Subjective Ratings of Medication Strength Over 6 Months in Elderly Subjects with Moderate or Severe Insomnia Treated with Lemborexant

Abstract

<h3>Introduction</h3> Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries including the United States, Japan, Canada, Hong Kong, Australia, and India, for the treatment of adults with insomnia. Patient-reported perceptions of medication effectiveness and strength, and perceptions of insomnia severity can be assessed by the Patient Global Impression–Insomnia (PGI-I) and Insomnia Severity Index (ISI) questionnaires, respectively. PGI-I items 1-3 assess perceived effects (positive, neutral, or negative) of the study medication on sleep (helped/worsened sleep; decreased/increased time to fall asleep; and increased/decreased total sleep). PGI-I item 4 assesses the perceived appropriateness of study medication strength ("too strong," "just right," or "too weak"). In Study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), significantly greater percentages of subjects with insomnia disorder age ≥65y (elderly) treated with LEM indicated a positive effect of their medication compared with placebo (PBO), as assessed by items 1-3 of the PGI-I at 1, 3, and 6 months. A significantly greater percentage of these elderly subjects also indicated on PGI-I item 4 that their medication strength was "just right" at these time points. Additionally, significantly greater decreases from baseline in ISI total score were also observed with LEM vs PBO in elderly subjects, as assessed at 1, 3, and 6 months. In this post hoc analysis, potential tolerance to LEM was evaluated in the elderly subgroup by analyzing ratings of medication strength on PGI-I item 4 in the subsets of elderly subjects who had moderate (ISI total score 15-21) or severe (ISI total score 22-28) insomnia at baseline. <h3>Methods</h3> Study 303 was a 12-month, double-blind, PBO-controlled (first 6 months [Treatment Period 1]), phase 3 study in subjects ≥18y with insomnia disorder and baseline ISI total score ≥15. Subjects were randomized to PBO, LEM 5mg (LEM5), or LEM 10mg (LEM10). During the second 6 months (Treatment Period 2, not reported here), PBO-treated subjects were rerandomized to LEM, while LEM-treated subjects continued their originally assigned dose. During Treatment Period 1, the PGI-I and ISI were administered at 1, 3, and 6 months; the ISI was also administered at baseline. Titration to higher or lower doses was not permitted during the study. <h3>Results</h3> Of 949 subjects in the Full Analysis Set, 262 (27.6%; [PBO, n=89; LEM5, n=87; LEM10, n=86]) were age ≥65y. Among these subjects, 193 (73.7% [PBO, n=66; LEM5, n=63; LEM10, n=64]) had moderate insomnia, and 61 (23.3%; [PBO, n=20; LEM5, n=21; LEM10, n=20]) had severe insomnia at baseline, respectively. In both insomnia severity groups, greater percentages of LEM-treated than PBO-treated subjects rated their medication strength as "just right" at 1 month (moderate: LEM5=47.4%; LEM10=46.4%; PBO=21.3%; severe: LEM5=47.6%; LEM10=44.4%; PBO=5.3%), at 3 months (moderate: LEM5=60.4%; LEM10=53.8%; PBO=34.4%; severe: LEM5=47.4%; LEM10=64.7%; PBO=22.2%) and at 6 months (moderate: LEM5=59.6%; LEM10=51.0%; PBO=34.4%; severe: LEM5=76.5%; LEM10=68.8%; PBO=25.0%). The majority of LEM-treated subjects who rated their medication strength as "just right" had an ISI total score ≤14 (ie, subthreshold insomnia) at each of the time points. Ratings of "too weak" were greater with PBO than with LEM and did not increase over time (Months 1, 3, and 6) in subjects with moderate (LEM10: 42.9%; 34.6%; 38.8%; LEM5: 50.9%; 39.6%, 40.4%; PBO: 75.4%, 65.6%, 65.6%) or severe (LEM10: 55.6%, 35.3%, 31.3%; LEM5: 52.4%, 52.6%, 23.5%; PBO: 89.5%, 77.8%, 75.0%) insomnia at baseline. In subjects with moderate insomnia, ratings of "too strong" at 1, 3, and 6 months were higher with LEM10 (10.7%, 11.5%, 10.2%) than with LEM5 (1.8%, 0%, 0%) or PBO (3.3%, 0%, 0%). However, no LEM5- or LEM10-treated subjects with severe insomnia at baseline rated their medication as "too strong" at any time point. LEM was well tolerated with adverse events being mild or moderate in severity. <h3>Conclusions</h3> These analyses suggest that tolerance to LEM5 and LEM10 does not develop over time, as ratings of "too weak" did not increase across the study period. In both insomnia severity groups, ratings of "just right" were more common in subjects treated with LEM5 or LEM10 than PBO. These data support LEM as a long-term treatment option in adults ≥65y with insomnia. <h3>This research was funded by</h3> Supported by Eisai Inc.