Reimbursement Review

Daridorexant (Quviviq)

Sponsor: Idorsia Pharmaceuticals Canada Ltd.

Therapeutic area: Insomnia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

CBT-I = cognitive behavioural therapy for insomnia; CID = chronic insomnia disorder; CYP3A4 = cytochrome P450 3A4; ISI = Insomnia Severity Index; NOC = Notice of Compliance.

Introduction

Insomnia is a sleep disorder characterized by persistent difficulties falling asleep, maintaining sleep, or waking up too early, despite having adequate opportunities to sleep.¹ For a diagnosis of chronic insomnia disorder (CID), symptoms must occur at least 3 times per week for at least 3 months and be present despite adequate conditions for sleep, per the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5).¹ It must also be associated with significant distress or impairment of daytime functioning, and impairment in social, occupational, academic, behavioural, or other important areas of functioning. The consequences of untreated insomnia include decreased work productivity, increased health care use, and a higher risk of accidents. Insomnia is more prevalent in older adults, females, and those with a family history of insomnia or coexisting psychiatric and medical conditions.² Both CID and decreased total sleep time are independent risk factors for suicidal ideation and behaviour.²

Cognitive behavioural therapy for insomnia (CBT-I) is considered a first-line treatment for insomnia;³ however, it is not effective in all patients and has limitations related to adherence and accessibility in Canada.^4-8 Pharmacological treatments, such as benzodiazepines, nonbenzodiazepine gamma-aminobutyric acid (GABA) agonists, and other hypnotics, are frequently used but are associated with adverse effects, including next-day sedation, cognitive impairment, increased risk of falls and accidents, and the potential for tolerance, dependence, and withdrawal symptoms.^9-11 Consensus recommendations for the management of chronic insomnia in Canada, published in October 2024, note that there is a lack of long-term data on the efficacy of these pharmacotherapies; their use is generally recommended for short-term management. The consensus recommendations also note that dual orexin receptor antagonists (DORAs) may have benefits that outweigh their risks for long-term use;¹² however, no DORAs are publicly funded in Canada at the time of this review. A 2023 RAND Europe report estimated that the global prevalence of CID in the general adult population ranges from 6.0% to 14.8% based on data from 7 studies comprising 6 countries in Europe, the UK, and the US.¹³ The report estimated that the prevalence of CID in the general adult population in Canada at the time was 8.8% (95% confidence interval [CI], 5.0% to 12.0%).¹³

Daridorexant (Quviviq) is a DORA that acts on both orexin 1 receptors and orexin 2 receptors and is equipotent on both. The terminal half-life of daridorexant is approximately 8 hours. Tablets of daridorexant are available in 25 mg and 50 mg formats. The recommended dose of daridorexant for adults is 50 mg orally once per night, taken in the evening in the 30 minutes before bedtime, when at least 7 hours remain before planned awakening. For patients with moderate hepatic impairment or who use moderate cytochrome P450 3A4 (CYP3A4) inhibitors, the recommended dose of daridorexant is 25 mg.¹⁴ Daridorexant received a Health Canada Notice of Compliance on April 28, 2023, for the management of adult patients with insomnia that is characterized by difficulties with sleep onset and/or sleep maintenance. The Health Canada indication is broader than the sponsor’s reimbursement request, which is for the treatment of insomnia in adults who have received a diagnosis of CID based on the most recent version of the DSM.¹⁵

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of daridorexant, 25 mg and 50 mg oral tablets, used in the treatment of patients with moderate to severe CID when CBT-I is inappropriate, unavailable, or has failed. CID is characterized by difficulty initiating or maintaining sleep, early awakenings; at least 3 times weekly, lasting a minimum duration of 3 months, and an Insomnia Severity Index (ISI) score of at least 15.

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of input provided to Canada’s Drug Agency (CDA-AMC) by the patient and clinician groups that responded to our call for input and from clinical experts consulted by for the purpose of this review.

Patient Input

CDA-AMC received patient input from 4 groups, including the Gastrointestinal Society, which provided information from meetings with health care experts and researchers, as well as results from surveys conducted on digestive and liver diseases and disorders; Menopause Chicks, which surveyed women aged 45 years to 64 years who were experiencing sleep disruptions; a group of 8 adults in Canada living with CID who represent a range of patient groups; and a joint submission from Mood Disorders Society of Canada (MDSC) and Migraine Canada, which surveyed and interviewed patients with insomnia, including 1 patient with experience with the treatment under review.

The input from the Gastrointestinal Society noted that CID is an independent condition that is also closely linked to a range of comorbidities, including cardiovascular disease, diabetes, obesity, cancer, and gastrointestinal diseases. In the survey conducted by Menopause Chicks, more than 85% of patients surveyed believe the underlying cause of their insomnia to be hormone changes. The input from adults in Canada living with CID stated that the negative effects of CID are often underestimated; impacts on the daily life of those affected are significant, with symptoms including persistent fatigue, difficulty concentrating, physical discomfort (such as joint pain and muscle soreness), a pervasive lack of energy that impedes self-care and routines (i.e., exercise, maintaining household responsibilities, childcare), emotional strain (feelings of frustration and anxiety), and social isolation due to exhaustion. Patients expressed that those around them often fail to understand their struggles, adding to feelings of isolation. They also noted that sleep difficulties exacerbate other health conditions, like migraines and depression, and they often miss time at work, school, or volunteering because of their symptoms. The Gastrointestinal Society noted that beyond the workplace, insufficient sleep can affect an individual’s emotional well-being, behaviour, and interactions, contributing to memory lapses, accidents, injuries, and mood disturbances. In the MDSC and Migraine Canada input, patients reported concerns about the long-term impacts of CID on their mental and physical health. Those patients also noted that partners and family members often endure sleepless nights alongside their loved ones, leading to stress, frustration, and relationship strain.

Pharmacological treatments that patients have used include sedative-hypnotics, GABA agonists, antidepressants, antipsychotics, DORAs (lemborexant), and cannabinoids. Input from Menopause Chicks noted that most patients surveyed were prescribed selective serotonin reuptake inhibitors as a sleep aid. The inputs from adults in Canada living with CID and MDSC and Migraine Canada highlighted that patients also try nonpharmaceutical options, including lifestyle adjustments, strict sleep routines, meditation, and exercise. Because of high unmet needs, some patients also take over-the-counter supplements and drugs, such as antihistamines, melatonin, magnesium, L-theanine, herbal products (e.g., chamomile, lavender, valerian root), and antihistamines (diphenhydramine). Patients reported that these treatment options provide short-term relief, relaxation, and minor sleep support; however, drawbacks include grogginess, impaired functioning, inconsistent results with continued persistent daily fatigue, and high costs. Across the patient group inputs, many patients expressed fear of dependency on medicated sleep aids and concerns about long-term side effects, including potential cognitive impacts, and many patients noted that currently available treatment options do not address the core issue of achieving deep, restorative sleep.

As such, the patient groups emphasized the need for treatments that offer consistent and restorative sleep, reduced or eliminated grogginess, and a low risk of dependency and cognitive side effects. Patients noted that addressing these unmet needs could reduce physical, emotional, and financial strains, as well as offer a better quality of life, through improved sleep and daily functioning. For the 1 patient who reported experience with daridorexant in the MDSC and Migraine Canada input, caregivers reported an improvement in the patient’s ability to fall asleep and stay asleep without any outward signs of next-day side effects.

Clinician Input

Input From Clinical Experts Consulted for This Review

The clinical experts consulted by CDA-AMC for this review noted that, because of the multifactorial nature of CID and its frequent comorbidities, it is important to have a variety of pharmacological and nonpharmacological approaches in addition to CBT-I. The experts agreed that, to improve compliance, there is a need for targeted therapies to address the multiple factors contributing to insomnia (e.g., physiologic, biologic, circadian, psychiatric) that are associated with long-term efficacy, improved tolerance, and fewer adverse effects.

The experts noted that when CBT-I is not helpful or not possible, daridorexant may be a first-line pharmacological option for insomnia disorder. However, the experts noted that deprescribing the traditional sedative-hypnotics poses a challenge, as patients often prefer current treatment options because of their rapid onset of action. As such, transitioning to daridorexant may be difficult, as DORAs may take 4 weeks to 8 weeks to demonstrate results.

Per the clinical experts, patients with CID, especially those who may have significant functional impairment, would benefit the most from new treatments such as daridorexant, whereas other drugs might be more appropriate for patients with comorbid conditions such as chronic pain or depression. The experts suggested using DORAs preferentially in patients for whom minimizing adverse effects is a priority, given their favourable side-effect profile. Narcolepsy would be an absolute contraindication for DORAs.

The clinical experts mentioned that response to treatment is usually assessed with the patient’s impression of improvement in sleep quality, sleep quantity, daytime functioning, and other symptoms. They noted that patients will likely have their own subjective standard of what they would define as an adequate benefit from treatment. The clinical experts also noted that optimal treatment response to daridorexant may not be observed until 8 weeks of treatment. As such, patients may opt to discontinue treatment because of lack of efficacy. Adverse effects (e.g., hallucinations; vivid, disturbing dreams; suicidality) that outweigh any potential benefits are also potential reasons for the discontinuation of treatment.

Clinician Group Input

Twelve clinician submissions provided input for this review, including from the Mood Disorders Research and Treatment Service, the Family Physician Airways Group of Canada, the Canadian Consortium of Sleep and Sleep Interested Physicians, the Synergy Medical Clinic, and MedSleep, as well as from psychiatrists in British Columbia and Quebec, family physicians, a neurologist, and an inpatient mental health pharmacist. All contributors had experience working with patients diagnosed with CID. The input stated that current treatment options for insomnia include nonpharmacological therapies, such as sleep hygiene and CBT-I, which can be costly and have limited availability in Canada. The input stated that pharmacological options, particularly GABA agonists, are only prescribed for short-term use, are limited by poor efficacy and next-day sedation, often require dose escalation, can lead to dependence or nonresponse, can lead to withdrawal symptoms upon discontinuation, and are associated with cognitive side effects. In addition, there are limited or no clinical data supporting their use for patients with CID. As such, to improve patient outcomes, the clinician submissions noted that there is a need for treatments that improve daytime functioning and are tolerable, affordable, and safe.

The clinician input highlighted the unique mechanism of action of daridorexant, which reduces wakefulness without causing sedation. Daridorexant would be used in the first-line setting for CID, after CBT-I or when CBT-I is not suitable, according to the input. With regard to assessing response to treatment, the clinician groups noted that, given the prevalence of insomnia in Canada and limited resources, frequent polysomnograms are not practical for use in clinical practice. Some of the clinician groups highlighted the use of the ISI screening tool and other patient-reported outcomes used in research to assess treatment response; however, the clinical experts consulted for this review noted that the ISI tool may not be used commonly in Canadian clinical practice. The clinician groups noted that a clinically meaningful response to treatment includes improved next-day functioning, improved duration and quality of sleep, and a reduction in ISI score. Potential reasons for discontinuing treatment include side effects such as reduced daytime functioning, nightmares, and sleep paralysis. Various clinicians agreed that daridorexant would be particularly suitable for patients at risk for drug dependence or abuse and for older patients, given the unsuitability of many other drugs because of the potential for cognitive impairment and falls. The clinicians agreed with the clinical experts consulted for this review that daridorexant would likely be prescribed by primary care physicians in outpatient settings, and that no specific dependence or rebound issues would need to be addressed for patients discontinuing daridorexant.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues: relevant comparators, initiation of therapy, continuation or renewal of therapy, discontinuation of therapy, prescribing of therapy, and care provision issues. Refer to Table 4 for details.

Clinical Evidence

Systematic Review

Description of Studies

Two phase III, double-blind, placebo-controlled, randomized trials — Study 301 (N = 930) and Study 302 (N = 617) — were included in this review. Both studies were designed to assess the efficacy and safety of daridorexant (50 mg and 25 mg in Study 301, and 25 mg in Study 302) in adult patients with CID after month 1 and month 3 of treatment. The primary outcomes in the included trials were change from baseline in sleep maintenance (wakefulness after sleep onset [WASO]) and sleep onset (latency to persistent sleep [LPS]), measured objectively with polysomnography (PSG). Other outcomes relevant to the current review were change from baseline in sleep duration (subjective total sleep time [sTST]), sleep quality, daytime functioning, ISI score, total sleep time (TST) for each sleep stage, and safety.

Both studies enrolled adult patients with moderate to severe CID, based on DSM-5 criteria. Patients with specific comorbid conditions were excluded, such as those with acute or unstable psychiatric conditions, suicidal ideation with intent, alcohol or drug abuse, any lifetime history of suicide attempt, sleep-related breathing disorders, or narcolepsy. Patients who were unable or unwilling to discontinue concomitant use of moderate CYP3A4 inhibitors were also excluded from the trials. The baseline characteristics of the patients enrolled in Study 301 and Study 302 were generally similar across treatment groups, with a mean age of 55.1 years (standard deviation [SD] = 15.4 years) to 56.7 years (SD = 14.1 years) in the 2 studies. Most patients identified as white (86.7% to 92.6%), 6.0% to 9.7% identified as Black or African American, and 0.6% to 3.6% identified as Asian. In both studies, CBT-I was rarely used; only 3 patients in Study 301 received CBT-I at screening.

Efficacy Results

Sleep Maintenance

Sleep maintenance, reported as change from baseline in WASO, was 1 of the primary outcomes in Study 301 and Study 302. In Study 301, the mean WASO at baseline was 95.48 minutes (SD = 37.81 minutes) in the daridorexant 50 mg arm, 97.87 minutes (SD = 38.77 minutes) in the daridorexant 25 mg arm, and 102.51 minutes (SD = 40.77 minutes) in the placebo arm. At month 1, the least squares mean (LSM) change from baseline in WASO was –28.98 minutes (95% CI, –32.67 to –25.30 minutes), –18.40 minutes (95% CI, –22.13 to –14.67 minutes), and –6.20 minutes (95% CI, –9.93 to –2.48 minutes) in the daridorexant 50 mg, daridorexant 25 mg, and placebo groups, respectively. The LSM difference in change from baseline in WASO at 1 month compared to placebo was –22.78 minutes (97.5% CI, –28.75 to –16.82 minutes) in favour of daridorexant 50 mg and was –12.20 minutes (97.5% CI, –18.19 to –6.21 minutes) in favour of daridorexant 25 mg. At month 3, the LSM change from baseline was –29.41 minutes (95% CI, –33.40 to –25.43 minutes) in the daridorexant 50 mg arm, –22.97 minutes (95% CI, –26.96 to –18.99 minutes) in the daridorexant 25 mg arm, and –11.11 minutes (95% CI, –15.13 to –7.09 minutes) in the placebo arm. The LSM difference in change from baseline in WASO compared to placebo was –18.3 minutes (97.5% CI, –24.76 to –11.85 minutes) in favour of daridorexant 50 mg and was –11.86 minutes (97.5% CI, –18.30 to –5.42 minutes) in favour of daridorexant 25 mg.

In Study 302, the mean WASO at baseline was 106.31 minutes (SD = 49.10) in the daridorexant 25 mg arm and 108.07 minutes (SD = 48.71 minutes) in the placebo arm. At month 1, the LSM change from baseline was –24.19 minutes (95% CI, –28.47 to –19.91 minutes) for daridorexant 25 mg and –12.57 minutes (95% CI, –16.82 to –8.32 minutes) for placebo, corresponding to an LSM difference of –11.62 minutes (95% CI, –17.60 to –5.63 minutes) in favour of daridorexant 25 mg. Results of the subgroup analysis showed that in male patients, there was no difference between groups (mean difference = 3.94; 95% CI, –13.58 to 5.69). At month 3, the LSM change from baseline in the daridorexant 25 mg arm was –24.25 minutes (95% CI, –29.02 to –19.47 minutes) and in the placebo arm was –10.25 minutes (95% CI, –16.95 to –3.55 minutes), representing an LSM difference of –14.00 minutes (97.5% CI, –18.76 to –9.24 minutes) in favour of daridorexant 25 mg.

Sleep Onset

Sleep onset, reported as change from baseline in LPS, was 1 of the primary outcomes in Study 301 and Study 302. In Study 301, the mean LPS at baseline was 63.62 minutes (SD = 37.39 minutes) in the daridorexant 50 mg arm, 67.27 minutes (SD = 38.56 minutes) in the daridorexant 25 mg arm, and 66.54 minutes (SD = 39.77 minutes) in the placebo arm. At month 1, the LSM change from baseline in LPS was –31.20 minutes (95% CI, –34.51 to –27.90 minutes) in the daridorexant 50 mg arm, –28.17 minutes (95% CI, –31.51 to –24.83 minutes) in daridorexant 25 mg group, and –19.85 minutes (95% CI, –23.18 to –16.52 minutes) in the placebo group. The LSM difference in change from baseline in LPS at 1 month compared to placebo was –11.35 minutes (97.5% CI, –16.694 to –6.015 minutes) in favour of daridorexant 50 mg and –8.32 minutes (97.5% CI, –13.69 to –2.96 minutes) in favour of daridorexant 25 mg. At month 3, the LSM change from baseline in LPS was –34.80 minutes (95% CI, –38.12, to –31.49 minutes) in the daridorexant 50 mg arm, –30.73 minutes (95% CI, –34.04 to –27.41 minutes) in the daridorexant 25 mg arm, and –23.13 minutes (95% CI, –26.46 to –19.80 minutes) in the placebo arm. The LSM difference in change from baseline in LPS at 3 months compared to placebo was –11.67 minutes (97.5% CI, –17.03 to –6.32 minutes) in favour of daridorexant 50 mg and was –7.59 minutes (97.5% CI, –12.94 to –2.25 minutes) in favour of daridorexant 25 mg.

In Study 302, the mean LPS at baseline was 68.88 minutes (SD = 40.55 minutes) in the daridorexant 25 mg arm and 71.82 minutes (SD = 46.09 minutes) in the placebo arm. At month 1, the LSM change from baseline was –26.46 minutes (95% CI, –30.63 to –22.29 minutes) in the daridorexant 25 mg arm and –20.01 minutes (95% CI, –24.15 to –15.88 minutes) in the placebo arm, corresponding to an LSM difference of –6.45 minutes (95% CI, 12.28, to –0.61 minutes) in favour of daridorexant 25 mg. At month 3, the LSM change from baseline was –28.91 minutes (95% CI, –33.41 to –24.40 minutes) in the daridorexant 25 mg arm and –19.89 minutes (95% CI, –24.38 to –15.41 minutes) in the placebo arm, representing an LSM difference of –9.01 minutes (97.5% CI, –15.34 to –2.68 minutes) in favour of daridorexant 25 mg.

Sleep Duration

Sleep duration, measured subjectively, was reported as change from baseline in sTST was a secondary outcome in Study 301 and Study 302.

In Study 301, the mean sTST at baseline was 313.18 minutes (SD = 57.60 minutes) in the daridorexant 50 mg arm, 309.85 minutes (SD = 60.11 minutes) in the daridorexant 25 mg arm, and 315.89 minutes (SD = 53.14 minutes) in the placebo arm. At month 1, the LSM change from baseline in sTST was 43.62 minutes (95% CI, 38.17 to 49.06 minutes) in the daridorexant 50 mg arm, 34.18 minutes (95% CI, 28.72 to 39.65 minutes) in the daridorexant 25 mg arm, and 21.56 minutes (95% CI, 16.10 to 27.02 minutes) in the placebo arm. The LSM difference in change from baseline in sTST at 1 month compared to placebo was 22.06 minutes (97.5% CI, 13.30 to 30.18 minutes) in favour of daridorexant 50 mg and 12.62 minutes (97.5% CI, 3.85 to 21.39 minutes) in favour of daridorexant 25 mg. At month 3, the LSM change from baseline was 57.67 minutes (95% CI, 51.17 to 64.17 minutes) in the daridorexant 50 mg arm, 47.83 minutes (95% CI, 41.33 to 54.33 minutes) in the daridorexant 25 mg arm, and 37.90 minutes (95% CI, 31.39 to 44.40) in the placebo arm, representing an LSM difference of 19.77 minutes (97.5% CI, 9.30 to 30.24 minutes) in favour of daridorexant 50 mg and 9.93 minutes (97.5% CI, –0.54 to 20.40 minutes) in favour of daridorexant 25 mg.

In Study 302, the mean sTST at baseline was 308.49 minutes (SD = 52.85 minutes) in the daridorexant 25 mg arm and 307.57 minutes (SD = 51.52 minutes) in the placebo arm. At month 1, the LSM change from baseline in sTST was 43.77 minutes (95% CI, 38.14 to 49.41) in the daridorexant 25 mg arm and 27.64 minutes (95% CI, 22.02 to 33.27 minutes) in the placebo arm. The mean change from baseline in sTST was 16.13 minutes longer with daridorexant 25 mg than with placebo (95% CI, 8.22 to 24.04 minutes). At month 3, the LSM change from baseline in sTST was 56.18 minutes (95% CI, 49.81 to 62.55 minutes) in the daridorexant 25 mg arm and 37.12 minutes (95% CI, 30.78 to 43.46 minutes) in the placebo arm, representing an LSM difference of 19.06 minutes (95% CI, 10.13 to 27.99 minutes) in favour of daridorexant 25 mg.

Sleep Quality

Sleep quality was determined with the Sleep Diary Questionnaire (SDQ) and was considered an exploratory outcome in the included studies. In Study 301, the mean visual analogue scale (VAS) score for sleep quality at baseline was 36.23 (SD = 17.03) in the daridorexant 50 mg arm, 35.56 (SD = 17.77) in the daridorexant 25 mg arm, and 35.60 (SD = 17.78) in the placebo arm. At month 1, the mean change from baseline was 14.21 points (SD = 18.95 points) in the daridorexant 50 mg arm, 11.35 points (SD = 15.65 points) in the daridorexant 25 mg arm, and 7.04 points (SD = 13.74 points) in the placebo arm. At month 3, the mean change from baseline was 20.21 points (SD = 22.15 points) in the daridorexant 50 mg arm, 18.20 (SD = 19.10 points) in the daridorexant 25 mg arm, and 13.95 points (SD = 18.85 points) in the placebo arm.

In Study 302, the mean VAS sleep quality score at baseline was 37.94 (SD = 15.02) in the daridorexant 25 mg arm and 36.91 (SD = 14.77) in the placebo arm. At month 1, the mean change from baseline was 11.20 points (SD = 15.55 points) in the daridorexant 25 mg arm and 9.41 points (SD = 14.44 points) in the placebo arm. At month 3, the mean change from baseline was 17.77 points (SD = 18.55 points) in the daridorexant 25 mg arm and 13.18 points (SD = 17.33 points) in the placebo arm.

Change From Baseline in IDSIQ Total Score

In Study 301, the mean Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) total score at baseline was 74.52 points (SD = 25.16 points) in the daridorexant 50 mg arm, 73.06 points (SD = 24.55 points) in the daridorexant 25 mg arm, and 73.55 points (SD = 24.64 points) in the placebo arm. At month 1, the LSM difference in change from baseline in IDSIQ total score compared to placebo was –7.24 points (95% CI, –9.785 to –4.698 points) in favour of daridorexant 50 mg and –2.94 points (95% CI, –5.487 to –0.385 points) in favour of daridorexant 25 mg. At month 3, the LSM difference between groups compared to placebo was –7.20 points (95% CI, –10.544 to –3.862 points) in favour of daridorexant 50 mg and –3.46 points (95% CI, –6.809 to –0.113 points) in favour of daridorexant 25 mg.

In Study 302, the mean IDSIQ total score at baseline was 73.14 points (SD = 21.21 points) in the daridorexant 25 mg arm and 74.48 points (SD = 20.26 points) in the placebo arm. At month 1, the mean difference from baseline was 3.11 points (95% CI, –5.807 to –0.412 points) lower in the daridorexant arm than in the placebo arm. At month 3, the IDSIQ total score was 4.23 points (95% CI, –7.477 to –0.986 points) lower in the daridorexant 25 mg arm than in the placebo arm.

Change From Baseline in ISI Score

The change from baseline in ISI score was an exploratory outcome in the included trials. In Study 301, the mean ISI score at baseline was 19.3 points (SD = 4.0 points) in the daridorexant 50 mg arm, 19.0 points (SD = 4.3 points) in the daridorexant 25 mg arm, and 19.2 points (SD = 4.0 points) in the placebo arm. At month 1, the LSM change from baseline was –4.81 points (95% CI, –5.36 to –4.26 points) in the daridorexant 50 mg arm, –4.07 points (95% CI, –4.63 to –3.51 points) in the daridorexant 25 mg arm, and –3.05 points (95% CI, –3.60 to –2.50 points) in the placebo arm. Compared to placebo, there was a decrease in ISI score of –1.76 points (95% CI, –2.54 to –0.99 points) in the daridorexant 50 mg arm and –1.02 points (95% CI, –1.80 to –0.24 points) in the daridorexant 25 mg arm. At month 3, the LSM change from baseline was –7.17 points (95% CI, –7.84 to –6.50 points) in the daridorexant 50 mg arm, –6.02 points (95% CI, –6.69 to –5.35 points) in the daridorexant 25 mg arm, and –5.19 points (95% CI, –5.86 to –4.52 points) in the placebo arm. Compared to placebo, there was a decrease in ISI score of –1.98 points (95% CI, –2.92 to –1.04 points) in the daridorexant 50 mg arm and –0.83 points (95% CI, –1.78 to 0.11 points) in the daridorexant 25 mg arm.

In Study 302, the mean ISI score at baseline was 19.5 points (SD = 4.0 points) in the daridorexant 25 mg arm and 19.6 points (SD = 4.1 points) in the placebo arm. At month 1, the mean change in ISI score from baseline was –5.1 points (SD = 5.2 points) in the daridorexant 25 mg arm and –3.8 points (SD = 4.6 points) in the placebo arm. At month 3, the mean change from baseline in ISI score was –6.9 points (SD = 6.0 points) in the daridorexant 25 mg arm and –5.4 points (SD = 5.5 points) in the placebo arm.

Change From Baseline in Duration of TST in Each Sleep Stage

The change from baseline in duration of TST in each sleep stage (i.e., stage 1 [S1], stage 2 [S2], slow-wave sleep [SWS], and rapid eye movement [REM]) was an exploratory end point in the included trials.

In Study 301, for S1 at month 1, the change from baseline was 5.41 minutes in the daridorexant 50 mg arm, 4.26 minutes in the daridorexant 25 mg arm, and 2.59 minutes in the placebo arm. For S2 at month 1, the change from baseline was 34.74 minutes in the daridorexant 50 mg arm, 29.79 minutes in the daridorexant 25 mg arm, and 16.10 minutes in the placebo arm. For SWS at month 1, the change from baseline was 2.16 minutes in the daridorexant 50 mg arm, 0.71 minutes in the daridorexant 25 mg arm, and1.60 minutes in the placebo arm. For REM at month 1, the change from baseline was 15.51 minutes in the daridorexant 50 mg arm, 13.50 minutes in the daridorexant 25 mg arm, and 9.22 minutes in the placebo arm. For S1 at month 3, the change from baseline was 6.89 minutes in the daridorexant 50 mg arm, 5.67 minutes in the daridorexant 25 mg arm, and 4.51 minutes in the placebo arm. For S2 at month 3, the change from baseline was 37.69 minutes in the daridorexant 50 mg arm, 36.19 minutes in the daridorexant 25 mg arm, and 25.07 minutes in the placebo arm. For SWS at month 3, the change from baseline was –0.20 minutes in the daridorexant 50 mg arm, 0.20 minutes in the daridorexant 25 mg arm, and –1.54 minutes in the placebo arm. For REM at month 3, the change from baseline was 16.21 minutes in the daridorexant 50 mg arm, 12.55 minutes in the daridorexant 2,550 mg arm, and 11.65 minutes in the placebo arm.

In Study 302, for S1 at month 1, the change from baseline was 3.64 minutes in the daridorexant 25 mg arm and 1.81 minutes in the placebo arm. For S2 at month 1, the change from baseline was 31.54 minutes in the daridorexant 25 mg and 24.09 minutes in the placebo arm. For SWS at month 1, the change from baseline was 0.45 minutes in the daridorexant 25 mg arm and 0.90 minutes in the placebo arm. For REM at month 1, the change from baseline was 14.19 minutes in the daridorexant 25 mg arm and 7.31 minutes in the placebo arm. For S1 at month 3, the change from baseline was 5.46 minutes in the daridorexant 25 mg arm and 2.10 minutes in the placebo arm. For S2 at month 3, the change from baseline was 31.36 minutes in the daridorexant 25 mg arm and 25.45 minutes in the placebo arm. For SWS at month 3, the change from baseline was –0.91 minutes in the daridorexant 25 mg arm and 0.65 minutes in the placebo arm. For REM at month 3, the change from baseline was 13.86 minutes in the daridorexant 25 mg arm and 6.94 minutes in the placebo arm.

Harms Results

The overall incidence of treatment-emergent adverse events (TEAEs) in Study 301 was generally similar across groups, affecting 41.3% of patients in the daridorexant 25 mg arm, 39.3% in the daridorexant 50 mg arm, and 37.2% in the placebo arm. The most common TEAEs in the daridorexant 25 mg, daridorexant 50 mg, and placebo arms were nasopharyngitis (9.0% versus 7.8% versus 7.8%) and headache (5.5% versus 6.5 versus 3.9%). Serious adverse events (SAEs) were experienced by 2 (0.6%) patients in the daridorexant 25 mg arm, 3 (1.0%) patients in the daridorexant 50 mg arm, and 7 (2.3%) patients in the placebo arm. Adverse events (AEs) leading to withdrawals were reported for 7 patients (2.3%) in the daridorexant 25 mg arm, 3 patients (1.0%) in the daridorexant 50 mg arm, and 10 patients (3.2%) in the placebo arm. One patient died from a myocardial infarction, although it was not considered to be related to treatment.

In Study 302, the overall incidence of TEAEs was similar in the daridorexant 25 mg arm and the placebo arm (41.2% versus 36.3%). The most common TEAEs in the daridorexant 25 mg arm and the placebo arm were nasopharyngitis (4.2% versus 6.5%) and headache (5.2% versus 3.6%). SAEs were reported in 3 patients (1%) in the daridorexant 25 mg arm and 4 patients (1.3%) in the placebo arm. Four patients (1.3%) in the daridorexant 25 mg arm and 7 patients (2.3%) in the placebo arm stopped treatment because of AEs. No deaths were reported in Study 302.

Critical Appraisal

Study 301 and Study 302 were multicentre, double-blind, phase III, randomized controlled trials (RCTs). The randomization and allocation concealment processes used in the studies were judged to be appropriate. Treatment allocation was stratified by age (< 65 years or ≥ 65 years), which, according to the clinical experts consulted for this review, is a clinically important variable, particularly with regard to harms (i.e., morning sedation and night dizziness) and the risk of injury from a fall. Overall, baseline characteristics were generally balanced and similar in the treatment groups in both studies. Treatment discontinuations were relatively infrequent (7.1% to 9.0% in Study 301 and 5.8% to 7.4% in Study 302), and most of the patients in Study 301 and Study 302 completed the double-blinded treatment period; thus, the risk of attrition bias was considered low. In both studies, the overall rate of missing data was low (< 10% missing) for all relevant outcomes. Low overall missingness and balanced discontinuation rates across groups reduced concerns related to this potential overestimation, but do not completely rule out bias from informative missingness. Sensitivity analyses using multiple imputation under missing-not-at-random assumptions further supported the robustness of results, as statistical significance was maintained even under conservative imputations. Therefore, any impact of bias because of missing data on the study results was likely low. Multiplicity adjustment using alpha-splitting was conducted for primary and secondary outcomes to control for type I error. Other outcomes (e.g., other efficacy outcomes and exploratory outcomes) were not adjusted for multiplicity, so there is an increased risk of false-positive conclusions in statistically significant results. The primary outcomes in both studies were objectively measured using PSG during sleep studies, and subjectively measured outcomes were captured using patient self-assessment of sleep or validated questionnaires. Although PSG provides objective data on sleep parameters and is less prone to reporting bias, results may not fully capture real-world sleep patterns. Sleep disturbances related to the sleep-study setting may alter sleep architecture and limit the accuracy and generalizability of PSG results. According to the clinical experts consulted for this review, self-reporting of a patient’s sleep may not align with the more objective measures. The experts noted, for example, that patients with insomnia have been shown to overestimate the time taken to fall asleep (sleep onset latency) and underestimate total sleeping time. The clinical experts emphasized that insomnia is largely a subjective condition and that sleep complaints are very individualized; therefore, self-reported sleep quality and perceived changes in a patient’s sleep may be more clinically meaningful than PSG-derived metrics. However, subjective measures may be more prone to bias, including recall bias and placebo effects, that cannot be easily measured or accounted for, making it difficult to determine the true magnitude and certainty of treatment effects. Thresholds of clinical significance for all relevant outcomes, except for sleep quality on VAS, were provided by the sponsor. According to the clinical experts consulted for this review, these provided thresholds were clinically relevant and acceptable.

There were several limitations in the included studies that could affect the generalizability of results to the clinical setting in Canada. In both studies, most patients who were screened for the trials failed (72.4% in Study 301 and 74.9% in Study 302). The most common reason for screening failure was not meeting the inclusion or exclusion criteria, although the submission did not provide any details on the exact criteria that were failed during screening. Patients who did not meet specific sleep parameters on PSG and those with comorbidities (e.g., acute or unstable psychiatric conditions) were excluded. According to the clinical experts, PSG or other sleep studies are not used to diagnose CID and are not routinely performed in clinical settings for patients with CID. Also, patients who were excluded because of comorbidities could have otherwise been potential candidates for treatment with daridorexant. Thus, the screening process may have led to a study population that does not reflect the broader population with CID in Canada, thereby limiting the generalizability of the results. Although mean age, duration of disease, and distribution of sex in the study populations were consistent with Canadian settings, the clinical experts noted that the proportion of Asian patients were considerably lower in the 2 studies (especially Study 301) than in Canadian settings. It is unclear whether this could affect the study results beyond cultural differences related to sleep among different racial groups. According to the Health Canada product monograph, daridorexant is contraindicated for patients who use strong CYP3A4 inhibitors, although daridorexant 25 mg is indicated for patients receiving moderate CYP3A4 inhibitors (or those with moderate hepatic impairment). However, the use of moderate or strong CYP3A4 inhibitors was prohibited during the studies, and patients unwilling or unable to discontinue those medications were excluded from both studies. Therefore, any interpretation of efficacy or harms results in the daridorexant 25 mg treatment group presents a challenge. Several medications, including concomitant pharmacological treatments for insomnia or other central nervous system (CNS)-related medications, were prohibited in the studies. According to the clinical experts, patients with CID seen in Canadian clinical settings would often be taking 1 or more CNS-related medications prohibited in the studies. Although only a minority of patients in Canada receive CBT-I as first-line therapy, the clinical experts noted that the proportion would likely be higher than that observed in the trials (n = 3 [0.3%] in Study 301 and n = 0 in Study 302). As previously noted, sleep studies are not used in clinical settings to diagnose or assess insomnia; instead, patients are usually interviewed about their sleep and how they feel. Additionally, subjective measures used in the studies, such as IDSIQ, ISI, and SDQ, are not routinely used in clinical practice, per the clinical experts consulted for this review.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for Grading of Recommendations Assessment, Development and Evaluation (GRADE) was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• efficacy outcomes (sleep maintenance, sleep onset, sleep duration, sleep quality)

• harms outcomes (SAEs).

Table 2: Summary of Findings for Daridorexant 50 mg vs. Placebo for Patients With CID

CI = confidence interval; CID = chronic insomnia disorder; LPS = latency to persistent sleep; LSM = least squares mean; NA = not applicable; NR = not reported; RCT = randomized controlled trial; SAE = serious adverse event; SD = standard deviation; sTST = subjective total sleep time; VAS = visual analogue scale; vs. = versus; WASO = wake after sleep onset.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aAfter hypothesis-testing adjustment for multiplicity, the alpha or threshold of significance was estimated to be 0.025. Thus, 97.5% CIs are reported for these between-group differences.

^bRated down once for serious indirectness. The outcomes were measured using polysomnography (PSG). According to the clinical experts, PSG is not used in clinical settings to assess the efficacy of treatment. The external validity of the trial is limited by the large number of patients excluded at screening.

^cRated down once for serious imprecision. Based on a minimal important difference (MID) threshold of 20 minutes, the point estimate of the effect and the 97.5% CI includes the possibility of a trivial effect as well as a nontrivial effect.

^dRated down once for serious imprecision. Based on an MID threshold of 10 minutes, the point estimate of the effect is larger than the threshold, but the 97.5% CI includes the possibility of a trivial effect as well as a nontrivial effect.

^eRated down once for serious indirectness. The outcome was self-reported. Clinical experts confirmed that patients are likely to underestimate one’s own duration of sleep. The external validity of the trial is also limited by the large number of patients excluded at screening.

^fRated down once for serious imprecision. Based on an MID threshold of 30 minutes, the point estimate of the effect, as well as the 97.5% CI, includes the possibility of a trivial effect as well as a nontrivial effect.

^gAnalysis of this outcome was not adjusted for multiplicity; the results are considered to be supportive evidence.

^hRated down once for serious indirectness. Rated down twice for very serious imprecision. The absolute difference between the groups, with CIs, was unavailable. The MID threshold for this outcome is unclear.

ⁱEven though the external validity of the trial is limited by the large number of patients excluded at screening, not rated down for indirectness.

^jRated down once for serious imprecision. The number of events did not meet the optimal information size.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence, Clinical Study Reports for Study 301¹⁶ and Study 302,¹⁷ and additional information provided by the sponsor.

Long-Term Extension Study

Description of Study

Study 303 was a 40-week, long-term extension (LTE) study (N = 804) that assessed the safety and tolerability of daridorexant in adult and older patients with CID. It was a multicentre, double-blind, placebo-controlled trial conducted at 94 sites in 14 countries, including 7 in Canada. Patients who completed Study 301 or Study 302 were eligible, and patients who had previously received placebo were rerandomized to continue placebo or to receive daridorexant 25 mg. In total, there were 137 patients receiving daridorexant 50 mg (all from Study 301), 270 receiving daridorexant 25 mg (132 from Study 301 and 138 from Study 302), and 255 patients receiving placebo, who were rerandomized in a 1:1 ratio to either daridorexant 25 mg (N = 127 [66 from Study 301 and 61 from Study 302], termed the ex-placebo to daridorexant 25 mg arm) or placebo (N = 128). Study 303 also included a daridorexant 10 mg arm (N = 142), though daridorexant 10 mg is not a Health Canada–approved dose and was not summarized within this report. A 30-day safety follow-up period assessed AEs and medications. Of the 662 patients in the 4 relevant treatment groups, 459 (69.3%) completed the study. Demographic and most baseline characteristics were balanced across treatment groups, consistent with prior studies.

Efficacy Results

Change From Baseline in sWASO

Throughout the extension study, mean subjective wake after sleep onset (sWASO) reductions from baseline were maintained across treatment groups. At week 36, LSM differences between the treatment and placebo groups in the change in sWASO from the confirmatory study baseline was –2.01 minutes (95% CI, –14.71 to 10.68 minutes; P = 0.7554) in the daridorexant 50 mg group and –1.51 minutes (95% CI, –12.65 to 9.62 minutes; P = 0.5148) in the daridorexant 25 mg group.

Change From Baseline in sLSO

In the extension study, mean reductions in subjective latency to sleep onset (sLSO) from baseline were observed in all treatment groups, with numerically greater improvements in the active treatment groups than in the placebo groups. At week 36, compared to placebo, the LSM treatment difference in sLSO from confirmatory study baseline was –9.19 minutes (95% CI, –18.45 to 0.07 minutes; P = 0.0517) in the daridorexant 25 mg group and –8.76 minutes (95% CI, –19.34 to 1.82 minutes; P = 0.1044) in the 50 mg group.

Change From Baseline in sTST

In the extension study, changes in sTST from confirmatory study baseline were numerically greater in the daridorexant groups than in the placebo group, with the most pronounced change in the 50 mg group. At week 36, compared to placebo, the LSM treatment difference in sTST was 17.77 minutes (95% CI, –0.35 to 35.90 minutes; P = 0.0546) in the daridorexant 50 mg group and 5.26 minutes (95% CI, –10.59 to 21.11 minutes; P = 0.5148) in the daridorexant 25 mg group.

ISI Score

At week 40, the mean change in ISI score was –9.8 in the daridorexant 50 mg group, –8.5 in the daridorexant 25 mg group, –4.3 in the ex-placebo to daridorexant 25 mg group, and –7.5 in the placebo group. A 6-point or greater decrease in ISI score was achieved by 74.7% of patients in the 50 mg group, 66.1% in the 25 mg group, 35.8% in the ex-placebo group, and 53.9% in the placebo group.

Change From Baseline in SDQ VAS Scores

Improvements from baseline in quality of sleep (VAS) were maintained in all treatment groups throughout the extension study. At week 36, the mean change from baseline was 27.4 (SD = 23.6) in the daridorexant 50 mg group, 22.4 (SD = 21.6) in the daridorexant 25 mg group, 9.7 (SD = 16.3) in the ex-placebo to daridorexant 25 mg group, and 21.9 (SD = 19.2) in the placebo group. Similar results were reported for all other VAS domain end points.

Change From Baseline in IDISQ Total Score

Mean reductions in IDSIQ total score from baseline were maintained throughout the extension study among patients in the daridorexant 50 mg and 25 mg groups. At week 36, the LSM treatment difference in IDSIQ total score, compared to placebo, was –9.12 (95% CI, –15.59 to –2.66; P = 0.0058) in the daridorexant 50 mg group and –4.52 (95% CI, –10.15 to 1.12, P = 0.11161) in the daridorexant 25 mg group.

Harms Results

In Study 303, from the double-blind treatment period until up to 30 days after the double-blind study treatment end date, the proportion of patients experiencing TEAEs was 40.1% in the daridorexant 50 mg group, 38.4% in the daridorexant 25 mg group, 38.1% in the ex-placebo to daridorexant 25 mg group, and 35.2% in the placebo group. Most TEAEs were mild or moderate, with nasopharyngitis being the most common (4.7% to 8.7%). The incidence of SAEs was less than 5.2% in all treatment groups. Most SAEs were reported by a single patient and were not considered to be related to the study medication, except for 1 case of orthostatic intolerance (in the daridorexant 25 mg group) and 1 instance of depression and/or suicidal ideation (in the placebo group). One death occurred in the daridorexant 25 mg group, but it was unrelated to treatment.

In terms of adverse events of special interest (AESIs), less than 3% of patients in each group experienced falls or other events; hallucinations and/or sleep paralysis, narcolepsy-like symptoms, and suicide and/or self-harm were reported by 1 patient each. No patients reported suicidal ideation or suicidal behaviour during the double-blind portion of the study or during the placebo run-out period. Mean Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) scores were low and similar across treatment groups, with minor changes from the last double-blind assessment to the placebo run-out period. There was no indication of rebound insomnia, assessed with mean sTST, in any treatment group during the placebo run-out period. Next-morning residual effects, assessed with mean VAS morning sleepiness score, improved from baseline throughout the study for all treatment groups.

Critical Appraisal

In the extension study, baseline characteristics were balanced across groups, consistent with the confirmatory studies. However, only patients who completed Study 301 or Study 302 were included, which could bias the results in favour of treatment. Furthermore, patients in the placebo arm of Study 303 were already receiving placebo in their confirmatory study (Study 301 or Study 302). Their continued participation suggests that they were likely good responders to placebo, which may explain their improved sleep-related outcomes (i.e., sTST, sWASO, and sLSO) reported in the extension study. The study lacked multiplicity adjustments, had many tests, and had no statistical sample size considerations, raising the risk of type I error. High dropout rates (28.5% to 35.2%) could have overrepresented patients more likely to benefit from treatment.

Of the 662 patients in the 4 treatment groups assessed in this review, 7 (1.1%) identified as Asian, 38 (5.7%) as Black or African American, 2 (0.3%) as another race, and 421 (63.6%) as white, which doesn't reflect the ethnic diversity seen in patients with CID , according to the clinical experts consulted. Additionally, the exclusion of individuals with acute and unstable mental health conditions and the low percentage of patients (7.3%) with psychiatric disorders in the extension study limits the generalizability of results to this patient population. The clinical experts also noted that tools like ISI and IDSIQ are not commonly used in clinical practice, further limiting generalizability.

Indirect Comparisons

The sponsor determined that it was infeasible and inappropriate to conduct an indirect treatment comparison for daridorexant; thus, no indirect evidence was submitted for this review.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the evidence were submitted by the sponsor for this review.

Conclusions

CID is a common condition with a significant clinical burden on daily life, including impaired daytime functioning and severe negative impacts on mental and physical health and on quality of life. The limited effective or well-tolerated, long-term treatment options available highlights an unmet clinical need for novel treatments that address the multiple facets of insomnia.

Evidence for this review came from 2 double-blind, placebo-controlled trials (Study 301 and Study 302), which evaluated the efficacy and safety of daridorexant 50 mg and daridorexant 25 mg in adults with CID, defined according to DSM-5 criteria, and 1 LTE study (Study 303). Outcomes evaluated in the studies were clinically relevant and aimed to address the needs identified by patients and clinicians, including sleep maintenance, onset, duration, and quality. Study 301 demonstrated that at 3 months, compared to placebo, treatment with daridorexant 50 mg resulted in a statistically significant improvement (reduction) in sleep maintenance measured by WASO (LSM difference, –18.3 minutes; 97.5% CI, –24.76 to –11.85 minutes) and in sleep onset measured by LPS (LSM difference, –11.67 minutes; 97.5% CI, –17.03 to –6.32 minutes), and an increase in sleep duration (LSM difference, 19.77 minutes; 97.5% CI, 9.30 to 30.24 minutes). However, it is uncertain whether the results for these outcomes were clinically meaningful, given the effect sizes and 97.5% CIs, which contained the possibility of benefit as well as the possibility of no benefit. Results for change from baseline in insomnia symptoms (measured with ISI) and daytime functioning (measured with IDSIQ) appeared to improve, but given the subjective nature of the outcomes, are uncertain. It is also unclear whether the results were clinically meaningful compared to placebo, although the pharmacokinetic profile of daridorexant is theoretically beneficial for daytime symptoms. DORAs are known to have an acceptable safety profile, and the harms observed in the pivotal trials were considered manageable by the clinical experts consulted for this review. Additionally, no safety signals were identified for rebound insomnia, next-morning residual effects, or suicidality. The findings were generally consistent in the LTE study. There is no direct or indirect comparative evidence between daridorexant and relevant treatments for patients with CID; thus, the comparative efficacy and safety of daridorexant remain unknown.

Both Study 301 and Study 302 evaluated the 25 mg dose of daridorexant, and results were consistent with the 50 mg dose, although the magnitude of the results was not as high. As such, there was evidence of a dose-response relationship with respect to efficacy outcomes; however, this was not observed for harms. Because the population of patients meeting the indication for daridorexant 25 mg (i.e., patients receiving moderate CYP3A4 inhibitors or with moderate hepatic impairment) was excluded from the trials, limited conclusions can be drawn about the efficacy and safety of the daridorexant 25 mg dose. Because CID frequently occurs alongside other psychiatric or medical conditions, the exclusion of patients with comorbid psychiatric disorders and those using certain medications (e.g., antidepressants or antipsychotics) from the pivotal studies limits the generalizability of the findings to real-world clinical practice.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of daridorexant, 25 mg oral tablet and 50 mg oral tablet, in the treatment adult patients with CID.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

Insomnia is characterized by persistent sleep difficulty, despite adequate sleep opportunity, and is associated daytime dysfunction.¹ Patients with insomnia experience dissatisfaction with the quality or duration of their sleep because of difficulties initiating or maintaining sleep or waking up too early. For a diagnosis of CID — defined in the DSM-5 as an insomnia disorder — symptoms must occur at least 3 times per week for at least 3 months and be present despite adequate conditions for sleep.¹ It must also be associated with significant distress, the impairment of daytime functioning, or the impairment of social, occupational, academic, behavioural, or other important areas of functioning. The etiology of insomnia includes a combination of predisposing factors that increase the risk for CID (e.g., chronic mental health or neurologic conditions); precipitating events that lead to sleep disruption (e.g., severe accident leading to physical injury, death of a close family member, or change in occupation); and perpetuating factors that consist of behavioural and cognitive compensatory responses to ѕlеерlеѕsոеѕs that may contribute to persistent physiologic arousal and to the continuation of insomnia (e.g., worry about sleep loss or clock-watching in bed).¹⁸

A range of risk factors has been implicated in the development of insomnia, including older age, family history of insomnia, and female sex.² Insomnia often coexists with psychiatric disorders (e.g., anxiety, depression, bipolar disorder), medical conditions (e.g., pulmonary disease, diabetes, cancer), and neurologic conditions (e.g., epilepsy, dementias, multiple sclerosis).² CID has a negative impact on the daytime functioning, safety, and quality of life of patients. Patients with CID report increased fatigue, confusion, tension, anxiety, and depression. Although patients tend to overestimate the magnitude of their performance deficits, as well as the magnitude of their sleep deficits,² insomnia has been associated with decreased work productivity, increased health care use, and an increased risk of accidents. Patients with CID frequently seek over-the-counter remedies and have an increased risk of developing substance use disorders. When untreated, the symptoms of insomnia can exacerbate existing health issues and lead to new physical and mental health complications over time, including cardiovascular, psychiatric, and neurologic conditions. Both CID and decreased total sleep time are independent risk factors for suicidal ideation and behaviour.²

There is a wide range of prevalence estimates for insomnia² because of variances in case definitions, assessment procedures, sample characteristics, and lengths of assessment.¹⁹ In general, approximately 30% of adults report experiencing insomnia symptoms of any severity at some point in their lives, with around 10% to 15% also experiencing daytime consequences, such as fatigue.¹⁹ When the more stringent diagnostic criteria of the DSM-5 or the International Classification of Sleep Disorders are used, CID prevalence rates tend to cluster between 6% and 10%.¹⁹ A 2023 RAND Europe report estimated that the global prevalence of CID in the general adult population to range from 6.0% to 14.8%, based on data from 7 studies comprising 6 countries in Europe, the UK, and the US.¹³ The report estimated the prevalence of CID in the general adult population in Canada at the time to be 8.8% (95% CI, 5.6% to 12.0%).¹³

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

The goal of treatment for patients with CID is to reduce nighttime and daytime symptoms (i.e., improving daytime functioning over a long period of time because of the chronicity of the disease). Consensus recommendations for the management of CID in Canada, published in October 2024, highlight the importance of specifically treating insomnia, even in the presence of comorbidities.¹² This consensus aligns with international guidelines, including the European Sleep Research Society 2023 update. The consensus recommendations, the European guidelines, and the clinical experts consulted for this review recommend CBT-I as the first-line treatment for chronic insomnia.^12,20 The clinical experts noted that CBT-I is effective for many but not all patients, and in Canada, given the limited provider awareness, limited access to CBT-I, and financial constraints, pharmacological treatment remains necessary.^4-8

There are currently no approved or recommended pharmacological treatments indicated for CID on Canadian public drug plans. The clinical experts consulted for this review noted that trazadone, an atypical antidepressant, is commonly used off-label in Canada because of its hypnotic effects at low doses. Other currently used pharmacotherapeutic options in Canada include hypnotics (e.g., Z-drugs [zolpidem and zopiclone]), off-label benzodiazepines, and GABA agonists. The clinical experts explained that the efficacy of pharmacotherapeutic options, including benzodiazepines and Z-drugs, has been confirmed in multiple short-term studies (up to 4 weeks), but long-term data (3 months to 12 months) are limited. There is also the potential for misuse with these drugs as long-term therapy in the absence of suitable alternatives. Moreover, these therapies are associated with potentially concerning adverse effects, including daytime drowsiness, risk of falls, risk of addiction and abuse, and rebound insomnia after discontinuation.^9-11 The consensus recommendations for the management of chronic insomnia in Canada, published in October 2024, note that there is a lack of long-term data on the efficacy of these pharmacotherapies, and their use is generally recommended for short-term management. Although the consensus recommendations note that DORAs may have benefits that outweigh risks for long-term use,¹² no DORAs are publicly funded in Canada as of this review. The risks associated with these pharmacological drugs are particularly pronounced in older, more frail adults, which is a population with a high prevalence of CID.^21-23 Thus, these options should be limited to the short-term management of insomnia. There is also a lack of evidence supporting the benefit of off-label antidepressants and antipsychotics in patients with CID, as well as concerns regarding their safety profile. The clinical experts highlighted the need to reduce the use of medications with limited evidence or low risk-benefit ratios as newly approved pharmacotherapies are integrated.¹²

Drug Under Review

The key characteristics of daridorexant and other treatments available for CID are summarized in Table 3. Health Canada approval for daridorexant was granted in April 2023.¹⁴

Daridorexant is a DORA that acts on both orexin 1 receptors and orexin 2 receptors equipotently. Daridorexant antagonizes the activation of orexin receptors through orexin neuropeptides, which, consequently, decreases the wake drive, allowing sleep to occur. The terminal half-life of daridorexant is approximately 8 hours. Tablets of daridorexant are available in 25 mg and 50 mg doses. The recommended dose of daridorexant for adults is 1 tablet of 50 mg once per night, taken orally in the evening in the 30 minutes before bedtime, when at least 7 hours remain before planned awakening. For patients with moderate hepatic impairment or who use moderate CYP3A4 inhibitors, the recommended dose of daridorexant is 25 mg.¹⁴

Daridorexant is indicated for the management of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The sponsor’s request for reimbursement is for a more targeted indication than that specified in the product monograph. Specifically, the request is for patients with moderate to severe CID in whom CBT-I is inappropriate, unavailable, or has failed, and whose CID is characterized by difficulty initiating or maintaining sleep, early awakenings; occurring at least 3 times weekly, lasting a minimum duration of 3 months, and an ISI score of at least 15.¹⁵

Table 3: Key Characteristics of Daridorexant, Lemborexant, Z-Drugs, Benzodiazepines, Doxepin, Antidepressants, and Antipsychotics

CNS = central nervous system; CYP3A4 = cytochrome P450 3A4; GABA = gamma-aminobutyric acid; MAOI = monoamine oxidase inhibitor; NA = not applicable; OX1R = orexin receptor 1; OX2R = orexin receptor 2; TCA = tricyclic antidepressants.

^aHealth Canada–approved indication.

Sources: Product monographs for daridorexant,¹⁴ Dayvigo (lemborexant),²⁴ Sublinox (zolpidem),²⁵ Restoril (temazepam),²⁶ Silenor (doxepin),²⁷trazodone,²⁸ and Apo-Quetiapine XR (quetiapine fumarate extended-release).²⁹

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

CDA-AMC received patient input from 4 groups, including the Gastrointestinal Society, which provided information from meetings with health care experts and researchers, as well as results from surveys conducted on digestive and liver diseases and disorders; Menopause Chicks, which surveyed women aged 45 years to 64 years who were experiencing sleep disruptions; a group of 8 adults in Canada living with CID who represent a range of patient groups; and a joint submission from MDSC and Migraine Canada, which surveyed and interviewed patients with insomnia, including 1 patient who had experience with the treatment under review.

The input from the Gastrointestinal Society noted that CID is an independent condition that is closely linked to a range of comorbidities, including cardiovascular disease, diabetes, obesity, cancer, and gastrointestinal diseases. In the survey conducted by Menopause Chicks, more than 85% of patients said they believe the underlying cause of their insomnia is hormone changes. The group of adults in Canada living with CID stated that the negative effects of CID are often underestimated, and explained that symptoms can have significant impacts on their daily life, including persistent fatigue, difficulty concentrating, physical discomfort (such as joint pain and muscle soreness), a pervasive lack of energy that impedes self-care and routines (i.e., exercise, maintaining household responsibilities, childcare), emotional strain (feelings of frustration and anxiety), and social isolation due to exhaustion. The patients explained that those around them often fail to understand their struggles, adding to feelings of isolation. The group’s input noted that sleep difficulties exacerbate other health conditions, like migraines and depression, and that patients often miss time at work, school, or volunteering due to their symptoms. The Gastrointestinal Society noted that beyond the workplace, insufficient sleep can affect an individual’s emotional well-being, behaviour, and interactions, contributing to memory lapses, accidents, injuries, and mood disturbances. The input from MDSC and Migraine Canada described patients’ concerns about the long-term impacts of CID on their mental and physical health. The input also noted that partners and family members often endure sleepless nights alongside their loved ones, leading to stress, frustration, and relationship strain.

Pharmacological treatments that patients have used include sedatives-hypnotics, GABA agonists, antidepressants, antipsychotics, DORAs (lemborexant), and cannabinoids. Input from Menopause Chicks noted that most patients surveyed were prescribed selective serotonin reuptake inhibitors as a sleep aid. Inputs from the group of adults in Canada living with CID and from MDSC and Migraine Canada highlighted that often patients try nonpharmaceutical options, including lifestyle adjustments, strict sleep routines, meditation, and exercise. Because of high unmet needs, some patients also take over-the-counter supplements and drugs such as antihistamines, melatonin, magnesium, L-theanine, herbal products (e.g., chamomile, lavender, valerian root), and antihistamines (diphenhydramine). Patients reported that these treatment options provide short-term relief, relaxation, and minor sleep support. However, drawbacks include grogginess, impaired functioning, inconsistent results with continued persistent daily fatigue, and high costs. Across inputs, many patients expressed a fear of dependency on medicated sleep aids and concerns about long-term side effects, including potential cognitive impacts; however, patients across submissions noted that currently available treatment options do not address the core issue of achieving deep, restorative sleep.

As such, the patient groups emphasized the need for treatments that offer consistent and restorative sleep, reduced or eliminated grogginess, and a low risk of dependency or cognitive side effects. Patients noted that addressing these unmet needs could reduce physical, emotional, and financial strains, as well as offer a better quality of life through improved sleep and daily functioning. For the 1 patient who had experience with daridorexant in the MDSC and Migraine Canada input, caregivers reported an improvement in the patient’s ability to fall asleep and stay asleep, without any outward signs of next-day side effects.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of CID.

Unmet Needs

Given the multifactorial nature of CID and its frequent comorbidities, the clinical experts noted that it is important to have a variety of pharmacological and nonpharmacological approaches, in addition to CBT-I. While CBT-I is a known and effective treatment for insomnia disorder, issues related to access to CBT-I, such as financial barriers and provider awareness, limit the use of this intervention in clinical practice. The experts also highlighted that up to a third of patients may not respond to CBT-I. In terms of pharmacological options, the experts agreed that there is a need for targeted therapies to address the multiple factors that contribute to insomnia (e.g., physiologic, biologic, circadian, psychiatric) and are associated with long-term efficacy, improved tolerance, and a reduction in adverse effects, improving compliance.

Place in Therapy

The clinical experts indicated that daridorexant may be a first-line pharmacological therapy for insomnia disorder, if CBT-I is not effective or not possible. The experts stated that deprescribing traditional sedative-hypnotics poses a challenge, as patients often prefer current treatment options due to their rapid onset of action. As such, they noted that transitioning to daridorexant may be difficult as DORAs may take 4 weeks to 8 weeks to demonstrate results. The experts also noted the utility of DORAs used in combination with other pharmacologic drugs; this is specifically reserved for patients with complex insomnia difficulties.

Patient Population

According to the clinical experts, applying the generally agreed upon symptomatic diagnosis of CID is appropriate to identify patients suitable for treatment with daridorexant. Individuals with significant functional impairment (e.g., social, occupational, physical) are most in need of intervention. They noted that other drugs might be more appropriate for patients with comorbid conditions, such as chronic pain or depression. The experts suggested using DORAs preferentially for patients in whom minimizing adverse effects is a priority, given their favourable side-effect profile. Narcolepsy would be an absolute contraindication for DORAs.

Because CID is mostly symptom guided, the clinical experts mentioned that, generally, diagnostic tests or sleep studies (e.g., PSG) are not needed unless there is evidence of treatment resistance or other disorders (e.g., comorbid obstructive sleep apnea and insomnia or periodic limb movement disorder).

Assessing the Response Treatment

The clinical experts mentioned that response to treatment would initially be assessed after about 8 weeks of treatment and would be determined by a patient’s impression of improvement in sleep quality, quantity, and daytime functioning, and other symptoms. They noted that every patient will likely have their own subjective standard of what they would define as adequate benefit from treatment and that it is presently unclear which patients would best respond to treatment. Formal questionnaires or objectively measured end points are likely not used in clinical settings.

Discontinuing Treatment

According to the clinical experts, lack of efficacy after a reasonable trial at an optimal dose and/or possible adverse effects (e.g., hallucinations, vivid disturbing dreams, suicidality) that outweigh any potential benefits are potential reasons to discontinue treatment. The experts also noted that the optimal time to determine treatment efficacy is after around 8 weeks of treatment. The clinical experts also flagged that patients may opt to discontinue treatment sooner, citing a lack of efficacy because they are used to the immediate hypnotic effects of Z-drugs and benzodiazepines.

Prescribing Considerations

The clinical experts mentioned that any physician or nurse practitioner can diagnose and treat CID with daridorexant as a first-line therapy. They also noted that a specialist is not required for diagnosis or treatment, and should generally be reserved for resistant insomnia or multiple concomitant sleep disorders. The experts noted that the dosing schedule is straightforward as indicated and that the side-effect profile of daridorexant is generally manageable and easy to discuss with the patients.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Twelve clinician submissions provided input for this review, including from the Mood Disorders Research and Treatment Service, the Family Physician Airways Group of Canada, the Canadian Consortium of Sleep and Sleep Interested Physicians, the Synergy Medical Clinic, and MedSleep, as well as from psychiatrists in British Columbia and Quebec, family physicians, a neurologist, and an inpatient mental health pharmacist. All contributors had experience working with patients diagnosed with CID. The input stated that current treatment options for insomnia include nonpharmacological therapies, such as sleep hygiene and CBT-I, which can be costly and has limited availability in Canada. The input stated that pharmacological options, particularly GABA agonists, are only prescribed for short-term use, are limited by poor efficacy and next-day sedation, often require dose escalation, can lead to dependence or nonresponse, can lead to withdrawal symptoms upon discontinuation, and are associated with cognitive side effects. In addition, there are limited or no clinical data supporting their use for patients with CID. As such, to improve patient outcomes, the clinician submissions noted that there is a need for treatments that improve daytime function, are tolerable, affordable, and safe.

The clinician input highlighted the unique mechanism of action of daridorexant, which reduces wakefulness without causing sedation. Daridorexant would be used in the first-line setting for CID, after CBT-I or when CBT-I is not suitable, according to the input. With regard to assessing response to treatment, the clinician submissions noted that, given the prevalence of insomnia in Canada and limited resources, frequent polysomnograms are not practical for use in clinical practice. Some of the clinician submissions highlighted the use of the ISI screening tool and other patient-reported outcomes used in research to assess treatment response; however, the clinical experts consulted for this review noted the ISI tool may be less commonly used in Canadian clinical practice. The clinician submissions noted that a clinically meaningful response to treatment includes improved next-day functioning, improved duration and quality of sleep, and a reduction in ISI score. Potential reasons for discontinuing treatment include side effects, such as reduced daytime functioning, nightmares, and sleep paralysis. Various clinicians agreed that daridorexant would be particularly suitable for patients at risk for drug dependence or abuse and for older patients, given the unsuitability of many other drugs because of the potential for cognitive impairment and falls. The clinicians agreed with the clinical experts consulted for this review that daridorexant would likely be prescribed by primary care physicians in outpatient settings, and no specific dependence or rebound issues would need to be addressed for patients discontinuing daridorexant.

Drug Program Input

The drug programs provide input on each drug being reviewed through the Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by for this review are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ADHD = attention-deficit/hyperactivity disorder; BMI = body mass index; CBT-I = cognitive behavioural therapy for insomnia; CID = chronic insomnia disorder; CDEC = Canadian Drug Expert Committee; DORA = dual orexin receptor antagonist; ISI = Insomnia Severity Index; MMSE = Mini Mental State Examination; vs. = versus.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of daridorexant 25 mg and 50 mg oral tablets in the treatment of moderate to severe CID when CBT-I is inappropriate, unavailable, or has failed. CID is characterized by difficulty initiating or maintaining sleep, early awakenings, at least 3 occurrences weekly, a minimum duration of 3 months, and an ISI score of at least 15. The focus will be placed on comparing daridorexant to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of daridorexant is presented in 2 sections, with a CDA-AMC critical appraisal of the evidence included at the end of each section. The first section, the Systematic Review, includes pivotal studies and RCTs that were selected in accordance with the sponsor’s systematic review protocol, plus additional evidence that was identified as relevant to the indication under review. The CDA-AMC assessment of the certainty of the evidence in the first section, using the GRADE approach, follows the critical appraisal of the evidence. The second section includes a sponsor-submitted LTE study. No indirect evidence or additional studies were included.

Included Studies

Clinical evidence from the following are included in the review and appraised in this document:

• 2 pivotal trials identified in the systematic review

• 1 LTE study.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5. Two phase III, double-blind, parallel-group, placebo-controlled, randomized trials were included in this review. Both studies were conducted between 2018 and 2020, with database locks on March 31, 2020 (Study 301), and June 18, 2020 (Study 302). Study 301 was conducted across 10 countries in Europe and North America, including 4 sites in Canada. Study 302 was conducted across 11 countries in Europe, North America, and Asia, including 5 sites in Canada.

Study 301 and Study 302 were both designed to assess efficacy and safety of daridorexant in patients with insomnia disorder. Study 301 compared daridorexant 50 mg and daridorexant 25 mg to placebo, whereas Study 302 compared daridorexant 10 mg and daridorexant 25 mg to placebo. Because the 10 mg dosage is not approved by Health Canada, data are not presented for that group.

Table 5: Details of Studies Included in the Systematic Review — Study 301 and Study 302

BMI = body mass index; CBT = cognitive behavioural therapy; CYP3A4 = cytochrome P450 3A4; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition); EODBT = end of double-blind treatment; EOS = end of study; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; ISI = Insomnia Severity Index; LPS = latency to persistent sleep; PGA-S = Patient Global Assessment of Disease Severity; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; PSG = polysomnography; REM = rapid eye movement; SDQ = Sleep Disorders Questionnaire; sLSO = subjective latency to sleep onset; sTST = subjective total sleep time; SWS = slow-wave sleep; S1 = stage 1 sleep; S2 = stage 2 sleep; TST = total sleep time; VAS = visual analogue scale; WASO = wake after sleep onset.

^aAs reported in the SDQ, completed at home between visit 2 and visit 3.

Sources: Clinical Study Report for Study 301,¹⁶ Mignot et al.,³¹ Clinical Study Report for Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and Clinical Study Reports.

Figure 1 shows the design of Study 301 and Study 302. Both studies consisted of a screening phase, a double-blind treatment phase, and a safety follow-up phase. Patients who completed study treatment (double-blind treatment and placebo run-out treatment) in the core study were eligible to enter an extension study (Study 303).

The screening period lasted from 7 days to 18 days (from visit 1 to visit 2) and consisted of an initial verification of eligibility, followed by a one-night PSG assessment and a minimum of 7 daily SDQ entries. The screening phase also included a placebo run-in period that lasted from 13 days to 24 days (from visit 2 to visit 4) and consisted of confirmation of eligibility, single-blind placebo treatment once daily, and 2 PSG nights (visit 3) performed after patients had completed at least 7 daily SDQ entries.

The double-blind treatment phase ran from randomization (day 1, visit 4) until the end of double-blind treatment (morning of day 85, visit 8). Randomization was performed with an Interactive Response Technology system, and treatment allocation was stratified by age into 2 categories (< 65 years and ≥ 65 years). In Study 301, patients were randomized in a 1:1:1 ratio to daridorexant 25 mg, daridorexant 50 mg, or placebo; in Study 302, patients were randomized to daridorexant 25 mg or placebo. Double-blind study treatment was given once daily from day 1 to day 84.

The safety follow-up phase consisted of 2 periods. The first period was a placebo run-out period, from the end of double-blind treatment (evening of day 85, visit 9) until the end of treatment (day 92, visit 10), which included 7 days of single-blind placebo treatment once daily (day 85 to day 91) and 1 PSG night (day 85 to day 86). The second period involved a safety follow-up period, from the end of treatment (day 92, visit 10) until the end of the study, which was either the enrolment date in Study 303 or the date of the 30-day follow-up telephone call (day 115, visit 11) for patients who did not enter the extension study. During this period, information on AEs, SAEs, and concomitant medications was collected.

Figure 1: Study Design of Study 301 and Study 302

ACT-541468 = daridorexant; EODBT = end of double-blind treatment; EOT = end of treatment; EOS = end of study; V = visit.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷

Populations

Inclusion and Exclusion Criteria

Study 301 and Study 302 enrolled adult patients, aged 18 years or older, who were diagnosed with insomnia disorder, according to the DSM-5 criteria. Patients with moderate to severe insomnia per the ISI (a score of 15 or more) at screening were deemed eligible for enrolment. Other key inclusion criteria included self-reported insufficient sleep quantity for at least 3 nights a week for at least 3 months before the screening visit, and for at least 3 of 7 nights on the SDQ completed during the placebo run-in period before the run-in PSG nights. Patients also had to meet sleep parameters on the PSG nights at visit 3, such as average TST less than 420 minutes, WASO for 30 minutes or more, or a sleep onset time of 20 minutes or more. Key exclusion criteria included self-reported daytime napping of at least 1 hour per day on at least 3 days per week. Patients with specific conditions were also excluded, such as those with acute or unstable psychiatric conditions, suicidal ideation with intent or any lifetime history of suicide attempt, alcohol or drug abuse, sleep-related breathing disorders, periodic limb movement disorder, restless legs syndrome, circadian rhythm disorder, REM behaviour disorder, narcolepsy, or apnea and/or hypopnea.

Interventions

In both trials, the study phases alternated between a single-blind placebo period, a double-blind treatment period, and another single-blind placebo period. The placebo periods included a run-in period (13 days to 24 days) and a run-out period (7 + 2 days), during which patients were administered placebo tablets that matched the daridorexant tablets.

During the double-blind treatment period, patients received the following interventions, based on their assigned treatment arm.

Study 301:

• Daridorexant film-coated tablets, 25 mg, with 1 tablet taken in the evening, orally, during the randomized double-blind treatment period (84 ± 2 days)

• Daridorexant film-coated tablets, 50 mg, with 1 tablet taken in the evening, orally, during the randomized double-blind treatment period (84 ± 2 days)

• Placebo film-coated tablets, with 1 tablet taken in the evening, orally, during the single-blind placebo run-in period (13 days to 24 days), the randomized double-blind treatment period (84 ± 2 days), and the single-blind placebo run-out period (7 + 2 days).

Study 302:

• Daridorexant film-coated tablets, 25 mg, with 1 tablet taken in the evening, orally, during the randomized double-blind treatment period (84 ± 2 days)

• Placebo film-coated tablets, with 1 tablet taken in the evening, orally, during the single-blind placebo run-in period (13 days to 24 days), the randomized double-blind treatment period (84 ± 2 days), and the single-blind placebo run-out period (7 + 2 days).

The investigational treatment and its matching placebo were indistinguishable, and all treatment wallets were packaged in the same way. At the site, 1 tablet of study treatment was taken orally at least 2 hours after the last meal and 30 ± 5 minutes before lights off on the evening of each PSG night. At home, the study treatment was taken orally at bedtime. If 1 or more doses were missed, the next dose had to be taken on the evening of the following day.

Concomitant pharmacological treatments for insomnia or other CNS-related medications were prohibited during the study to optimize the evaluation of the safety and efficacy profile of daridorexant. Cognitive behaviour therapy (CBT) for any indication was only allowed if the treatment started at least 1 month before visit 3 and the patient agreed to continue CBT throughout the study.

Outcomes

A list of efficacy and safety end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence, as well as any outcomes identified as important to this review by the clinical experts consulted for this review and in input from patient and clinician groups and public drug plans. Using the same considerations, CDA-AMC selected end points that were considered to be most relevant to expert committee deliberations and finalized this list of end points in consultation with members of the expert committee.

Select summarized efficacy end points were assessed using GRADE. They included sleep maintenance, sleep onset, sleep duration, and sleep quality. For the safety end points, the incidence of SAEs was assessed using GRADE.

Objective Outcomes

Objective outcomes were measured in both studies using PSG.

Sleep Maintenance (WASO)

One of the primary efficacy end points in Study 301 and Study 302 was change from baseline in WASO, defined as the time spent awake after the onset of persistent sleep (beginning of the first continuous 20 epochs [i.e., 10 minutes]) scored as nonawake. Improved sleep is indicated by a decrease in WASO duration.

PSG recordings were performed by technologists during sleep-study visits over the course of the study. The sponsors reported that the construct validity of the end point was demonstrated with a positive and statistically significant correlation (Spearman rank correlation, 0.61; P value < 0.0001) between the actigraphy-derived measure, which is another objective measure of sleep disorders, and the PSG-derived measure of WASO.³⁵ The mean of multiple WASO measurements over 3 nights demonstrated substantial test-retest reliability, with an intraclass correlation coefficient of 0.64 (95% CI, 0.52 to 0.73) in patients with insomnia.³⁶ According to American Academy of Sleep Medicine (AASM) expert consensus, the threshold for a clinically meaningful difference from placebo in group-level results is a mean change of at least 20 minutes between the treated and placebo arms.³⁷ The clinical experts consulted for this review confirmed that this minimal important difference (MID) is clinically meaningful.

Table 6: Outcomes Summarized From the Studies Included in the Systematic Review

AESI = adverse event of special interest; C-SSRS = Columbia Suicide Severity Rating Scale; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; ISI = Insomnia Severity Index; LPS = latency to persistent sleep; REM = rapid eye movement; SAE = serious adverse event; SDQ = Sleep Diary Questionnaire; sTST = subjective total sleep time; SWS = slow-wave sleep; TEAE = treatment-emergent adverse event; TST= total sleep time; VAS = visual analogue scale; WASO = wake after sleep onset.

^aBaseline: mean of the 2 polysomnography (PSG) nights at visit 3.

^bTo account for the concurrent evaluation (multiple comparison) of 2 distinct end point categories (sleep maintenance and sleep onset), a Bonferroni correction was applied. The remaining hypotheses were tested using the gatekeeping strategy.

^cMonth 1 and month 3: mean of the 2 PSG nights at visit 6 and visit 8, respectively.

^dBaseline: mean value based on the screening SDQ or IDSIQ entries performed at home in the 7 days immediately preceding the first PSG at visit 3.

^eMonth 1 and month 3: mean value based on the SDQ or IDSIQ entries performed at home in the 7 days immediately preceding the first PSG at visit 6 and visit 8, respectively.

^fMonth 3: visit 8 or, if that is missing, week 12 of the questionnaire.

^gAn Independent Safety Board reviewed blinded data on selected adverse events and safety assessment results and adjudicated whether the submitted cases were AESIs.

^hPlacebo run-out period: mean value based on the SDQ entries performed in the 7 days immediately after the PSG night at visit 9.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302¹⁷. Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Sleep Onset (LPS)

The other primary end point in Study 301 and Study 302 was the change from baseline in LPS (i.e., sleep onset). LPS was defined as the time from the start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minute) scored as nonawake (i.e., epochs scored as S1, S2, SWS, or REM), on PSG. An improved sleep is indicated by a decrease in LPS duration. According to AASM expert consensus, the suggested threshold for a clinically meaningful difference from placebo in group-level results is defined as a mean change of at least 10 minutes between the treated and placebo arms.³⁷ The clinical experts consulted for this review confirmed that this MID is clinically meaningful.

Subjective Outcomes

Patient-reported outcome instruments were used in Study 301 and Study 302 to evaluate patients' perceptions of their sleep issues and how these problems affect their daytime activities. They included quality of sleep measured on a VAS of SDQ, ISI, and IDSIQ. Table 7 presents the descriptions of the outcome measures and a summary of the interpretation and validity of these instruments.

Sleep Duration (sTST)

The secondary end point was the change from baseline in sTST. sTST provides an overall assessment of sleep times, incorporating time to sleep onset and wake time after sleep onset. According to the sponsor, sTST data permitted the translation of the PSG results to a benefit felt by patients. sTST was defined as the time reported by the patient in response to the SDQ morning questionnaire question: In total, how long did you sleep last night? In addition, rebound insomnia, an exploratory end point, was evaluated by comparing the sTST value obtained during the placebo run-out period to the baseline sTST value. In terms of end point validity, sTST has demonstrated a moderate to strong convergent validity with total ISI score, actigraphy-derived TST, and PSG-derived TST.^38-40 Following an assessment of data from an open-label, phase II trial of zolpidem and pooled data from a phase III, placebo-controlled trial of daridorexant in patients with moderate to severe insomnia, it was concluded that an improvement of 55 minutes from baseline in sTST is considered a clinically meaningful improvement of this outcome.^41,42 Of note, according to AASM expert consensus, the suggested threshold for a clinically meaningful difference from placebo in group-level results is defined as a mean change of at least 30 minutes between the treated and placebo arms.³⁷

Sleep Quality

Change from baseline in sleep quality was an exploratory end point of the included trials, and was measured using the SDQ, which is described in Table 7. The SDQ was developed by the sponsor, based on the Consensus Sleep Diary, morning administration, questionnaire and adapted for use in clinical trials. The SDQ was completed by the patient, without study staff input or interference, and included a morning and evening questionnaire and a VAS. The morning and evening questionnaire collected information on self-reported sleep characteristics (sleep induction and maintenance), habitual napping, bedtime, and timing of study treatment intake. The VAS collected information on quality of sleep, depth of sleep, and morning sleepiness (all assessed in the morning), and daytime alertness and daily ability to function (both assessed in the evening) by asking patients to report their feelings by placing a mark on a VAS.

Daytime Functioning

Daytime functioning was measured using IDSIQ total score, which is described in Table 7. The IDSIQ is a patient-reported outcome measure structured in 3 domains (alert/cognition, mood, sleepiness). The IDSIQ sleepiness domain score, based on patient responses to 4 items, could range from 0 to 40 (whole numbers only), with higher scores indicating a greater burden of illness during the daytime.

Insomnia Symptoms

The assessment of global insomnia symptom severity was conducted using the ISI, which is described in Table 7. Eligible patients had to have self-reported insomnia of at least moderate severity (ISI score ≥ 15) at screening. The ISI is a 7-item questionnaire that assesses insomnia symptoms and their impact on the severity of sleep onset and sleep maintenance difficulties, and any insomnia-related interference with daytime functioning. The assessment is based on a 5-point Likert scale (range, 0 to 4), where the composite score was obtained by summing the 7 rated dimensions that measure patients’ perceptions of their insomnia. A score of 15 to 21 indicates a moderate level of insomnia, and a score of 22 to 28 indicates severe insomnia.

Safety End Points

Safety end points included AEs reported by the investigators (i.e., TEAEs, SAEs, AEs leading to premature discontinuation of study treatment), independent safety board–adjudicated AESIs (i.e., narcolepsy-like symptoms and suicide and/or self-injury). Other safety end points relevant to the current review include next-morning residual effect, rebound insomnia, and the occurrence of suicidal ideation and/or behaviour.

Next-Morning Residual Effect

The next-morning residual effect was a safety end point assessed using changes from baseline in the morning sleepiness score on the VAS of the SDQ. For the quality of sleep end point, a positive change from baseline indicates a better outcome, meaning a decrease in morning sleepiness.

Rebound Insomnia

Rebound insomnia, characterized by the return or exacerbation of sleep onset or sleep maintenance difficulties upon discontinuation of the treatment, was a safety outcome of interest in this review. It was assessed using WASO, LPS at the start of the placebo run-out period (visit 9) compared to baseline (visit 3), and the subjective sleep parameter sTST from the placebo run-out period compared to baseline.

Occurrence of Suicidal Ideation and/or Behaviour

The Columbia Suicide Severity Rating Scale (C-SSRS) questionnaire was used to identify the presence and severity of suicidal ideation and suicidal behaviours, which were safety end points. The C-SSRS also captures information on the intensity of ideation (frequency, duration, controllability, and deterrents) and reasons for the most severe types of ideations. The C-SSRS contains 10 outcome categories, each of which can be responded to with a binary response (yes or no). A trained health care professional, in accordance with local requirements and local clinical practice, was required to complete the questionnaire together with the patient on a tablet device and assess the findings. Moreover, good convergent and divergent validity was demonstrated between the C-SSRS and other multi-informant suicidal ideation and behavioural scales.⁴³

Table 7: Summary of Outcome Measures and Their Measurement Properties

AASM = American Academy of Sleep Medicine; AUC = area under the curve; CI = confidence interval; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition); ICC = intraclass correlation coefficient; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; ISI = Insomnia Severity Index; LPS = latency to persistent sleep; MID = minimal important difference; PGA-S: Patient Global Assessment of Disease Severity; PGI-C = Patient Global Impression of Change; PROMIS = Patient-Reported Outcomes Measurement Information System; PSG = polysomnography; PSQI = Pittsburgh Sleep Quality Index; RCT = randomized controlled trial; ROC = receiver operating characteristic; SDQ = Sleep Diary Questionnaire; SF-12 = 12-Item Short Form Survey; sTST = subjective total sleep time; TST = total sleep time; VAS = visual analogue scale; WASO = wake after sleep onset.

Statistical Analysis

Sample Size and Power Calculation

Study 301 and Study 302 used similar assumptions and calculations to estimate sample size. The difference compared to placebo in the mean change from baseline to month 1 and to month 3 (± the assumed SD for each treatment group) for WASO, LPS, and sTST was assumed to be 15 minutes (± 40 minutes), 15 minutes (± 40 minutes), and 20 minutes (± 54 minutes), respectively (based on phase II data from 2 studies: AC-078A201 and AC-078A202).^56,57 The corresponding effect size (mean/SD) was approximately 0.37.

In Study 301, based on a two-sample z-test, a sample size of at least 900 patients randomized to daridorexant 25 mg, daridorexant 50 mg, or placebo in a 1:1:1 ratio (i.e., 300 per group) would provide 98.9% power to detect an effect size of 0.37 for a single hypothesis test. Similarly, in Study 302, a sample size of at least 900 patients randomized to daridorexant 10 mg, daridorexant 25 mg, or placebo would provide that power to detect an effect size of 0.37. In both studies, this accounts for the Bonferroni correction, in which the significance level (alpha) is halved and set to a 2-sided 2.5% significance level. However, as the number of null hypotheses (end points) to test increases, the power decreases. The power calculation assumed that all null hypotheses were independent, which is a conservative assumption for power calculations. Consequently, 900 subjects were needed to provide at least 90% power to detect an effect size of 0.37 when 9 independent null hypotheses were tested.

Efficacy End Points

In both studies, the analysis of the primary and key secondary end points, involving change from baseline in WASO, LPS, and sTST, employed a longitudinal data analysis method (specifically, a linear mixed-effect model). They are outlined in Table 8.

The analysis models were adjusted for multiple values, such as the baseline value of the relevant response variable (WASO, LPS, or sTST), age group (< 65 years, ≥ 65 years), treatment (higher dose, lower dose, placebo), visit (month 1, month 3), and the interaction of treatment by visit and baseline by visit. Study-wise type I error control was implemented across the 2 primary and 2 secondary end points, as well as across 2 time points of outcome assessments (month 1 and month 3) and 2 dose-level comparisons versus placebo. Thus, overall, 16 independent null hypotheses were tested in the study, with appropriate type I error control for each of the included studies.

As a way to evaluate the efficacy hypotheses, appropriate contrasts were computed to test the treatment differences of interest. Difference of interest was the difference in LSM change from baseline between higher-dose daridorexant and placebo and between lower-dose daridorexant and placebo, both at month 1 and month 3.

The analysis of the other efficacy end points, specifically concerning the IDSIQ total score, was performed using the same model as the main analysis, which is the linear mixed-effects model. The LSM for each treatment group at each time point was displayed along with associated standard errors and 95% CIs.

For all end points, observed values at month 1 and month 3, along with baseline data, are reported as mean (SD). The analysis of the exploratory end points (change from baseline to month 1 and to month 3 of the respective variables), as well as the safety end points, was summarized descriptively using the observed values.

Partially missing data were handled with implicit imputation, which means that missing data points are given the same value as the mean of the nonmissing data points of that same time point or week. WASO and LPS values were handled as follows: if 1 of the 2 values was missing for baseline, month 1, or month 3, the single value available was used as the mean for that time point. If both values were missing for a time point, then the mean value was considered missing for that time point. The same approach was used for the Sheehan Disability Scale. For sTST and IDSIQ sleepiness domain score values, patients had to have at least 2 days of data during each week to calculate a weekly mean. Otherwise, the mean value was considered missing for that week. The same approach was used for the IDSIQ total score and VAS scores.

Statistical Testing

The type I error rate was controlled for the testing of multiple null hypotheses associated with the primary and secondary end points assessed at month 1 and month 3 of treatment and the 2 dose levels (i.e., 25 mg and 50 mg in Study 301 and 10 mg and 25 mg in Study 302) included in the studies. For each of the primary end points (change from baseline in WASO [sleep maintenance] and LPS [sleep onset]) and secondary end points (change from baseline in sTST [sleep quantity], and IDSIQ sleepiness domain score [daytime function]), 4 null hypotheses were defined as follows:

Hypothesis 1: Higher dose – placebo = 0 at month 1

Hypothesis 2: Higher dose – placebo = 0 at month 3

Hypothesis 3: Lower dose – placebo = 0 at month 1

Hypothesis 4: Lower dose – placebo = 0 at month 3

In these 4 hypotheses, higher dose (i.e., 50 mg in Study 301, 25 mg in Study 302), lower dose (i.e., 25 mg in Study 301, 10 mg in Study 302), and placebo represent the mean change from baseline for the given end point (WASO, LPS, sTST, or IDSIQ sleepiness domain score) and time point (month 1 or month 3).

Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the respective end point at the given dose and time point, compared to placebo.

The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure that controlled the study-wise type I error at a two-sided 5% significance level.⁵⁸ To account for the concurrent evaluation (multiple comparison) of 2 distinct end point categories (i.e., sleep maintenance and sleep onset), a Bonferroni correction was applied. Both end point categories were tested at half of the two-sided 5% significance level.

The remaining hypotheses were tested using the gatekeeping strategy, moving from month 1 to month 3 for higher-dose daridorexant versus placebo and then from month 1 to month 3 for lower-dose daridorexant versus placebo. The prespecified proportion of alpha (weight) that was distributed once a given null hypothesis (node) was rejected is shown on the arrow in Figure 2 (Study 301) and Figure 3 (Study 302). If a certain null hypothesis could not be rejected, then the alpha level used for that test was absorbed at that node and not distributed further.

For the other secondary end point, change from baseline in IDSIQ total score, nominal two-sided P values (versus placebo) were not adjusted under type I error rate control (i.e., not adjusted for multiplicity).

For the primary and secondary end points, the linear mixed-effects model was run using an unstructured covariance matrix, shared across treatment groups, to model the correlation among repeated measurements. A restricted maximum likelihood approach was used to derive (unbiased) estimates of variance components. The Kenward-Roger approximation was used to compute the denominator degrees of freedom and adjust standard errors.⁵⁹

Subgroup Analyses

Subgroup analyses for the primary and secondary efficacy end points, as outlined in the statistical analysis plan and included as a relevant subgroup in the systematic literature review, were conducted in both studies. The subgroups were based on age (≥ 65 years, < 65 years) and sex (male, female) in the studies.

Various efficacy end points were analyzed, including the change from baseline in WASO, LPS, sTST, and ISI score. The next-morning residual effect was assessed as a safety end point. Regarding primary and secondary end points, the same model as for the main analysis (i.e., linear mixed-effects model) was used, except that age was not used as covariate in the model. Treatment effect estimates (LSM difference between daridorexant 50 mg and placebo, along with 95% CIs) are depicted in forest plots for primary and secondary efficacy end points. All results presented are descriptive, as these secondary analyses were not controlled for type I error rate or specifically powered. For the same reasons, tests for interactions between the treatment groups and age were not conducted.

Figure 2: Hypothesis and Overall Testing Strategy — Study 301

H = hypothesis; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; LPS = latency to persistent sleep; sTST = subjective total sleep time; WASO = wake after sleep onset.

Source: Clinical Study Report for Study 301.¹⁶

Figure 3: Hypothesis and Overall Testing Strategy — Study 302

H = hypothesis; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; LPS = latency to persistent sleep; sTST = subjective total sleep time; WASO = wake after sleep onset.

Source: Clinical Study Report for Study 302.¹⁷

Sensitivity Analyses

Regarding sensitivity analyses, models based on the multiple imputation method were performed to assess the robustness of the conclusions of the main analysis and departures from the missing-at-random assumption, and the bias that could result when the outcomes for patients who discontinued the study differed from those who completed the study.⁶⁰ For this matter, 2 models that adopted missing-not-at-random assumptions were used: a control-based imputation method called jump to reference; and a delta-adjusted imputation method. In addition, to provide a reference for the sensitivity analyses under MNAR, the main analyses were repeated using a multiple imputation method under the missing-at-random assumption. For all multiple imputation analyses, a preliminary step was performed to obtain a monotone missing data pattern. Any nonmonotone (or intermediate) missing data were imputed using the Markov chain Monte Carlo method under missing-at-random assumptions within each treatment group. Imputation for monotone missing data was performed sequentially, 1 visit at a time, using the linear regression method.

Table 8: Statistical Analysis of Efficacy End Points — Study 301 and Study 302

IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; ISI = Insomnia Severity Index; LPS = latency to persistent sleep; MAR = missing at random; MI = multiple imputation; MNAR = missing not at random; NA = not applicable; REM = rapid eye movement; S1 = stage 1 sleep; S2 = stage 2 sleep; SDQ = Sleep Diary Questionnaire; sTST = subjective total sleep time; SWS = slow-wave sleep; VAS = visual analogue scale; WASO = wake after sleep onset.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302,¹⁷ statistical analysis plan.⁶⁰ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Analysis Populations

Table 9 summarizes the analysis populations defined in Study 301 and Study 302.

Table 9: Analysis Populations — Study 301 and Study 302

BWSQ = Benzodiazepine Withdrawal Symptom Questionnaire; sTST = subjective total sleep time.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

Patient disposition in Study 301 and Study 302 is shown in Table 10. In Study 301, a total of 3,326 patients were screened. Most patients (n = 2,396 [72%]) failed screening, either at the screening stage or after the single-blind run-in period. Not meeting the inclusion or exclusion criteria was the most common reason for screening failure, although no information was provided on which of the criteria were failed during screening. Overall, 930 patients were randomized in a 1:1:1 ratio to daridorexant 25 mg (N = 310), daridorexant 50 mg (N = 310), or placebo (N = 310). In total, 91.2% of randomized patients completed Study 301. Treatment was discontinued by 24 patients (7.7%) in the daridorexant 25 mg arm, 22 patients (7.1%) in the daridorexant 50 mg arm, and 28 patients (9.0%) in the placebo arm, primarily due to patient withdrawal (2.6% to 2.9%) and AEs (1.0% to 3.2%).

In Study 302, a total of 3,683 patients were screened. Most patients (n = 2,759 [74.9%]) failed screening, either at the screening stage or after the single-blind run-in period. Not meeting the inclusion or exclusion criteria was the most common reason for screening failure, although no information was provided on which of the criteria were failed during screening. Overall, 924 patients were randomized in a 1:1:1 ratio to daridorexant 10 mg (N = 307; data not shown), daridorexant 25 mg (N = 309), or placebo (N = 308). In total, 91.9% of randomized patients completed Study 302. Treatment was discontinued by 23 patients (7.4%) in the daridorexant 25 mg arm and 18 patients (5.8%) in the placebo arm, primarily due to patient withdrawal (4.2% versus 1.3%) and AEs (1.3% versus 2.3%).

Table 10: Summary of Patient Disposition — Study 301 and Study 302

DB = double-blind; SB = single-blind.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Baseline Characteristics

The baseline characteristics outlined in Table 11 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

The baseline characteristics of the patients enrolled were similar between groups within studies, and generally comparable across the trials. The mean age per treatment group ranged from 55.1 years (SD = 15.4 years) to 56.7 years (SD = 14.1 years) across the studies. There was roughly an equal proportion of patients aged 65 years or older in the 2 studies. More than two-thirds of participants in both studies were female, and the male-female distribution was generally similar across treatment groups and studies. Most patients identified as white (86.7% to 92.6%), but 6.0% to 9.7% identified as Black or African American, and 0.6% to 3.6% identified as Asian. People of other races made up a smaller proportion of those enrolled. Of note, there was a higher proportion of patients who identified as Asian in Study 302 than in Study 301, likely because some study sites for Study 302 were located in South Korea. On average, the patients enrolled in the studies had been diagnosed with CID for 10 or more years, and the mean ISI score at baseline ranged from 19 (SD = 4.3) to 19.6 (SD = 4.1).

Table 11: Summary of Baseline Characteristics — Study 301 and Study 302

IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; ISI = Insomnia Severity Index; LPS = latency to persistent sleep; SD = standard deviation; sTST = subjective total sleep time; WASO = wake after sleep onset.

Sources: Clinical Study Report for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Exposure to Study Treatments

Exposure to study medications is summarized in Table 12. In both studies, treatment adherence was measured by the amount of study drug returned at each study visit. Patients also recorded their adherence in the SDQ every morning. Overall, there was high adherence to the interventions in both studies (more than 98%).

Table 12: Summary of Patient Exposure From the Studies Included in the Systematic Review

SD = standard deviation.

^aComprised all patients in the safety set who received at least 1 dose of the single-blind placebo treatment in the placebo run-out period.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Table 13: Concomitant Medications Used During the Double-Blind Treatment Phase (Safety Set) — Study 301 and Study 302

ACE = angiotensin-converting enzyme; CBT = cognitive behavioural therapy; HMG-CoA = beta-hydroxy-beta-methylglutaryl coenzyme A.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Efficacy

Sleep Maintenance

Sleep maintenance reported as change from baseline in WASO was 1 of the primary outcomes in Study 301 and Study 302. Results for change from baseline in WASO at month 1 and month 3 are presented in Table 14.

Study 301

In Study 301, the mean WASO at baseline was 95.48 minutes (SD = 37.81 minutes) in the daridorexant 50 mg arm, 97.87 minutes (SD = 38.77 minutes) in the daridorexant 25 mg arm, and 102.51 minutes (SD = 40.77 minutes) in the placebo arm.

At month 1, the LSM change from baseline in WASO was –28.98 minutes (95% CI, –32.67 to –25.30 minutes) in the daridorexant 50 mg arm, –18.40 minutes (95% CI, –22.13 to –14.67 minutes) in the daridorexant 25 mg arm, and –6.20 minutes (95% CI, –9.93 to –2.48 minutes) in the placebo arm. The LSM difference in change from baseline in WASO at 1 month compared to placebo was –22.78 minutes (97.5% CI, –28.75 to –16.82 minutes) in favour of daridorexant 50 mg and –12.20 minutes (97.5% CI, –18.19 to –6.21 minutes) in favour of daridorexant 25 mg.

At month 3, the LSM change from baseline was –29.41 minutes (95% CI, –33.40 to –25.43 minutes) in the daridorexant 50 mg arm, –22.97 minutes (95% CI, –26.96 to –18.99 minutes) in the daridorexant 25 mg arm, and –11.11 minutes (95% CI, –15.13 to –7.09 minutes) in the placebo arm. The LSM difference in change from baseline in WASO compared to placebo was –18.3 minutes (97.5% CI, –24.76 to –11.85 minutes) in favour of daridorexant 50 mg and –11.86 minutes (97.5% CI, –18.30 to –5.42 minutes) in favour of daridorexant 25 mg.

Results of the subgroup analysis based on age (< 65 years or ≥ 65 years) and sex (male or female) followed the same general pattern as the overall population, as shown in Appendix 1.

Study 302

In Study 302, the mean WASO at baseline was 106.31 minutes (SD = 49.10) in the daridorexant 25 mg arm and 108.07 minutes (SD = 48.71) in the placebo arm.

At month 1, the LSM change from baseline was –24.19 minutes (95% CI, –28.47 to –19.91 minutes) in the daridorexant 25 mg arm and –12.57 minutes (95% CI, –16.82 to –8.32 minutes) in the placebo arm, corresponding to an LSM difference of –11.62 minutes (95% CI, –17.60 to –5.63 minutes) in favour of daridorexant 25 mg. Results of the subgroup analysis showed that in male patients, there was no difference between groups (mean difference = 3.94; 95% CI, –13.58 to 5.69). Findings from the rest of the subgroups were consistent with the main results, as shown in Appendix 1.

At month 3, the LSM change from baseline was –24.25 minutes (95% CI, –29.02 to –19.47) in the daridorexant 25 mg arm and –14.00 minutes (95% CI, –18.76 to –9.24 minutes) in the placebo arm, representing an LSM difference of –10.25 minutes (95% CI, –16.95 to –3.55 minutes) in favour of daridorexant 25 mg. Results of the subgroup analysis were generally consistent with the main results, as shown in Appendix 1.

Sleep Onset

Sleep onset, reported as change from baseline in LPS, was 1 of the primary outcomes in Study 301 and Study 302. Table 14 presents the results at month 1 and month 3.

Study 301

In Study 301, the mean LPS at baseline was 63.62 minutes (SD = 37.39 minutes) in the daridorexant 50 mg arm, 67.27 minutes (SD = 38.56 minutes) in the daridorexant 25 mg arm, and 66.54 minutes (SD = 39.77 minutes) in the placebo arm.

At month 1, the LSM change from baseline in LPS was –31.20 minutes (95% CI, –34.51 to –27.90 minutes) in the daridorexant 50 mg arm, –28.17 (95% CI, –31.51 to –24.83 minutes) in the daridorexant 25 mg arm, and –19.85 minutes (95% CI, –23.18 to –16.52 minutes) in the placebo arm. The LSM difference in change from baseline in LPS at 1 month compared to placebo was –11.35 minutes (97.5% CI, –16.694 to –6.015 minutes) in favour of daridorexant 50 mg and –8.32 minutes (97.5% CI, –13.69 to –2.96 minutes) in favour of daridorexant 25 mg.

At month 3, the LSM change from baseline in LPS was –34.80 minutes (95% CI, –38.12, to –31.49 minutes) in the daridorexant 50 mg arm, –30.73 minutes (95% CI, –34.04 to –27.41 minutes minutes) in the daridorexant 25 mg arm, and –23.13 minutes (95% CI, –26.46 to –19.80 minutes) in the placebo arm. The LSM difference in change from baseline in LPS at 3 months compared to placebo was –11.67 minutes (97.5% CI, –17.03 to –6.32 minutes) in favour of daridorexant 50 mg and–7.59 minutes (97.5% CI, –12.94 to –2.25 minutes) in favour of daridorexant 25 mg.

Results of the subgroup analysis based on age (< 65 years or ≥ 65 years) and sex (male or female) followed the same general pattern as the overall population as shown in Appendix 1.

Table 14: Change From Baseline to Month 1 and Month 3 in WASO and LPS — Study 301 and Study 302 (Full Analysis Set)

CI = confidence interval; CL = confidence limit; LPS = latency to persistent sleep; LSM = least squares mean; NA = not applicable; SD = standard deviation; vs. = versus; WASO = wake after sleep onset.

^aThe P value has been adjusted for multiple testing. Note that alpha levels were based on hypothesis testing. For WASO: daridorexant 50 mg at month 1, alpha = 0.025; daridorexant 50 mg at month 3, alpha = 0.025; daridorexant 25 mg at month 1, alpha = 0.025; daridorexant 25 mg at month 3, alpha = 0.01875. For LPS: daridorexant 50 mg at month 1, alpha = 0.025; daridorexant 50mg at month 3, alpha = 0.025; daridorexant 25 mg at month 1, alpha = 0.025; daridorexant 25 mg at month 3, alpha = 0.01875.

^bMixed models for repeated measures (MMRM) for change from baseline in WASO = baseline WASO + age group (< 65 years or ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

^cMMRM for change from baseline in LPS = baseline LPS + age group (< 65 years or ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

^dValues from Study 302 are 95% CI.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷

Study 302

In Study 302, the mean LPS at baseline was 68.88 minutes (SD = 40.55 minutes) in the daridorexant 25 mg arm and 71.82 minutes (SD = 46.09 minutes) in the placebo arm.

At month 1, the LSM change from baseline was –26.46 minutes (95% CI, –30.63 to –22.29 minutes) for daridorexant 25 mg and –20.01 minutes (95% CI, –24.15 to –15.88 minutes) for placebo, corresponding to an LSM difference of –6.45 minutes (95% CI, 12.28, to –0.61 minutes) in favour of daridorexant 25 mg. Findings from the subgroups were consistent with the main results, as shown in Appendix 1.

At month 3, the LSM change from baseline was –28.91 minutes (95% CI, –33.41 to –24.40 minutes) in the daridorexant 25 mg arm and –19.89 minutes (95% CI, –24.38 to –15.41 minutes) in the placebo arm, representing an LSM difference of –9.01 minutes (–15.34 to –2.68 minutes) in favour of daridorexant 25 mg. Results of the subgroup analysis were generally consistent with the main results, as shown in Appendix 1.

Sleep Duration

Sleep duration, measured subjectively, was reported as change from baseline in sTST and was a secondary outcome in Study 301 and Study 302. Table 15 presents the results at month 1 and month 3.

Study 301

In Study 301, the mean sTST at baseline was 313.18 minutes (SD = 57.60 minutes) in the daridorexant 50 mg arm, 309.85 minutes (SD = 60.11 minutes) in the daridorexant 25 mg arm, and 315.89 minutes (SD = 53.14 minutes) in the placebo arm.

At month 1, the LSM change from baseline in sTST was 43.62 minutes (95% CI, 38.17 to 49.06 minutes) in the daridorexant 50 mg arm, 34.18 minutes (95% CI, 28.72 to 39.65 minutes) in the daridorexant 25 mg arm, and 21.56 minutes (95% CI, 16.10 to 27.02 minutes) in the placebo arm. The LSM difference in change from baseline in sTST at 1 month compared to placebo was 22.06 minutes (97.5% CI, 13.30 to 30.18 minutes) in favour of daridorexant 50 mg and 12.62 minutes (97.5% CI, 3.85 to 21.39 minutes) in favour of daridorexant 25 mg.

At month 3, the LSM change from baseline was 57.67 minutes (95% CI, 51.17 to 64.17 minutes) in the daridorexant 50 mg arm, 47.83 minutes (95% CI, 41.33 to 54.33 minutes) in the daridorexant 25 mg arm, and 37.90 minutes (95% CI, 31.39 to 44.40 minutes) in the placebo arm. The LSM difference in change from baseline in sTST compared to placebo was 19.77 minutes (97.5% CI, 9.30 to 30.24 minutes) in favour of daridorexant 50 mg and 9.93 minutes (97.5% CI, –0.54 to 20.40 minutes) in favour of daridorexant 25 mg.

Study 302

In Study 302, the mean sTST at baseline was 308.49 minutes (SD = 52.85 minutes) in the daridorexant 25 mg arm and 307.57 minutes (SD = 51.52 minutes) in the placebo arm.

At month 1, the LSM change from baseline in sTST was 43.77 minutes (95% CI, 38.14 to 49.41 minutes) in the daridorexant 25 mg arm and 27.64 minutes (95% CI, 22.02 to 33.27 minutes) in the placebo arm. The mean change from baseline in sTST was 16.13 minutes longer with daridorexant 25 mg than with placebo (95% CI, 8.22 to 24.04 minutes).

At month 3, the LSM change from baseline in sTST was 56.18 minutes (95% CI, 49.81 to 62.55 minutes) in the daridorexant 25 mg arm and 37.12 minutes (95% CI, 30.78 to 43.46 minutes) in the placebo arm. The LSM difference compared to placebo was 19.06 minutes (95% CI, 10.13 to 27.99 minutes) in favour of daridorexant 25 mg.

Table 15: Change From Baseline to Month 1 and Month 3 in sTST — Study 301 and Study 302 (Full Analysis Set)

CI = confidence interval; LSM = least squares mean; NA = not applicable; SD = standard deviation; sTST = subjective total sleep time; vs. = versus.

^aThe P value has been adjusted for multiple testing. Note that alpha levels were based on hypothesis testing. For sTST, daridorexant 50 mg at month 1, alpha = 0.025; daridorexant 50 mg at month 3, alpha = 0.025; daridorexant 25 mg at month 1, alpha = 0.025; daridorexant 25 mg at month 3, alpha = 0.0375

^bMixed models for repeated measures for change from baseline in sTST = baseline sTST + age group (< 65 years or ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

^cValues from Study 302 are 95% CI.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Sleep Quality

Sleep quality was determined using the SDQ and was considered an exploratory outcome in the included studies. Table 16 presents the reported sleep quality in Study 301 and Study 302 at month 1 and month 3.

Study 301

The mean VAS score for sleep quality at baseline was 36.23 (SD = 17.03) in the daridorexant 50 mg arm, 35.56 (SD = 17.77) in the daridorexant 25 mg arm, and 35.60 (SD = 17.78) in the placebo arm. In Study 301, there were within-group improvements in sleep quality from baseline in all groups, with numerically greater improvements in the active treatment groups than in the placebo group.

At month 1, the mean change from baseline was 14.21 points (SD = 18.95 points) in the daridorexant 50 mg arm, 11.35 points (SD = 15.65 points) in the daridorexant 25 mg arm, and 7.04 points (SD = 13.74 points) in the placebo arm.

At month 3, the mean change from baseline was 20.21 points (SD = 22.15 points) in the daridorexant 50 mg arm, 18.20 (SD = 19.10 points) in the daridorexant 25 mg arm, and 13.95 points (SD = 18.85 points) in the placebo arm.

Study 302

The mean VAS sleep quality score at baseline was 37.94 (SD = 15.02) in the daridorexant 25 mg arm and 36.91 (SD = 14.77) in the placebo arm. In Study 302, there were within-group improvements in sleep quality from baseline in both groups, with numerically greater improvements in the active treatment group than in the placebo group.

At month 1, the mean change from baseline was 11.20 points (SD = 15.55 points) in the daridorexant 25 mg arm and 9.41 points (SD = 14.44 points) in the placebo arm.

At month 3, the mean change from baseline was 17.77 points (SD = 18.55 points) in the daridorexant 25 mg arm and 13.18 points (SD = 17.33 points) in the placebo arm.

Change From Baseline in IDSIQ Total Score

The change from baseline in the IDSIQ total score, which is the sum of 3 IDSIQ domain scores (i.e., alert/cognition, sleepiness, and mood), was another efficacy end point in the included trials. The results are presented in Table 16. Per the sponsor’s request, results for the IDSIQ sleepiness domain are provided in Table 31 of Appendix 1.

Study 301

The mean IDSIQ total score at baseline was 74.52 points (SD = 25.16 points) in the daridorexant 50 mg arm, 73.06 points (SD = 24.55 points) in the daridorexant 25 mg arm, and 73.55 points (SD = 24.64 points) in the in the placebo arm.

The LSM difference in change from baseline in IDSIQ total score compared to placebo at month 1 was –7.24 points (95% CI, –9.785 to –4.698 points) in favour of daridorexant 50 mg and –2.94 points (95% CI, –5.487 to –0.385 points) in favour of daridorexant 25 mg. The LSM difference between groups at month 3 compared to placebo was –7.20 points (95% CI, –10.544 to –3.862 points) in favour of daridorexant 50 mg and –3.46 points (95% CI, –6.809 to –0.113 points) in favour of daridorexant 25 mg.

Study 302

The mean IDSIQ total scores at baseline were 73.14 points (SD = 21.21) in the daridorexant 25 mg arm, and 74.48 points (SD = 20.26) in the placebo arm.

At month 1, the mean difference from baseline in IDSIQ total score was 3.11 points (95% CI, –5.807 to –0.412 points) lower in the daridorexant arm than in the placebo arm. At month 3, the IDSIQ total score was 4.23 points (95% CI, –7.477 to –0.986) lower in the daridorexant 25 mg arm than in the placebo arm.

Table 16: Change From Baseline to Month 1 and Month 3 in Sleep Quality and IDSIQ Total Score — Study 301 and Study 302 (Full Analysis Set)

CI = confidence interval; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; LSM = least squares mean; NA = not applicable; SD = standard deviation; VAS = visual analogue scale; vs. = versus.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Change From Baseline in ISI Score

The change from baseline in ISI score was an exploratory outcome in the included trials. The results are presented in Table 17.

Study 301

The mean ISI score at baseline was 19.3 points (SD = 4.0 points) in the daridorexant 50 mg arm, 19.0 points (SD = 4.3 points) in the daridorexant 25 mg arm, and 19.2 (SD = 4.0 points) in the placebo arm.

At month 1, the LSM change from baseline was –4.81 points (95% CI, –5.36 to –4.26 points) in the daridorexant 50 mg arm, –4.07 points (95% CI, –4.63 to –3.51 points) in the daridorexant 25 mg arm, and –3.05 points (95% CI, –3.60 to –2.50 points) in the placebo arm. Compared to placebo, there was a decrease in ISI score of –1.76 points (95% CI, –2.54 to –0.99) in the daridorexant 50 mg arm and of –1.02 points (95% CI, –1.80 to –0.24) in the daridorexant 25 mg arm.

At month 3, the LSM change from baseline was –7.17 points (95% CI, –7.84 to –6.50 points) in the daridorexant 50 mg arm, –6.02 points (95% CI, –6.69 to –5.35 points) in the daridorexant 25 mg arm, and –5.19 points (95% CI, –5.86 to –4.52 points) in the placebo arm. Compared to placebo, there was a decrease in ISI score of –1.98 points (95% CI, –2.92 to –1.04 points) in the daridorexant 50 mg arm and –0.83 points (95% CI, –1.78 to 0.11 points) in the daridorexant 25 mg arm.

Study 302

The mean ISI score at baseline was 19.5 points (SD = 4.0 points) in the daridorexant 25 mg arm and 19.6 points (SD = 4.1 points) in the placebo arm. At month 1, the mean change from baseline was –5.1 points (SD = 5.2 points) in the daridorexant 25 mg arm and –3.8 points (SD = 4.6 points) in the placebo arm. At month 3, the mean change from baseline was –6.9 points (SD = 6.0 points) in the daridorexant 25 mg arm and –5.4 points (SD = 5.5 points) in the placebo arm.

Table 17: Change From Baseline to Month 1 and Month 3 in ISI Total Score — Study 301 and Study 302 (Full Analysis Set)

CI = confidence interval; ISI = Insomnia Severity Index; LSM = least squares mean; NA = not applicable; NR = not reported; SD = standard deviation; vs. = versus.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Change From Baseline in Duration of TST in Each Sleep Stage

The change from baseline in the duration of TST in each sleep stage (i.e., S1, S2, SWS, and REM) was an exploratory end point in the included trials. The results are presented in Table 18.

Study 301

For S1, the change from baseline to 1 month was 5.41 minutes in the daridorexant 50 mg arm, 4.26 minutes in the daridorexant 25 mg, and 2.59 minutes in the placebo arm. For S2, the change from baseline to 1 month was 34.74 minutes in the daridorexant 50 mg arm, 29.79 minutes in the daridorexant 25 mg arm, and 16.10 minutes in the placebo arm. For SWS, the change from baseline to 1 month was 2.16 minutes in daridorexant 50 mg arm, 0.71 minutes in the daridorexant 25 mg arm, and 1.60 minutes in the placebo arm. For REM, the change from baseline to 1 month was 15.51 minutes in the daridorexant 50 mg arm, 13.50 minutes in the daridorexant 25 mg arm, and 9.22 minutes in the placebo arm.

For S1, the change from baseline to 3 months was 6.89 minutes in the daridorexant 50 mg arm, 5.67 minutes in the daridorexant 25 mg arm, and 4.51 minutes in the placebo arm. For S2, the change from baseline was 37.69 minutes in the daridorexant 50 mg arm, 36.19 minutes in the daridorexant 25 mg arm, and 25.07 minutes in the placebo arm. For SWS, the change from baseline was –0.20 minutes in the daridorexant 50 mg arm, 0.20 minutes in the daridorexant 25 mg arm, and –1.54 minutes in the placebo arm. For REM, the change from baseline was 16.21 minutes in the daridorexant 50 mg arm, 12.55 minutes in the daridorexant 25 mg arm, and 11.65 minutes in the placebo arm.

Study 302

For S1, the change from baseline to month 1 was 3.64 minutes in the daridorexant 25 mg arm and 1.81 minutes in the placebo arm. For S2, the change from baseline to 1 month was 31.54 minutes in the daridorexant 25 mg arm and 24.09 minutes in the placebo arm. For SWS, the change from baseline to 1 month was 0.45 minutes in the daridorexant 25 mg arm and 0.90 minutes in the placebo arm. For REM, the change from baseline to 1 month was 14.19 minutes in the daridorexant 25 mg arm and 7.31 minutes in the placebo arm.

For S1, the change from baseline to month 3 was 5.46 minutes in the daridorexant 25 mg arm and 2.10 minutes in the placebo arm. For S2, the change from baseline to month 3 was 31.36 minutes in the daridorexant 25 mg arm and 25.45 minutes in the placebo arm. For SWS, the change from baseline to month 3 was –0.91 minutes in the daridorexant 25 mg arm and 0.65 minutes in the placebo arm. For REM. and the change from baseline to month 3 was 13.86 minutes in the daridorexant 25 mg arm and 6.94 minutes in the placebo arm.

The pattern of distribution of changes was similar across the groups, as shown in Appendix 1.

Table 18: Change From Baseline to Month 1 and Month 3 in Duration of TST in Each Sleep Stage — Study 301 and Study 302 (Full Analysis Set)

REM = rapid eye movement; SD = standard deviation; SWS = slow-wave sleep; TST = total sleep time.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Harms

Detailed harms data are summarized in Table 19.

Adverse Events

The overall incidence of TEAEs in Study 301 was generally similar across the groups; 41.3% of patients in the daridorexant 25 mg arm experienced TEAEs, as did 39.3% in the daridorexant 50 mg and 37.2% in the placebo arm. Similarly, in Study 302, the overall incidence of TEAEs was 41.2% in the daridorexant 25 mg arm and 36.3% in the placebo arm.

In Study 301, the most common TEAEs in the daridorexant 25 mg, daridorexant 50 mg, and placebo arms were nasopharyngitis (9.0% versus 7.8% versus 7.8%) and headache (5.5% versus 6.5% versus 3.9%). Other notable TEAEs included accidental overdose (1.9% versus 2.6% versus 1.9%), fatigue (2.3% versus 2.6% versus 0.6%), and dizziness (1.9% versus 2.3% versus 0.6%). The incidence of somnolence was similar in all groups, including the placebo group (3.5% versus 1.9% versus 2.3%).

In Study 302, the most common TEAEs in the daridorexant 25 mg and placebo arms were nasopharyngitis (4.2% versus 6.5%) and headache (5.2% versus 3.6%). Other notable TEAEs included accidental overdose (1.6% versus 1.0%), fatigue (3.6% versus 0.7%), and dizziness (2.3% versus 1.6%). The incidence of somnolence was 3.2% in the daridorexant 25 mg arm and 1.3% in the placebo arm.

Serious Adverse Events

The incidence of SAEs was generally low in both studies. In Study 301, SAEs were reported in 2 patients (0.6%) in the daridorexant 25 mg arm, 3 patients (1.0%) in the daridorexant 50 mg arm, and 7 patients (2.3%) in the placebo arm. In Study 302, SAEs were reported in 3 patients (1%) in the daridorexant 25 mg arm and 4 patients (1.3%) in the placebo arm.

Withdrawals Due to Adverse Events

In Study 301, AEs leading to withdrawal were reported in 7 patients (2.3%) in the daridorexant 25 mg, 3 patients (1.0%) in the daridorexant 50 mg arm, and 10 patients (3.2%) in the placebo arm. In Study 302, 4 patients (1.3%) in the daridorexant 25 mg arm and 7 patients (2.3%) in the placebo arm stopped treatment due to AEs.

Mortality

In Study 301, there was 1 death due to myocardial infarction, although it was not considered to be related to treatment (Table 19). No deaths were reported in Study 302.

Notable Harms

Notable harms of interest to this review included next-morning residual effects, rebound insomnia, and suicidal ideation, which were evaluated as part of the safety outcomes in Study 301 and Study 302. Other AESIs to this review included hallucinations and narcolepsy-like symptoms.

Next-Morning Residual Effect

Next-morning residual effect was a safety outcome in both studies and was flagged as important by the clinical experts. The morning sleepiness scores on the SDQ VAS were similar in the daridorexant and placebo groups at baseline in both studies. At month 1 and month 3, the mean observed values for morning sleepiness were higher than at baseline in all groups. In Study 301, change from baseline values at 3 months improved by 14.85 points in the daridorexant 25 mg arm, 15.28 points in the daridorexant 50 mg arm, and 11.50 points in the placebo arm. In Study 302, change from baseline values at 3 months improved by 14.91 points in the daridorexant 25 mg arm and 11.40 points in the placebo arm. In both studies, the change from baseline was numerically higher in the daridorexant groups than in the placebo groups; however, no statistical comparisons were made. Results are presented in Appendix 1.

Rebound Insomnia

Clinical experts consulted for this review noted that rebound insomnia, characterized by the worsening of sleep parameters upon discontinuation of the medication, as an important safety outcome. In Study 301 and Study 302, during the placebo run-out period, WASO and LPS were numerically lower, and the mean self-reported total sleep time was higher than baseline values, indicating an absence of rebound insomnia in both the daridorexant and placebo groups (Table 32). However, no statistical comparisons were made. Results are presented in Appendix 1.

Suicidal Ideation

In Study 301, no patients reported any TEAEs related to suicide or self-injury. Based on the C-SSRS, no patient-reported suicidal ideation or behaviour occurred during the study treatment (double-blind and placebo run-out) periods (data not shown).

In Study 302, 1 patient in the daridorexant 25 mg arm was found to have an AESI related to suicide or self-injury. Based on the C-SSRS, no patient-reported suicidal ideation or behaviour occurred during the study treatment (double-blind and placebo run-out) periods (data not shown).

Other Harms of Interest

In Study 301 and Study 302, 1 patient each (both in the daridorexant 25 mg arms) reported having hallucinations. Narcolepsy-like symptoms related to complex sleep behaviour, including hallucinations and sleep paralysis, were reported in 3 patients in each of the 2 studies. The results are presented in Table 19.

Table 19: Summary of Harms Results — Study 301 and Study 302

SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aOccurring from the start of double-blind study treatment up until 30 days after the end of double-blind study treatment or enrolment in the Study 303 extension.

^bAn Independent Safety Board reviewed blinded clinical patient data on selected adverse events and safety assessment results and adjudicated whether the submitted cases were adverse events of special interest.

Sources: Clinical Study Reports for Study 301¹⁶ and Study 302.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence and the Clinical Study Reports.

Critical Appraisal

Internal Validity

Study 301 and Study 302 were multicentre, double-blind, phase III, randomized placebo-controlled trials. Randomization processes (i.e., using Interactive Response Technology) and the allocation concealment process used in the studies were judged to be appropriate and ensuring an overall balanced distribution of patients to either the active treatment or placebo groups. Treatment allocation was stratified by age (< 65 years or ≥ 65 years). According to the clinical experts, age is a clinically important variable, particularly with regard to harms (i.e., morning sedation and night dizziness) and the risk of injury due to a fall, and the stratification conducted in the included studies was appropriate.

Treatment discontinuations were relatively infrequent (7.1% to 9.0% in Study 301 and 5.8% to 7.4% in Study 302), as were permanent study discontinuations (7.1% to 9.7% in Study 301 and 7.1% to 9.4% in Study 302), and most of the participants in Study 301 and Study 302 completed the double-blinded treatment period; thus, the risk of attrition bias was considered low. Additionally, treatment adherence was more than 98% in both studies. Overall, the harms observed in the study, and the similar discontinuation rates across arms and studies, suggest that unblinding was unlikely.

Multiplicity adjustment using alpha-splitting was conducted for the primary and secondary outcomes to control for type I error. Other outcomes (i.e., efficacy outcomes such as IDSIQ total score and exploratory outcomes such as sleep quality, ISI scores, and duration of TST during each sleep stage) were not adjusted for multiplicity, so there is an increased risk of false-positive conclusions for statistically significant results. Similarly, subgroup analyses were not adjusted for multiplicity. Missing data were evaluated using implicit imputation, which raised concerns about bias that would overestimate the effect of daridorexant. As noted, discontinuations were infrequent and the overall rate of missing data was low (< 10%) in both studies for all relevant outcomes. Low overall missingness and balanced discontinuation rates across groups reduced concerns related to this potential overestimation, but did not completely rule out bias from informative missingness. Sensitivity analyses using multiple imputation under missing-not-at-random assumptions further supported the robustness of the results, as statistical significance was maintained even under conservative imputations. Therefore, any impact of bias due to missing data on study results was likely low.

The primary outcomes in both studies were objectively measured using PSG during sleep studies, whereas subjectively measured outcomes were captured using self-assessment of patients’ sleep or validated questionnaires. Although PSG provides objective data on sleep parameters and is less prone to reporting bias, its results may not fully capture real-world sleep patterns. Sleep disturbances related to sleep-study settings — including factors such as a separate sleeping location and the presence of monitoring equipment (e.g., connected probes) — may alter sleep architecture and limit the accuracy and generalizability of PSG results. According to the clinical experts consulted for this review, patients’ self-reporting of sleep may not align with the more objective measures. They noted, for example, that patients with insomnia have been found to overestimate the time taken to fall asleep (sleep onset latency) and to underestimate total sleeping time. The clinical experts emphasized that insomnia is largely a subjective condition and that sleep complaints are very individualized; therefore, self-reported sleep quality and perceived changes in patients’ sleep may be more clinically meaningful than PSG-derived metrics. However, subjective measures may be more prone to bias, including recall bias and placebo effects, that cannot be easily measured or accounted for, making it difficult to determine the true magnitude and certainty of treatment effects. Thresholds of clinical significance for all relevant outcomes, except for sleep quality by VAS, were provided by the sponsor. According to the clinical experts consulted for this review, these thresholds were clinically relevant and acceptable. They noted that the most clinically useful measure of improved sleep is a patient’s own perception. However, it can be difficult to quantify an exact value for improved sleep.

External Validity

There were several limitations in the included studies that could affect the generalizability of results to Canadian clinical settings. Among the patients who were screened for the trials, most patients failed screening (72.4% in Study 301 and 74.9% in Study 302), either at the initial screening stage or after the single-blind run-in period. The most common reason for screening failure was not meeting the inclusion or exclusion criteria, although the submission did not provide any additional details on the exact criteria that were failed during screening. Based on the eligibility criteria for the trials, patients who did not meet specific sleep parameters on PSG and those with comorbidities (e.g., acute or unstable psychiatric conditions) were excluded. According to the clinical experts, CID is diagnosed based on clinical assessment and patient interview rather than PSG or other sleep studies, which are not performed in clinical settings. Also, patients who were excluded based on comorbidities could have otherwise been potential candidates for treatment with daridorexant. Thus, the screening process may have led to a study population that does not reflect the broader population with CID in Canada, limiting the generalizability of the results.

The clinical experts confirmed that the baseline characteristics of patients in Study 301 and Study 302 were generally similar to those of patients seen in Canadian clinical settings, with some notable limitations. Although mean age, duration of disease, and distributions of sex in the trial populations were consistent with those in settings in Canada, the clinical experts noted that the proportion of Asian patients was considerably lower in the studies (especially Study 301) than in Canadian settings. It is unclear whether this would affect the study results, beyond cultural differences related to sleep among different racial groups.

According to the Health Canada product monograph, daridorexant is contraindicated for patients who use strong CYP3A4 inhibitors, although daridorexant 25 mg is indicated for patients receiving moderate CYP3A4 inhibitors (or those with moderate hepatic impairment). However, the use of moderate or strong CYP3A4 inhibitors was prohibited during the studies, and those unwilling or unable to discontinue those medications were excluded from both studies. Therefore, any interpretation of efficacy or harms results in the daridorexant 25 mg treatment group was a challenge.

Several medications, including concomitant pharmacological treatments for insomnia or other CNS-related medications, were prohibited in the studies. According to the clinical experts, patients with CID seen in Canadian clinical settings would often be taking 1 or more of the CNS-related medications prohibited in the studies. One notable example of prohibited medications was antihistamines; many people in the real world take over-the-counter antihistamines to manage allergies. Patients in the included studies were allowed to continue CBT-I throughout the study. Although only a minority of patients receive CBT-I in the real world, the proportion would likely be higher than that observed in the trials (3 patients [0.3%] in Study 301, and no patients in Study 302), and the clinical experts noted that, generally, this would be considered a first-line treatment. In the included trials, the most common reason for not using CBT was patient unawareness that CBT was a treatment option. As noted by the clinical experts consulted for this review, physician and patient unawareness and limited accessibility are the most common reasons that patients in real-world settings do not receive CBT-I. Overall, concerns regarding concomitant medications could lower the generalizability of the results. However, it is worth noting that these exclusions were likely implemented to prevent concern about influence from other sleep-active drugs.

As previously noted, sleep studies are not used in clinical settings to diagnose or assess insomnia; instead, patients are usually interviewed about their sleep and how they feel. Additionally, subjective measures used in the studies, such as IDSIQ, ISI, and SDQ, are not routinely used in clinical practice, per the clinical experts consulted for this review.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^61,62

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for daridorexant 50 mg versus placebo. As daridorexant 25 mg is only used for patients receiving moderate CYP3A4 inhibitors or those with moderate hepatic impairment, this group was not included in the GRADE assessment. Further, there is a dose-response relationship associated with daridorexant 25 mg and daridorexant 50 mg; thus, only the results for the 50 mg dose were included in the GRADE assessment.

Long-Term Extension Studies

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Description of Studies

One LTE study (Study 303; N = 804) has been summarized to provide evidence on the long-term safety and tolerability of daridorexant in adult and older patients with CID. Study 303 was a multicentre, double-blind, parallel-group, randomized, placebo-controlled, 40-week extension to Study 301 and Study 302. Study 303 was conducted at 94 sites in 14 countries, with 7 sites in Canada.

As shown in Figure 4, Study 303 included a 30-day safety follow-up phase after the end of double-blind treatment to assess AEs, SAEs, and concomitant medications. This phase included an initial 7-day single-blind run-out period, during which all patients received a daily dose of placebo, followed by a safety follow-up period until the end of the study (week 44).

Figure 4: Study Design of Study 303

ACT-541468 = daridorexant; EODBT = end of double-blind treatment; EOS = end of study; EOT = end of treatment; ID-078A301 = Study 301; ID-078A302 = Study 302; V = visit.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Populations

For Study 303, eligible participants were required to have completed Study 301 or Study 302. Inclusion and exclusion criteria for Study 303 were generally in line with those in the pivotal trials, as identified in Table 5.

Interventions

Patients who received daridorexant in Study 301 or Study 302 maintained the same dose in Study 303, and patients who received placebo were rerandomized in a 1:1 ratio to continue to receive placebo or to receive daridorexant 25 mg. Because the Health Canada–recommended therapeutic daily dose of daridorexant for adults is 50 mg, or 25 mg for patients with moderate hepatic impairment, the results for the 10 mg dose were not included in this section. Prohibited concomitant therapies were in line with those in the pivotal trials.

Outcomes

Table 20 presents a list of relevant outcomes evaluated in Study 303. Unlike the pivotal trials, Study 303 assessed sWASO, which consisted of the self-reported time spent awake after sleep onset, reported in item 7 of the SDQ (In total, how long did these awakenings last?) and sLSO consisted of the self-reported time to fall asleep, reported in item 5 of the SDQ (How long did it take you to fall asleep?). Most efficacy results are presented in the table at week 12 and week 36 of the extension study, corresponding to month 6 and month 12 from the confirmatory study baseline.

Table 20: Key End Points in Study 303

AESI = adverse event of special interest; BWSQ = Benzodiazepine Withdrawal Symptom Questionnaire; C-SSRS = Columbia Suicide Severity Rating Scale; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; ISI = Insomnia Severity Index; SAE = serious adverse event; SDQ = Sleep Diary Questionnaire; sLSO = subjective latency to sleep onset; sTST = subjective total sleep time; sWASO = subjective wake after sleep onset; TEAE = treatment-emergent adverse event; VAS = visual analogue scale.

^aBaseline refers to the last nonmissing assessment or value measured before or on the first day of double-blind study treatment in Study 301 or Study 302, unless otherwise noted in the report.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence. ^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Statistical Analysis

The analyses of efficacy end points were performed using the full analysis set. For all efficacy end points, change from baseline was analyzed using the confirmatory baseline, which was defined as the last nonmissing assessment or value measured before or on the first day of double-blind study treatment in Study 301 or Study 302. A linear mixed-effects model was used for the analyses of change from baseline in sTST, sWASO, sLSO, and in IDSIQ total score, sleepiness domain score, alert/cognition domain score, and mood domain score. The model was adjusted for the baseline value of the relevant response variable, age group per assigned strata, treatment, visit, the interaction of treatment by visit, and the interaction of baseline by visit. An unstructured covariance matrix was used to model the correlation among repeated measurements.

The treatment differences between daridorexant groups (25 mg and 50 mg) and placebo at week 12, week 24, and week 36 were based on the LSM change from confirmatory study baseline. For each daridorexant dose compared to placebo, the placebo-adjusted LSM, standard errors, 95% CI, and unadjusted two-sided P value were presented.

The end points for VAS scores, ISI, and the number of self-reported awakenings were summarized descriptively.

Unless otherwise noted, the safety set was used for tables and listings of safety data. For safety end points, TEAEs, SAEs, and AESIs were summarized descriptively. These events were collected from the start of double-blind treatment until up to 30 days after the end of double-blind treatment. Changes from baseline in safety outcomes were analyzed using the confirmatory study baseline, as previously defined.

No adjustment for multiple testing was implemented.

Handling of Missing Data

For sTST, sWASO, sLSO, IDSIQ scores, VAS scores, and the number of self-reported awakenings, at least 2 days of data for each week was required to calculate a weekly mean. Otherwise, the mean value was considered missing for that week.

Subgroups

The treatment effect of daridorexant versus placebo was evaluated across different subgroups. These included age at screening in Study 301 (< 65 years, 65 to 74 years, ≥ 75 years) for all end points, as well as sex, region, race, and body mass index at screening (< 30 kg/m², ≥ 30 kg/m²) for sTST and IDSIQ scores. The analyses used the linear mixed-effects models previously described, applied separately to each subgroup.

Analysis Populations

The analysis sets used in Study 303 are described in Table 21.

Table 21: Analysis Populations in Study 303

BWSQ = Benzodiazepine Withdrawal Symptom Questionnaire; sTST = subjective total sleep time.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

A summary of patient disposition in Study 303 is presented in Table 22. In Study 303, all 137 patients in the daridorexant 50 mg group originated from the same dose group in Study 301. The daridorexant 25 mg group included 132 patients (48.9%) from Study 301 and 138 patients (51.1%) from Study 302, all from the corresponding dose group. Similarly, the placebo group comprised 57 patients (44.5%) from Study 301 and 71 patients (55.5%) from Study 302. Among the 127 patients who transitioned from placebo in the pivotal trials to daridorexant 25 mg in Study 303, 66 patients (52.0%) came from Study 301 and 61 patients (48.0%) from Study 302.

A total of 804 patients were enrolled in Study 303, with 662 patients enrolled into treatment arms of interest to this review. Across treatment arms of interest to this review, 208 patients (31.4%) prematurely discontinued treatment. The most frequent reason for treatment discontinuation was lack of efficacy, with the placebo group showing the highest rate (22.7%), followed by 10.7% the daridorexant 25 mg group, 9.5% in the daridorexant 50 mg group, and 7.9% in the ex-placebo to daridorexant 25 mg group. A total of 459 patients (69.3%) in these 4 treatment groups completed the study, and the remaining 203 patients (30.7%) discontinued prematurely, mainly due to patient withdrawal. The placebo group had the highest withdrawal rate (25.0%), followed by the ex-placebo to daridorexant 25 mg group (19.7%), the daridorexant 25 mg group (19.6%), and the daridorexant 50 mg group (15.3%).

Table 22: Patient Disposition in Study 303

^aComprised patients who received at least 1 dose of the study treatment during the extension study.

^bComprised patients in the safety set who received at least 1 dose of placebo run-out treatment.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics of patients enrolled into treatment arms of interest to this review from Study 303 are summarized in Table 23. A total of 662 patients were enrolled into treatment arms of interest from Study 303, with 137 patients in the daridorexant 50 mg group, 270 in daridorexant 25 mg group, 127 in the ex-placebo to daridorexant 25 mg group, and 128 patients in the placebo group. Demographic characteristics and baseline efficacy characteristics were generally balanced across treatment groups, and were similar to those in the pivotal studies, with mean age ranging from 56.5 years to 59.2 years across treatment groups. Baseline values at the start of the pivotal trials for efficacy variables, such as sTST, IDSIQ scores, sLSO, and sWASO, were well balanced in the daridorexant 25 group, the daridorexant 50 mg group, and the placebo group. IDSIQ scores in the ex-placebo to daridorexant 25 mg group were lower (improved) at Study 303 baseline than scores in the other treatment groups at Study 301 and Study 302 baseline. However, IDSIQ scores in the ex-placebo to daridorexant 25 mg group were comparable to those in the placebo group at the extension study baseline; mean score on the sleepiness domain was 18.44 (SD = 7.38), on the mood domain was 14.64 (SD = 8.62), and on the alert/cognition domain was 24.95 (SD = 10.77), and IDSIQ total score was 57.32 (SD = 25.83).

Table 23: Summary of Baseline Characteristics in Study 303 (Full Analysis Set)

BMI = body mass index; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; ISI = Insomnia Severity Index; SD = standard deviation; sTST = subjective total sleep time.

Note: Baseline values from confirmatory Study 301 or Study 302 are reported unless otherwise noted.

^aStudy concomitant therapies are any treatments that are either ongoing at the signing of informed consent for the extension study or initiated between the signing of informed consent and the end of the study.

^bA score of 15 to 21 indicates moderate insomnia; a score of 22 to 28 indicates severe insomnia.

^cValues are as reported at baseline of the extension study.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

A summary of treatment exposure in Study 303 is presented in Table 24. Overall exposure (mean duration of double-blind treatment in the extension study) was 231 days in the daridorexant 25 mg group, 222 days in the daridorexant 50 mg group, 232 days in the ex-placebo to daridorexant 25 mg group, and 210 days in the placebo group. Compliance during the double-blind treatment phase was high, with a mean of more than 99% of patients in each group adhering to treatment, and was generally consistent between the groups; there were no treatment interruptions.

Table 24: Study Treatment Exposure and Adherence During the Double-Blind Treatment Period in Study 303 (Safety Set)

SD = standard deviation.

^aDuring the treatment withdrawal set.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Concomitant Medications and Cointerventions

A summary of concomitant medications in Study 303 is presented in Table 25. As in Study 301, therapies deemed necessary for a patient's well-being and not classified as prohibited concomitant medications were allowed. The use of concomitant therapies during double-blind treatment was defined as treatments ongoing at the start of the double-blind treatment or initiated during the double-blind period and continued until up to 1 day after the last double-blind dose. During the double-blind treatment phase, 65% of patients in the daridorexant 50 mg group, 71.6% in the daridorexant 25 mg group, 74.6% in the ex-placebo to daridorexant 25 mg group, and 70.3% in the placebo group reported using at least 1 concomitant medication. The most frequently used concomitant medications were propionic acid derivatives, thyroid hormones, beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, angiotensin-converting-enzyme inhibitors, and proton pump inhibitors.

Table 25: Concomitant Medications Used During the Double-Blind Treatment Phase in Study 303 (Safety Set)

ACE = angiotensin-converting enzyme.

Sources: Clinical Study Report for Study 303 and sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

For the daridorexant 50 mg, daridorexant 25 mg, and placebo groups, baseline refers to assessments conducted on or before the start of the double-blind study treatment in Study 301 or Study 302, representing the confirmatory study baseline. For the ex-placebo to daridorexant 25 mg group, baseline refers to assessments conducted on or before the start of the double-blind study treatment in the extension study. The exploratory efficacy analysis included the same subjective end points as Study 301.

The results for change from baseline in sWASO, sLSO, sTST, and IDSIQ total score in Study 303 are presented in Table 26.

Change From Baseline in sWASO

During the extension study, mean sWASO reductions from baseline were maintained across treatment groups. The LSM difference in the change in sWASO from the confirmatory study baseline to week 36 between the daridorexant 50 mg group and the placebo group was –2.01 minutes (95% CI, –14.71 to 10.68 minutes; P = 0.7554) and between the daridorexant 25 mg group and the placebo group was –1.51 minutes (95% CI, –12.65 to 9.62 minutes; P = 0.5148). For the ex-placebo to daridorexant 25 mg group, mean sWASO values in the extension study from week 4 onward were comparable to the other daridorexant groups. The LSM difference in from the extension study baseline to week 36 between the ex-placebo to daridorexant 25 mg group and the placebo group was –3.92 minutes (95% CI, –13.87 to 5.99 minutes; P = 0.4342).

Change From Baseline in sLSO

In the extension study, improvements were numerically greater in the daridorexant groups than in the placebo group for mean sLSO. The LSM treatment difference in sLSO from confirmatory study baseline to week 36 between the daridorexant 50 mg group and the placebo group was –8.76 minutes (95% CI, –19.34 to 1.82 minutes; P = 0.1044) and between the daridorexant 25 mg group and the placebo group was –9.19 minutes (95% CI, –18.45 to 0.07 minutes; P = 0.0517). The LSM difference in sLSO from extension study baseline to week 36 between the ex-placebo to daridorexant 25 mg group and the placebo group was –15.14 minutes (95% CI, –25.52 to –4.76 minutes; P = 0.0046).

Change From Baseline in sTST

In the extension study, changes in sTST from confirmatory study baseline were numerically greater in the daridorexant groups than in the placebo group, with the most pronounced change in the daridorexant 50 mg group. The LSM treatment difference in sTST from confirmatory study baseline to week 36 between the daridorexant 50 mg group and the placebo group was 17.77 minutes (95% CI, –0.35 to 35.90 minutes; P = 0.0546) and between the daridorexant 25 mg group and the placebo group was 5.26 minutes (95% CI, –10.59 to 21.11 minutes; P = 0.5148). In a post hoc analysis, the LSM treatment difference in sTST from extension study baseline to week 36 between the ex-placebo to daridorexant 25 mg group and the placebo group was 25.74 minutes (95% CI, 9.51 to 41.96; minutes P = 0.0021).

Change from Baseline in IDISQ Total Score

Mean reductions in IDSIQ total score from baseline were maintained throughout the extension study across all treatment groups. The LSM treatment difference in IDSIQ total score from confirmatory study baseline to week 36 between the daridorexant 50 mg group and the placebo group was –9.12 (95%CI, –15.59 to –2.66; P = 0.0058) and between the daridorexant 25 mg group and the placebo group was –4.52 (95% CI, –10.15 to 1.12, P = 0.11161). The mean IDSIQ total score in the ex-placebo to daridorexant 25 mg group was in a range similar to that in the other daridorexant treatment groups from week 4 onward in the extension study. The LSM difference in IDSIQ total score from extension study baseline to week 36 between the ex-placebo to daridorexant 25 mg group and the placebo group was –3.42 (95% CI, –7.95 to 1.11; P = 0.1377). Similar findings were observed for the IDSIQ sleepiness, mood, and alert/cognition domain scores.

Table 26: Change From Baseline in sTST, sWASO, sLSO, and IDSIQ Total Score in Study 303 (Full Analysis Set)

CI = confidence interval; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; LSM = least squares mean; NA = not applicable; SD = standard deviation; sLSO = subjective latency to sleep onset; sTST = subjective total sleep time; sWASO = subjective wake after sleep onset; vs. = versus.

Note: Baseline values from confirmatory Study 301 or Study 302 are reported unless otherwise noted.

^aChange from extension study baseline between the placebo to daridorexant 25 mg group and the placebo group were conducted in a separate post hoc analysis.

^bValues are as reported at baseline of the extension study.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Change From Baseline in SDQ VAS Scores

The results for change from baseline in SDQ VAS scores in the extension study are presented in Table 27. Improvements from baseline in quality of sleep were maintained in all treatment groups throughout the extension study. The mean change from confirmatory study baseline to week 36 was 27.4 (SD = 23.6) in the daridorexant 50 mg group, 22.4 (SD = 21.6) in the daridorexant 25 mg group, 9.7 (SD = 16.3) in the ex-placebo to daridorexant 25 mg group, and 21.9 (SD = 19.2) in the placebo group.

Similar results were reported for the VAS depth of sleep, daytime alertness, and ability to function end points.

Table 27: Change From Baseline in VAS Scores in Study 303 (Full Analysis Set)

SD = standard deviation; VAS = visual analogue scale.

Note: Baseline values from confirmatory Study 301 or Study 302 are reported unless otherwise noted.

^aValues are as reported at baseline of the extension study.

^bChange from extension study baseline reported.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Change From Baseline in ISI Score

The results for change from baseline in ISI score in the extension study are presented in Table 28. In Study 303, the mean change from confirmatory study baseline to week 14, to week 27, and to week 40 in ISI score decreased in all treatment groups at each visit. At week 40, the mean change in ISI score was –9.8 (SD = 6.8) in the daridorexant 50 mg group, –8.5 (SD = 6.9) in the daridorexant 25 mg, –4.3 (SD = 5.7 in the ex-placebo to daridorexant 25 mg group, and –7.5 (SD = 7.0) in the placebo group. At week 40, a 6-point decrease in ISI score from confirmatory study baseline was achieved by 74.7% of patients in the daridorexant 50 mg group, in 66.1% of patients in the daridorexant 25 mg, in 35.8% of patients in the ex-placebo to daridorexant 25 mg group, and in 53.9% of patients in the placebo group.

Table 28: Change From Baseline in ISI Score in Study 303 (Full Analysis Set)

ISI = Insomnia Severity Index; SD = standard deviation.

Note: Baseline values from confirmatory Study 301 or Study 302 are reported unless otherwise noted.

^aValues are as reported at baseline of the extension study.

Sources: Clinical Study Report for Study 303 and the sponsor’s Summary of Clinical Evidence.^15,63 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

During the double-blind treatment period of Study 303, from baseline until up to 30 days after the double-blind study treatment end date, the incidence of TEAEs was generally comparable across treatment groups. The overall percentage of patients experiencing TEAEs was 40.1% in the daridorexant 50 mg group, 38.4% in the daridorexant 25 mg group, 38.1% in the ex-placebo to daridorexant 25 mg group, and 35.2% in the placebo group. Most TEAEs were mild or moderate in intensity, and the most reported AE was nasopharyngitis, with frequencies ranging between 4.7% (placebo) and 8.8% (daridorexant 50 mg). Several TEAEs were reported only in the daridorexant groups, such as accidental overdose, somnolence, pneumonia, back pain, tonsillitis, and increased hepatic enzymes.

Overall, the incidence of treatment-emergent SAEs was reported for less than 5.2% of patients in any treatment group. SAEs reported in the daridorexant treatment groups, compared to none in the placebo group, included diverticulitis (2 patients in the 50 mg group; 1 patient in the 25 mg group) and confusional state (1 patient in the 50 mg group and 1 patient in the 25 mg groups). The rate of treatment discontinuation due to AEs was 6.6% in the daridorexant 50 mg group and 4.7% in the placebo group. One death occurred in the daridorexant 25 mg group due to a myocardial infarction and was not attributed to the treatment under review.

Few TEAEs of special interest occurred, with less than 3% of patients in each treatment group experiencing falls. Other events included hallucinations and/or sleep paralysis (1 patient in the daridorexant 50 mg group), narcolepsy-like symptoms related to excessive daytime sleepiness (1 patient in the daridorexant 25 mg group), and suicidal ideation (1 patient in the placebo group). A TEAE of suicidal ideation was reported in the daridorexant 50 mg group, but it was not classified as an AESI due to other contributing factors.

Table 29: Key Harms Data in Study 303 (Safety Set)