Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study

Abstract

Introduction: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety.

Methods: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases).

Results: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition.

Conclusions: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment.

Trial registration: ClinicalTrials.gov identifier, NCT04742699.

Keywords: Insomnia; Lemborexant; Ramelteon; Suvorexant; Switching; Z-drugs.

Fig. 1

Study design. The dotted line of the BZRA in the SUV combination and RMT combination cohorts means that tapering of the BZRA was allowed. BZRA benzodiazepine receptor agonists, LEM lemborexant, RMT ramelteon, SUV suvorexant, Z-drug non-benzodiazepine sleeping pills

Fig. 2

Flow diagram of patients through the study. ADR adverse drug reaction, TEAE treatment-emergent adverse event, LEM lemborexant, RMT ramelteon, SUV suvorexant, Z-drug non-benzodiazepine sleeping pills

Fig. 3

Changes in PGI-I. Proportion of patients who chose the answer option. For items 1 to 3, choices are: blue = positive, gray = negative, white = neutral. For item 4, choices are: blue = just right, gray = too strong, and white = too weak. Percentages were calculated by dividing the number of patients who chose the response option by the number of patients who transitioned to the maintenance phase of treatment (given as “N = ” at the head of each figure). Thus, the percentages do not total 100. Week 2 indicates the end of the transition phase, and Week 14 indicates the end of the maintenance phase. PGI-I Patient Global Impression of Insomnia, RMT ramelteon, SUV suvorexant, Z-drug non-benzodiazepine sleeping pills

Fig. 4

ISI change from baseline after transitioning to LEM. ISI Insomnia Severity Index, LEM lemborexant, RMT ramelteon, SD standard deviation, SUV suvorexant, Z-drug non-benzodiazepine sleeping pills. P-value (vs baseline) calculated using the paired t-test. *p < 0.05, **p < 0.01, ***p < 0.001