Daridorexant Yields Better Daytime Functioning, Sleep Outcomes in Insomnia Patients

Higher dosage of resulted in better sleep outcomes in patients with insomnia disorder, according to new research.

A team, led by Emmanuel Mignot, MD, Stanford Center for Sleep Research and Medicine, assessed the safety and efficacy of on night-time and daytime symptoms of insomnia.

The Drug

While dual orexin receptor antagonists have shown efficacy treating insomnia disorder, they do not address the entirety of the disease.

The investigators used data from a pair of multicenter, randomized, double-blind, placebo-controlled, phase 3 trials at 156 sites in 17 countries on adults with insomnia disorder between June 4, 2018 and February 25, 2020.

Each patient was randomized to receive either 50 mg (n = 310), 25 mg (n = 310), or placebo (n = 310) in the first study or 25 mg (n = 309), daridorexant 10 mg ( n = 307), or placebo (n = 308) every evening for 3 months.

The investigators sought primary endpoints of the change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), which was measured by polysomnography at months 1 and 3. They also looked at secondary endpoints of the change from baseline in self-reported total sleep time and the sleepiness domain score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) at months 1 and 3.

The investigators also controlled for all pairwise comparisons of study-wise type I error rates and analyzed efficacy in all randomly assigned participants and safety for all participants who received at least 1 treatment dose.

The First Study

In the first study, WASO and LPS was significantly reduced in the daridorexant 50 mg group compared with placebo at month 1 (LSM difference, −22.8 min; 95% CI, −28.0 to −17.6; P <0.0001 for WASO; LSM difference, -11.4 min; 95% CI, −16.0 to −6.7; P <0.0001 for LPS) and month 3 (LSM difference, −18.3 min; 95% CI, −23.9 to −12.7; P <0.0001 for WASO; LSM difference, −11.7 min; 95% CI, −16.3 to −7.0], P<0.0001 for LPS).

This was also found to be true for the daridorexant 25 mg group compared to placebo at month 1 (LSM difference, −12.2 min; 95% CI, −17.4 to −7.0; P <0.0001 for WASO; LSM difference, –8.3 min; 95% CI, −13.0 to −3.6; P = 0.0005 for LPS) and month 3 (LSM difference, −11.9 min; 95% CI, −17.5 to −6.2; P <0.0001 for WASO; LSM difference, −7.6 min; 95% CI, −12.3 to −2.9; P=0.0015 for LPS).

In the daridorexant group, patients had significantly improved self-reported total sleep time at month 1 (LSM difference, 22.1 min; 95% CI, 14.4-29.7; P<0.0001) and month 3 (LSM difference, 19.8 min; 95% CI , 10.6-28.9; P <0.0001) and IDSIQ sleepiness domain scores at month 1 (LSM difference, -1.8; 95% CI, -2.5 to -1.0; P <0.0001) and month 3 (LSM difference, -1.9; 95% CI, -2.9 to -0.9; P=0.0002).

Daridorexant 25 mg resulted in an improvement in self-reported total sleep time at month 1 (LSM difference, 12.6 min; 95% CI, 5.0-20.3; P = 0.0013) and month 3 (LSM difference, 9.9 min; 95% CI, 0.8-19.1; P = 0.033), but not IDSIQ sleepiness domain scores (LSM difference, -0.8; 95% CI, -1.5 to 0.01; P = 0.055 at month 1; LSM difference, -1.0; 95% CI, -2.0 to 0.01; P = 0.053 at month 3) compared to placebo.

The Second Study

The results were similar in the second study, where daridorexant 25 mg significantly reduced WASO compared to placebo at month 1 (LSM difference, −11.6 min; 95% CI, −17.6 to −5.6; P = 0.0001) and month 3 (LSM difference , −10.3 min; 95% CI, −17.0 to −3.5; P = 0.0028). However, there was no significant differences in LPS observed at month 1 (LSM difference, -6.5 min; 95% CI, -12.3 to -0.6; P = 0.030) or month 3 (LSM difference, -9.0; 95% CI, – 15.3 to -2.7; P = 0.0053).

There was also significant improvement in self-reported total sleep time at month 1 (LSM difference, 16.1 min; 95% CI, 8.2-24.0; P <0.0001) and month 3 (LSM difference, 19.1; 95% CI, 10.1-28.0 ; P<0.0001) in the daridorexant 25 mg group compared to placebo.

However, this was not true for IDSIQ sleepiness domain scores (LSM difference, -0.8; 95% CI, -1.6 to 0.1; P = 0.073 at month 1; LSM difference, -1.3; 95% CI, -2.2 to -0.3; P = 0.012 at month 3).

There were also no significant differences found among patients in the daridorexant 10 mg group for WASO (LSM difference, -2.7 min; 95% CI, -8.7 to 3.2; P = 0.37 at month 1; LSM difference, -2.0; 95% CI -8.7 to 4.8; P = 0.57 at month 3), LPS (LSM difference, -2.6 min; 95% CI, -8.4 to 3.2; P = 0.38 at month 1; LSM difference, -3.2 min; 95% CI, –9.5 to 3.1; P = 0.32 at month 3), self-reported total sleep time (LSM difference, 13.4 min; 95% CI, 5.5-21.2; P = 0.0009 at month 1; LSM difference, 13.6 min; 95% CI , 4.7-22.5; P = 0.0028 at month 3), or IDSIQ sleepiness domain scores (LSM difference, -0.4; 95% CI, -1.3 to 0.4; P = 0.30 at month 1; LSM difference, -0.7; 95% CI , -1.7 to 0.2; P = 0.14 at month 3) compared to placebo.

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For safety, the incidence of adverse events was comparable between the different treatment groups (n = 116; 38% daridorexant 50 mg group; n = 117; 38% daridorexant 25 mg group; n = 105; 34% in the placebo group in study 1; n = 121; 39% daridorexant 25 mg group; n = 117; 38% daridorexant 10 mg group; n = 100; 33% in the placebo group).

The most common adverse events in all groups were nasopharyngitis and headaches with 1 death due to cardiac arrest occurring in the daridorexant 25 mg group in the first study that was deemed to not be treatment-related.

“Daridorexant 25 mg and 50 mg improved sleep outcomes, and daridorexant 50 mg also improved daytime functioning, in people with insomnia disorder, with a favorable safety profile,” the authors wrote.

The study, “Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials,” was published online in The Lancet Neurology.

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