Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials

Mignot, Emmanuel; Mayleben, David; Fietze, Ingo; Léger, Damien; Zammit, Gary; Bassetti, Claudio L.; Pain, Scott; Kinter, Dalma Seboek; Roth, Thomas

doi:10.1016/s1474-4422(21)00436-1

Cited by 135 publications

(219 citation statements)

References 25 publications

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“…A supratherapeutic dose of 100 mg daridorexant was included based on discussions with the FDA and recommendations in the applicable guidelines, to account for potentially higher exposure scenarios in subpopulations (e.g., caused by drug–drug interactions, or reduced clearance) 11 . From a safety perspective, a dose of 100 mg in middle‐aged and elderly subjects was acceptable because in the first‐in‐human study, doses up to 200 mg had been safely administered to healthy subjects, 13 and in the completed phase II/III program a dose of 50 mg was safely administered in the evening without any signs of next‐morning residual effects 17–19 . Daridorexant‐matching tablets for oral administration with the same appearance and weight as daridorexant were used as placebo.…”

Section: Methodsmentioning

confidence: 99%

“…This study was registered in the public registry of the Centrale Commissie Mensgebonden Onderzoek in the Netherlands (NL68520.056. 19) and in clinicaltrials.gov (NCT03892902).…”

Section: Subjectsmentioning

confidence: 99%

“…The orexin system promotes wakefulness by integrating the influence of metabolism, circadian rhythm, and the need to sleep through efferent orexinergic axons projecting to the cerebral cortex and structures involving the brain stem and limbic system 16 . Daridorexant is a potent and selective compound that blocks the actions of the orexin neuropeptides at both orexin‐1 (OX1R) and orexin‐2 (OX2R) receptors, and has shown promising sleep‐promoting effects in phase II studies and in the recently published confirmatory phase III trials 17–19 . As a sleep‐promoting drug, its pharmacokinetic (PK) profile is favorable with rapid absorption (median time to maximum concentration of ~ 1 to 2 hours) and relatively rapid elimination from plasma with a terminal half‐life ( t 1/2 ) of ~ 8 hours 13,14 .…”

mentioning

confidence: 99%

“…No clinically relevant objective or subjective PD effects were present the morning after drug intake. Furthermore, in patients with insomnia, no next‐morning residual effects were observed with daridorexant 50 mg in phase II and phase III studies using subjective and objective assessments 17–19 …”

mentioning

confidence: 99%

“…Furthermore, in patients with insomnia, no next-morning residual effects were observed with daridorexant 50 mg in phase II and phase III studies using subjective and objective assessments. [17][18][19] The US Food and Drug Administration (FDA) has issued a guidance on how to examine the untoward effects of new psychoactive drugs on driving ability. 11 A tiered approach is recommended, including pharmacological, toxicological, epidemiological, and clinical assessments.…”

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confidence: 99%

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Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator

Muehlan

Brooks

Vaillant

et al. 2022

Clin Pharma and Therapeutics

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Use of hypnotics is often associated with next-morning residual effects and a higher risk of motor vehicle accidents. Measuring next-morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male and female subjects (50-79 years of age) were randomized in a placebo-and active-controlled, four-way cross-over study. Each subject received evening administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in separate treatment phases of 4 days. Simulated driving performance was assessed after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard deviation of the lateral position (SDLP) was the main outcome. On both days, with zopiclone, SDLP increased significantly compared with placebo, which confirmed sensitivity of the simulator. With daridorexant, on day 2, the placebo-corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm (0.46-3.93) and 4.43 cm (2.72-6.15) for 50 and 100 mg, respectively. On day 5, SDLP values for both daridorexant doses were significantly below the prespecified threshold of impairment (2.6 cm) and statistically not different from placebo. Daridorexant showed a lower self-rated driving quality and higher effort compared to placebo on day 2 but not on day 5. In non-insomnia subjects, daridorexant impaired simulated driving after initial but not after repeated dosing. Subjects should be cautioned about driving until they know how daridorexant affects them.

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Section: Methodsmentioning

confidence: 99%

“…This study was registered in the public registry of the Centrale Commissie Mensgebonden Onderzoek in the Netherlands (NL68520.056. 19) and in clinicaltrials.gov (NCT03892902).…”

Section: Subjectsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator

Muehlan

Brooks

Vaillant

et al. 2022

Clin Pharma and Therapeutics

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Assessing the Risk of Bias in Randomized Clinical Trials With Large Language Models

Lai,

Ge,

Sun

et al. 2024

JAMA Netw Open

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ImportanceLarge language models (LLMs) may facilitate the labor-intensive process of systematic reviews. However, the exact methods and reliability remain uncertain.ObjectiveTo explore the feasibility and reliability of using LLMs to assess risk of bias (ROB) in randomized clinical trials (RCTs).Design, Setting, and ParticipantsA survey study was conducted between August 10, 2023, and October 30, 2023. Thirty RCTs were selected from published systematic reviews.Main Outcomes and MeasuresA structured prompt was developed to guide ChatGPT (LLM 1) and Claude (LLM 2) in assessing the ROB in these RCTs using a modified version of the Cochrane ROB tool developed by the CLARITY group at McMaster University. Each RCT was assessed twice by both models, and the results were documented. The results were compared with an assessment by 3 experts, which was considered a criterion standard. Correct assessment rates, sensitivity, specificity, and F1 scores were calculated to reflect accuracy, both overall and for each domain of the Cochrane ROB tool; consistent assessment rates and Cohen κ were calculated to gauge consistency; and assessment time was calculated to measure efficiency. Performance between the 2 models was compared using risk differences.ResultsBoth models demonstrated high correct assessment rates. LLM 1 reached a mean correct assessment rate of 84.5% (95% CI, 81.5%-87.3%), and LLM 2 reached a significantly higher rate of 89.5% (95% CI, 87.0%-91.8%). The risk difference between the 2 models was 0.05 (95% CI, 0.01-0.09). In most domains, domain-specific correct rates were around 80% to 90%; however, sensitivity below 0.80 was observed in domains 1 (random sequence generation), 2 (allocation concealment), and 6 (other concerns). Domains 4 (missing outcome data), 5 (selective outcome reporting), and 6 had F1 scores below 0.50. The consistent rates between the 2 assessments were 84.0% for LLM 1 and 87.3% for LLM 2. LLM 1’s κ exceeded 0.80 in 7 and LLM 2’s in 8 domains. The mean (SD) time needed for assessment was 77 (16) seconds for LLM 1 and 53 (12) seconds for LLM 2.ConclusionsIn this survey study of applying LLMs for ROB assessment, LLM 1 and LLM 2 demonstrated substantial accuracy and consistency in evaluating RCTs, suggesting their potential as supportive tools in systematic review processes.

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Exposure–Response Analyses of Polysomnography and Subjective Sleep Efficacy End Points From the Phase 3 Trials of Lemborexant, a Dual Orexin Receptor Antagonist for the Treatment of Insomnia

Lalovic

Landry

Moline

et al. 2023

The Journal of Clinical Pharma

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This report describes polysomnography and sleep diary exposure-response analyses from Study E2006-G000-304 (Study 304), a 1-month trial of 5or 10-mg lemborexant, zolpidem, or placebo; and Study E2006-G000-303 (Study 303), a 6-month trial of 5-or 10-mg lemborexant or placebo. Studies 304 and 303 included 1006 (86%) and 956 (68%) (female) participants, respectively; >40% were ≥65 years, with individual lemborexant exposures derived from a previously described pharmacokinetic model. Linear mixed-effects analyses of polysomnography: latency to persistent sleep (LPS), sleep efficiency (SE), and wake after sleep onset (WASO) quantified the change from baseline given lemborexant exposure, time, and covariates, guided by consensus recommendations regarding clinical significance. A small impact of sex, body weight, and race was predicted for LPS and SE, irrespective of treatment. Effect of age on LPS was small; baseline SE was estimated to be 8% higher for a 50-year-old versus an 80-year-old, decreasing to 6% by 1 month. Baseline WASO was 13 minutes longer for Black versus White subjects, corresponding to a 5-minute lower change from baseline at the end of the study. For subjective end points, the statistically significant covariate effects for age, sex, and race were not deemed therapeutically relevant, likely reflecting physiologic sleep pattern changes across age and study subgroups. Both polysomnography and subjective analyses indicated clinically meaningful differences from baseline for both lemborexant treatments, with effects being greater for 10-mg versus 5-mg lemborexant, while indicating that covariate-specific lemborexant dose adjustments are not warranted.

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Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials

Cited by 135 publications

References 25 publications

Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator

Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator

Assessing the Risk of Bias in Randomized Clinical Trials With Large Language Models

Exposure–Response Analyses of Polysomnography and Subjective Sleep Efficacy End Points From the Phase 3 Trials of Lemborexant, a Dual Orexin Receptor Antagonist for the Treatment of Insomnia

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