Evaluating the Efficacy and Safety of Daridorexant Transition From BZRAs in Insomnia Patients（EASY-TIP）

Overview

Brief Summary: This study is a prospective, multicenter, open-label cohort study designed to evaluate the efficacy and safety of transitioning adult patients with insomnia from benzodiazepine receptor agonists (BZRAs) to daridorexant. A total of 156 participants will be enrolled. The study consists of a 1-week baseline phase and a 9-week daridorexant treatment phase. During the treatment phase, daridorexant 50 mg is initiated once daily while BZRAs are gradually tapered and discontinued based on individual patient response. The primary outcome is the proportion of patients who successfully transition from BZRAs to daridorexant at Week 5, defined as a ≥50% reduction or complete discontinuation of the original BZRA dose, with continued willingness to take daridorexant and no withdrawal due to worsening insomnia or adverse events. Secondary outcomes include changes in Insomnia Severity Index (ISI) scores and patient-reported sleep outcomes. This study aims to provide real-world evidence for the safe and effective transition from BZRAs to daridorexant in clinical practice.

Detailed description

Detailed Description:

Background: Insomnia is a prevalent disorder that significantly impacts quality of life and daytime functioning. Benzodiazepine receptor agonists (BZRAs), including benzodiazepines and non-benzodiazepines, are commonly used but are associated with tolerance, dependence, withdrawal symptoms, and disruption of sleep architecture. Daridorexant, a dual orexin receptor antagonist (DORA), offers a novel mechanism by reducing hyperarousal and promoting physiological sleep, with a favorable safety profile and no withdrawal effects upon discontinuation. However, real-world evidence on transitioning patients from BZRAs to daridorexant remains limited.

Study Objective: To evaluate the efficacy and safety of transitioning adult insomnia patients from BZRAs to daridorexant in a clinical practice setting.

Study Design: This is a prospective, multicenter, open-label, cohort study. Patients will be enrolled across multiple sites in China. The study consists of two phases: a 1-week baseline phase (during which patients continue their usual BZRA therapy) and a 9-week daridorexant treatment phase. During the treatment phase, daridorexant 50 mg is initiated once daily, 30 minutes before bedtime, while the original BZRA is tapered and discontinued according to individual patient response, following a cross-tapering approach.

Population: A total of 156 adult patients (aged 18-70 years) with insomnia disorder according to DSM-5 criteria, who have been on stable BZRA monotherapy for at least 3 nights per week for the past month, and who are dissatisfied with or intolerant to their current therapy, will be enrolled. Key exclusion criteria include chronic insomnia \>5 years, severe psychiatric disorders, significant comorbidities, and prior use of DORA agents without response.

Intervention: Daridorexant tablets (50 mg) taken orally once nightly. Dose adjustment to 25 mg is permitted based on tolerability, but the maximum dose is 50 mg daily.

Outcomes:

Primary Outcome: The proportion of patients who successfully transition from BZRAs to daridorexant at Week 5, defined as a ≥50% reduction or complete discontinuation of the original BZRA dose, with continued willingness to take daridorexant, and no withdrawal due to worsening insomnia or adverse events.

Secondary Outcomes: Changes from baseline in Insomnia Severity Index (ISI) scores; patient-reported sleep outcomes (subjective total sleep time, sleep quality) assessed by electronic sleep diary; and patterns of daridorexant and BZRA dosing adjustments.

Safety Outcomes: Incidence and severity of treatment-emergent adverse events (TEAEs); assessment of benzodiazepine withdrawal symptoms using the Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ).

Visit Schedule: Patients will undergo 6 visits: at Day 0 (V1, screening), Day 7 (V2, baseline, daridorexant initiation), Day 14 (V3), Day 21 (V4), Day 42 (V5, primary endpoint), and Day 70 (V6, end of treatment). Assessments include ISI, electronic sleep diary, BWSQ, and safety monitoring at each visit.

Sample Size: Based on an expected transition success rate of 80% at Week 5, with a 95% confidence interval and 10% margin of error, and accounting for a 10% dropout rate, a total of 156 patients will be enrolled (78 per BZRA subgroup).

Statistical Analysis: The primary analysis will be performed on the full analysis set (FAS). Descriptive statistics will be used for baseline characteristics. The primary endpoint will be presented with a 95% confidence interval. Secondary endpoints will be analyzed using appropriate parametric or non-parametric methods. Safety data will be summarized descriptively.

Ethical Considerations: The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The protocol has been approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University. Written informed consent will be obtained from all participants.

Expected Impact: This study aims to provide real-world evidence on the safe and effective transition from BZRAs to daridorexant, informing clinical decision-making and potentially improving long-term insomnia management in Chinese patients.

Interventions

• Drug Daridorexant
  Daridorexant is a dual orexin receptor antagonist (DORA) supplied as 50 mg film-coated tablets for oral administration. Participants receive 50 mg once nightly, 30 minutes before bedtime, for up to 9 weeks. Dose reduction to 25 mg is permitted based on tolerability. The drug is provided by Jiangsu Simcere Pharmaceutical Co., Ltd.

Primary outcome measures

• Proportion of Participants Successfully Transitioning from BZRAs to Daridorexant at Week 5 [Time frame: At Week 5 (Visit 5, Day 42 ± 3 days)]

Eligibility criteria

Inclusion criteria

• Male or female, aged ≥18 and ≤70 years.
• Meet DSM-5 diagnostic criteria for insomnia disorder: dissatisfaction with nighttime sleep despite adequate sleep opportunity, manifested as difficulty initiating sleep, difficulty maintaining sleep (frequent awakenings or difficulty returning to sleep after awakening), or early-morning awakening with inability to resume sleep, accompanied by subjective experience of daytime dysfunction. Symptoms occur ≥3 times per week and persist for ≥3 months.
• Received stable BZRA monotherapy for at least 3 nights per week during the 1 month prior to enrollment.
• Bedtime duration of no less than 7 hours per night.
• Unsatisfactory response or intolerance to current therapy, with clinical need to adjust insomnia medication regimen.
• Hamilton Anxiety Rating Scale (HAMA-14) score <14.
• Hamilton Depression Rating Scale (HAMD-17) score <17.
• Willing and able to comply with the study protocol and provide written informed consent.

Exclusion criteria

• History of chronic insomnia >5 years.
• Other sleep disorders such as narcolepsy-related symptoms, restless legs syndrome, circadian rhythm sleep disorder, REM sleep behavior disorder, etc.
• Daytime napping ≥1 hour/day and ≥3 days/week.
• Daily BZRA dose exceeding the maximum recommended dose for insomnia treatment per package insert.
• BZRA use >5 nights per week.
• History of BZRA treatment ≥3 years.
• Concurrent use of two or more BZRAs within the past 3 months.
• Use of central nervous system depressants within the past 3 months.
• Use of long-acting sedative-hypnotics (e.g., clonazepam) within the past 3 months.
• Use of anxiolytics or antidepressants for off-label insomnia treatment within the past 3 months.
• Initiation of cognitive behavioral therapy for insomnia (CBT-I) within 1 month prior to Visit 1.
• Prior non-response to orexin receptor antagonists (daridorexant, lemborexant, suvorexant, etc.).
• Clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal) that may affect participant safety or interfere with study assessments, as judged by the investigator. Participants for whom sedative medications are contraindicated due to occupational or safety reasons are also excluded.
• Severe psychiatric disorder within the past 6 months, or severe alcohol/substance abuse/dependence within the past 2 years.
• Active suicidal ideation or behavior within the past 6 months.
• Pregnancy, lactation, or planned pregnancy within 90 days.
• Unable to avoid excessive alcohol consumption during the study.
• History of hypersensitivity to any component of daridorexant tablets.
• Severe hepatic impairment (Child-Pugh score ≥10).
• Unable to discontinue strong CYP3A4 inhibitors and strong or moderate CYP3A4 inducers during the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Xuanwu Hospital, Capital Medical University — Beijing

Publications

• Roch C, Bergamini G, Steiner MA, Clozel M. Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia. Psychopharmacology (Berl). 2021 Oct;238(10):2693-2708. doi: 10.1007/s00213-021-05954-0. Epub 2021 Aug 20. PMID 34415378
• Treiber A, de Kanter R, Roch C, Gatfield J, Boss C, von Raumer M, Schindelholz B, Muehlan C, van Gerven J, Jenck F. The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468. J Pharmacol Exp Ther. 2017 Sep;362(3):489-503. doi: 10.1124/jpet.117.241596. Epub 2017 Jun 29. PMID 28663311

Identifiers

NCT: NCT07733414 · CNS-DARI-IS_002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗