6) 1 (0.3) 1 (0.3) Adverse events of special interest (post - adjudication) Symptoms related to excessive daytime sleepiness 1 (0.3) 2 (0.6) 1 (0.3) Symptoms related to complex sleep behavior* 0 2 (0.6) 1 (0.3) Suicidal ideation/self-injury 0 0 0 *including hallucinations/sleep paralysis One fatal SAE (cardiac arrest), not considered treatment-related by investigator (daridorexant 25 mg) Analysis set: Safety set
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