Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2

Abstract

Study objectives: To assess long-term efficacy and safety of lemborexant (LEM), a novel dual orexin receptor antagonist, versus placebo in adults with insomnia disorder.

Methods: This was a 12-month, global, multicenter, randomized, double-blind, parallel-group phase 3 study comprising a 6-month placebo-controlled period (reported here) followed by a 6-month active-treatment-only period (reported separately). A total of 949 participants with insomnia (age ≥18 years) were randomized, received treatment with an oral dose of placebo or LEM (5 mg [LEM5] or 10 mg [LEM10]) and were analyzed. Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored throughout the study.

Results: Decreases from baseline in patient-reported (subjective) sleep onset latency and subjective wake after sleep onset, and increases from baseline in subjective sleep efficiency, were significantly greater with LEM5 and LEM10 versus placebo. Significant benefits over placebo were observed at the end of month 6, and at most time points assessed over the 6-month period, indicating long-term sustained efficacy of LEM. A significantly greater percentage of sleep onset responders and sleep maintenance responders were observed with LEM treatment versus placebo. Participants treated with LEM reported a significant improvement in quality of sleep after 6 months versus placebo. The majority of TEAEs were mild or moderate. There was a low rate of serious TEAEs and no deaths.

Conclusions: LEM5 and LEM10 provided significant benefit on sleep onset and sleep maintenance in individuals with insomnia disorder versus placebo, and was well tolerated.

Clinical trial registration: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

Keywords: clinical trial; insomnia; lemborexant; orexin; pharmacotherapy.

Figure 1.

Study design overview. BL, baseline; EOS, end of study; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; PBO, placebo; SCR, screening.

Figure 2.

Patient disposition flow chart. LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; PBO, placebo.

Figure 3.

Change from baseline for sSOL over 6 months. sSOL values were log-transformed and statistical analyses performed using the least squares geometric mean ratios. BL, baseline; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; PBO, placebo; sSOL, subjective sleep onset latency. *p < 0.0001; ^‡p < 0.01.

Figure 4.

Percentage of sleep onset responders over 6 months. Participants with missing information owing to early withdrawal or other reasons are considered as nonresponders in the analysis. Missing responders did not have an sSOL value for the visit owing to missing data, that is, early withdrawal from the study or incomplete diary data. Two-sided 95% confidence interval (CI) was based on normal approximation. p value is based on Cochran–Mantel–Haenszel test stratified by region and age group. CI, confidence interval; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; PBO, placebo. ^†p < 0.001; ^‡p < 0.01; ^§p < 0.05.

Figure 5.

Change from baseline for sSE over 6 months. p values are based on the mixed-effect repeated measures model evaluating the LSM treatment difference between PBO and LEM. LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; LSM, least squares mean; PBO, placebo SE, standard error; sSE, subjective sleep efficiency. *p < 0.0001; ^†p < 0.001; ^§p < 0.05.

Figure 6.

Change from baseline for sWASO over 6 months. p values are based on the mixed-effect repeated measures model evaluating the LSM treatment difference between PBO and LEM. LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; LSM, least squares mean; PBO, placebo; SE, standard error; sWASO, subjective wake after sleep onset. *p < 0.0001; ^†p < 0.001; ^‡p < 0.01; ^§p < 0.05.

Figure 7.

Percentage of sleep maintenance responders over 6 months. Participants with missing information owing to early withdrawal or other reasons are considered as nonresponders in the analysis. Missing responders did not have an sWASO value for the visit owing to missing data, that is, early withdrawal from the study or incomplete diary data. Two-sided 95% CI was based on normal approximation. p value is based on Cochran–Mantel–Haenszel test stratified by region and age group. CI, confidence interval; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; PBO, placebo. ^†p < 0.001; ^‡p < 0.01; ^§p < 0.05.

Figure 8.

Change from baseline for sTST over 6 months. p values are based on the mixed-effect repeated measures model evaluating the LSM treatment difference between PBO and lemborexant. LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; LSM, least squares mean; PBO, placebo; SE, standard error; sTST, subjective total sleep time. *p < 0.0001; ^†p < 0.001; ^‡p < 0.01; ^§p < 0.05.