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

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.

Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended-release for insomnia disorder subtypes defined based on polysomnographic findings.

STUDY OBJECTIVES: Patients with chronic insomnia may respond differently to therapeutic modalities. This study examined differences in response of individuals with 2 insomnia phenotypes-short sleep duration (I-SSD; < 6 hours) and normal sleep duration (I-NSD; ≥ 6 hours) determined by polysomnography-to treatment with lemborexant and zolpidem tartrate extended-release 6.25 mg (zolpidem ER), compared with placebo. METHODS: Study E2006-G000-304 (Study 304; SUNRISE-1; NCT02783729) was a global, randomized, double-blind, placebo, and active comparator-controlled, parallel-group study comparing lemborexant 5 and 10 mg in individuals aged ≥ 55 years with insomnia disorder. In this analysis, changes in subjective (self-reported) variables based on sleep diaries and objective variables based on polysomnographs were assessed after 1-month administration of study drugs. Data from participants with I-SSD and I-NSD were compared. RESULTS: In the I-SSD subgroup, both lemborexant doses provided significant benefit for sleep-onset latency (SOL), total sleep time (TST), and wake after sleep onset (WASO) vs placebo; zolpidem ER also provided significant benefit for TST and WASO, but not SOL, on both measures vs placebo. In the I-NSD subgroup, lemborexant and zolpidem ER provided significant benefit for TST and WASO vs placebo objectively but not subjectively; both doses of lemborexant provided significant benefit for SOL vs placebo subjectively, but not objectively. CONCLUSIONS: Both drugs, but lemborexant more consistently, showed subjective and objective benefits compared with placebo in participants with insomnia with objective short sleep duration. However, neither lemborexant nor zolpidem provided consistent benefits for participants with normal sleep duration on sleep-onset and sleep maintenance variables. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1); URL: https://clinicaltrials.gov/ct2/show/record/NCT02783729; Identifier: NCT02783729. CITATION: Inoue Y, Nishida M, Kubota N, et al. Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended-release for insomnia disorder subtypes defined based on polysomnographic findings. J Clin Sleep Med. 2023;19(3):519-528.

Reduced versus maximum tolerated methotrexate dose concomitant with adalimumab in patients with rheumatoid arthritis (MIRACLE): a randomised, open-label, non-inferiority trial.

BACKGROUND: Efficacy of combination therapy with methotrexate and biological disease-modifying antirheumatic drugs is well established in the management of patients with rheumatoid arthritis; however, the optimal dose of methotrexate to administer with a tumour necrosis factor inhibitor remains unclear. We aimed to clarify the efficacy and safety of adalimumab combined with reduced methotrexate dose compared with the maximum tolerated methotrexate dose in patients with rheumatoid arthritis and an inadequate response to methotrexate monotherapy. METHODS: In this open-label, randomised controlled trial, we recruited methotrexate-naive patients with rheumatoid arthritis and a disease duration of less than 2 years across 24 secondary or tertiary care hospitals across Japan, South Korea, and Taiwan. At initiation, methotrexate was given orally and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission on the basis of the Simplified Disease Activity Index (SDAI) at week 24 were randomly assigned (1:1) to receive adalimumab (40 mg biweekly) combined with a continued maximum tolerated dose of methotrexate or adalimumab combined with a reduced dose of methotrexate. The primary endpoint was non-inferiority of adalimumab plus reduced-dose methotrexate to adalimumab plus maximal-dose methotrexate based on SDAI remission at week 48, assessed in the modified full-analysis set with a pre-specified non-inferiority margin of -15%, based on a two-sided 90% CI. Adverse events were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03505008 and has been completed. FINDINGS: From April 18, 2018, to June 2, 2020, from 323 patients screened, 300 were enrolled, and 291 patients were included in the full analysis set. The mean age was 57·7 years (SD 15·2), 217 (75%) were female, 74 (25%) were male, and all patients were of Asian ethnicity. The mean SDAI at study enrolment was 26·5 (SD 12·4). 52 patients discontinued the study before week 24 or at week 24 before randomisation. At week 24, 105 (36%) of 291 patients achieved remission and continued methotrexate monotherapy through week 48. 134 (46%) did not achieve remission at week 24 and were randomly assigned to receive adalimumab plus the maximum tolerated dose of methotrexate (n=68) or adalimumab plus reduced-dose methotrexate (n=66). Remission at week 48 was achieved in 25 (38%) of 66 and 27 (44%) of 61 patients, respectively, with an adjusted risk difference of 6·4% (90% CI -7·0 to 19·8), which met the non-inferiority margin of -15%. Adverse events after week 24 tended to be more frequent in the maximum tolerated dose group than in the reduced-dose group (24 [35%] vs 13 [20%], p=0·054). Between week 24 and 48, there were 14 serious adverse events (6 in the methotrexate monotherapy group, 5 in the adalimumab plus maximal-dose methotrexate, and 3 in the adalimumab plus reduced-dose methotrexate group), and no deaths. INTERPRETATION: The MIRACLE study showed that the efficacy of adalimumab combined with reduced methotrexate dose was not inferior to that with the maximum tolerated methotrexate dose, with a tendency to a better safety profile. FUNDING: Eisai.

Evidence-based insomnia treatment strategy using novel orexin antagonists: A review.

Most conventional insomnia medications are gamma-aminobutylic acid receptor agonists. However, physical dependence is a concern and one of the major limiting factors for long-term treatment. The dual orexin receptor antagonists, suvorexant and lemborexant, were recently approved for treating chronic insomnia, giving a novel pharmacotherapeutic option. Because there are no comparative studies on these drugs, a network meta-analysis was conducted, which is suitable for comparing interventions. According to this analysis, 5- and 10-mg lemborexant were superior to 20-mg suvorexant because of the greater improvement in initiating sleep after 1-week administration. Furthermore, 5-mg lemborexant (not 10 mg) and suvorexant were similarly well tolerated, without requiring discontinuation due to adverse events. We also overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical outcomes. When compared to suvorexant, lemborexant quickly binds to the orexin receptors. The time to reach the maximum concentration after multiple administrations is shorter for lemborexant than for suvorexant. Considering these results, we recommend 5-mg lemborexant as an initial treatment for insomnia, followed by 10-mg lemborexant or suvorexant.