Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial

Abstract

Importance: Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population.

Objective: To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder.

Design, setting, and participants: The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties.

Interventions: Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime.

Main outcomes and measures: Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy.

Results: Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, -24.0 min; 95% CI, -30.0 to -18.0 min; P < .001 and for lemborexant 10 mg, -25.4 min; 95% CI, -31.4 to -19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, -6.7 min; 95% CI, -11.2 to -2.2 min; P = .004 and for lemborexant 10 mg, -8.0 min; 95% CI, -12.5 to -3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity.

Conclusions and relevance: In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated.

Trial registrations: ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Rosenberg reported receiving grants from Eisai, Merck, Idorsia, and Vanda Pharmaceuticals outside the submitted work. Dr Zammit reported receiving personal fees and other support from Clinilabs Inc, and grants from Eisai during the conduct of the study; receiving other support from Eisai, Idorsia, Jazz, Purdue, and Takeda outside the submitted work; and being a shareholder of Sleep Disorders Institute, Home Sleep and Respiratory Care. Dr Mayleben reported receiving grants from Eisai during the conduct of the study; and receiving grants from Actelion, Idorsia, Janssen, Jazz, Merck, Novartis, Takeda, and Vanda outside the submitted work. Dr Kumar reported being an employee of Eisai. Dr Dhadda reported being an employee of Eisai. Dr Filippov reported being an employee of Eisai Inc. Dr Moline reported being an employee of Eisai. Drs Dhadda, Filippov, Kumar, LoPresti, and Moline report having issued, pending, or planned patents broadly relevant to this work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram of Participants Through the Trial

The full analysis set included all randomized participants who received at least 1 dose of the study drug and had at least 1 postdose primary efficacy measurement. The safety analysis set included all participants who received at least 1 dose of the study drug and had a postdose safety assessment. ER indicates extended release.

Figure 2.. Sleep Onset and Sleep Maintenance Outcomes Assessed by Polysomnography, by Treatment Group

Outcomes were assessed at the beginning (nights 1 and 2) and end (nights 29 and 30) of treatment. A total of 208 participants received placebo, 263 received 6.5 mg of zolpidem tartrate extended release, 266 received 5 mg of lemborexant, and 269 received 10 mg of lemborexant. A, Mean change from baseline in latency to persistent sleep (LPS) (primary end point). As a result of the nonnormal distribution of LPS, the values were log transformed, and the geometric mean ratio was used to test for statistically significant treatment differences. B, The least squares mean (LSM) change from baseline in sleep efficiency (key secondary end point). C, The LSM change from baseline in wake-after sleep onset (WASO) (key secondary end point). D, The LSM change from baseline in WASO in the second half of the night (WASO2H) (key secondary end point). aP < .01 vs placebo. bP < .05 vs zolpidem. cP < .001 vs placebo. dP ≤ .001 vs zolpidem. eP < .01 vs zolpidem.

Figure 3.. Sleep Onset and Sleep Maintenance Outcomes Assessed by Sleep Diary, by Treatment Group

Outcomes were assessed at the beginning (first 7 nights) and end (end of month 1) of treatment. A total of 208 participants received placebo, 263 received 6.5 mg of zolpidem tartrate extended release, 266 received 5 mg of lemborexant, and 269 received 10 mg of lemborexant. A, Mean change from baseline in subjective sleep onset latency (sSOL). As a result of nonnormal distribution of sSOL latency, values were log transformed, and the geometric mean ratio was used to test for statistically significant treatment differences. B, The least squares mean (LSM) change from baseline in subjective sleep efficiency (sSE). C, The LSM change from baseline in subjective wake-after-sleep onset (sWASO). aP < .05 vs placebo. bP < .01 vs placebo. cP < .001 vs placebo. dP ≤ .01 vs zolpidem. eP < .05 vs zolpidem. fP < .001 vs zolpidem.