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Randomized Controlled Trial
. 2023 Jan;37(1):93-106.
doi: 10.1007/s40263-022-00980-8. Epub 2022 Dec 9.

Long-Term Safety and Tolerability of Daridorexant in Patients with Insomnia Disorder

Dieter Kunz #  1 , Yves Dauvilliers #  2 , Heike Benes  3 , Diego García-Borreguero  4 , Giuseppe Plazzi  5   6 , Dalma Seboek Kinter  7 , Preciosa Coloma  7 , Magdalene Rausch  7 , Mouna Sassi-Sayadi  7 , Stephen Thein  8
Affiliations
Randomized Controlled Trial

Long-Term Safety and Tolerability of Daridorexant in Patients with Insomnia Disorder

Dieter Kunz et al. CNS Drugs. 2023 Jan.

Abstract

Background and objective: Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. In two phase III, 12-week studies in patients with insomnia disorder, daridorexant improved sleep and daytime functioning while maintaining a favorable safety profile. The objective of this 40-week extension study was to assess the long-term safety and tolerability of daridorexant.

Methods: Adults with insomnia disorder who completed the 12-week studies were invited to enroll in this double-blind extension study. Patients originally randomised to daridorexant (10 mg/25 mg/50 mg) remained on their respective treatments; patients randomised to placebo were re-randomised to daridorexant 25 mg or placebo. The 40-week treatment period was followed by a 7-day placebo run-out. The primary objective was to assess safety/tolerability. Exploratory objectives were to evaluate the efficacy of daridorexant on sleep (self-reported total sleep time) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire).

Results: In total, 804 patients were enrolled in the study, of whom 801 received at least one dose of the study treatment and 550 patients (68.4%) completed the study. Overall incidence of treatment-emergent adverse events was similar across groups (35-40%). Daridorexant did not induce next-morning sleepiness and no withdrawal-related symptoms or rebound were observed after treatment discontinuation. Improvements in sleep and daytime functioning were maintained through to the end of the study and were most pronounced with daridorexant 50 mg. Daridorexant 50 mg, compared with placebo, increased self-reported total sleep time by a least-squares mean of 20.4 (95% confidence interval [CI] 4.2, 36.5), 15.8 (95% CI - 0.8, 32.5) and 17.8 (95% CI - 0.4, 35.9) minutes and decreased (i.e., improved) Insomnia Daytime Symptoms and Impacts Questionnaire total scores by a least-squares mean of - 9.3 (95% CI - 15.1, - 3.6), - 9.5 (95% CI - 15.4, - 3.5) and - 9.1 (95% CI - 15.6, - 2.7), at weeks 12, 24 and 36 of the extension study, respectively.

Conclusions: Treatment with daridorexant, for up to 12 months, was generally safe and well tolerated. Exploratory efficacy analyses suggest that the sustained improvements in sleep and daytime functioning with daridorexant 50 mg support its use for long-term treatment of insomnia disorder, without concerns of new safety signals.

Clinical trial registration: ClinicalTrials.gov (NCT03679884) [first posted: 21 September, 2018], https://clinicaltrials.gov/ct2/show/NCT03679884 .

Plain language summary

Insomnia disorder is the long-term inability to fall asleep or stay asleep with a significant impact on daily life. Left inadequately treated, this disorder may increase the risk of other health problems. For patients with insomnia disorder who require a sleep medication, many drugs are not recommended for long-term use and there is an unmet need for one that can be used safely and effectively over the long term. Daridorexant is a new insomnia treatment that was approved for adults following positive results in two 12-week clinical studies. Both studies showed that, in patients with insomnia disorder, daridorexant improved night-time sleep and patients’ ability to function during the day, while avoiding major safety concerns. Patients who completed these two studies could continue into a 40-week extension study enabling the safety and tolerability of daridorexant to be investigated for up to 1 year. Treatment remained double blind for the entire 1-year period. The extension study showed that daridorexant, at all doses studied (10 mg, 25 mg, 50 mg), continued to be generally safe and well tolerated. Patients showed no signs of tolerance, physical dependence, rebound nor any excessive daytime sleepiness. Exploratory efficacy analyses suggest that improved night-time and daytime symptoms of insomnia were sustained, in particular with the highest approved dose, 50 mg, and there were no signs that the benefits of the drug were wearing off at the end of the 1 year. These results support the use of daridorexant 50 mg for the long-term treatment of insomnia disorder in adults.

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Conflict of interest statement

DK has participated in advisory boards from Idorsia; DGB has participated in advisory boards from Idorsia, Roche and received a research grant from MSD; GP has participated in advisory boards from Takeda, Bioprojet, Jazz, Fidia and Idorsia; HB has participated in advisory boards from UCB, Jazz and Idorsia; ST has nothing to disclose; YD participated in advisory boards from UCB, Takeda, Bioprojet, Jazz, Orexia, Avadel and Idorsia; DSK, PC, MR and MS-S are employees of Idorsia Pharmaceuticals Ltd. The IDSIQ was developed by Buysse DJ, Thompson W, Scott J and Franzen PL. Germain A, Hall M, Moul, DE, Nofzinger , EA and Kupfer DJ of the University of Pittsburgh and as amended by Idorsia Pharmaceuticals Ltd. IDSIQ© 2020, University of Pittsburg. All rights reserved. IDSIQ-14 derivative created 2020 by Idorsia Pharmaceuticals Ltd under license and distributed by Idorsia Pharmaceuticals Ltd under license.

Figures

Fig. 1
Fig. 1
Patient disposition. Patients could withdraw from the study (and hence double-blind [DB] treatment) at any time. However, patients who prematurely discontinued DB treatment were not considered withdrawn from the study and could remain in the extension study and continue with all planned study procedures until the end of the study (apart from the placebo run-out). Therefore, the reason for a patient prematurely discontinuing treatment and for discontinuing the study could be different. SB single-blind
Fig. 2
Fig. 2
Mean changes from baselinea in self-reported total sleep time (sTST, minutes) and Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) total score over time from Trial 1. Mean of observed a sTST values and b IDSIQ total scores, at study timepoints in patients who entered the extension study from Trial 1 and received daridorexant 25 mg, daridorexant 50 mg or placebo. Two-sided p values shown are versus placebo, calculated using the linear-effects model for repeated measures. p values are for descriptive purposes only. Grey bars indicate the 7-day placebo run-out periods. Left panel shows the change from baseline over time in the pivotal 12-week study; right panel shows the change over time in the 40-week extension study. Figures do not include the placebo patients who were re-randomised to receive daridorexant 25 mg (ex-placebo/daridorexant 25 mg). aPivotal 12-week study baseline. RO run-out
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