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Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved for the treatment of insomnia in adults in multiple countries including the United States, Japan, Canada, Australia, and several Asian countries. Significant benefits were reported for LEM for sleep onset and sleep maintenance compared with placebo (PBO) in 2 pivotal phase 3 studies in subjects with insomnia disorder, Study E2006-G000-304 (Study 304; SUNRISE-1; NCT02783729) and Study E2006-G00-303 (Study 303; SUNRISE-2; NCT02952820).1,2 The mechanism of action of LEM, as a DORA, is different from benzodiazepines and z-drugs (ie, zolpidem, eszopiclone/zopiclone, and zaleplon) also used to treat insomnia, as the antagonism of orexin receptors by DORAs suppresses inappropriate wakefulness.3 In contrast, benzodiazepine hypnotics and z-drugs promote sleep-inducing pathways through a γ-aminobutyric acidergic mechanism of action.
Study E2006-A001-103 (Study 103; NCT03158025), which is presented here, was a phase 1, randomized, double-blind, PBO-controlled, 6-period crossover study with the primary objective to evaluate the abuse potential of single oral daytime doses of LEM (10 mg therapeutic dose [LEM10] and supratherapeutic doses 20 mg [LEM20] and 30 mg [LEM30], a choice of dose range informed by US Food and Drug Administration (US FDA) guidance4) compared with PBO in healthy, nondependent, recreational sedative users as determined by peak maximum effect for “at this moment” drug-liking.
The attractiveness of a drug for purposes of abuse, as well as drug safety, can be affected by the ability of a drug to induce changes in cognition or performance and the nature of those changes, as discussed by the US FDA and elsewhere.4,5 This approach is an objective way to assess potential psychoactive effects relative to prototypic benzodiazepines approved for treatment of insomnia and the effects associated with intoxication. As part of assessing the potential for abuse of LEM in Study 103, it was therefore important to evaluate the effects of LEM at therapeutic and supratherapeutic doses on cognitive and psychomotor performance. Key secondary endpoints of Study 103 were the choice reaction test (CRT) and the divided attention test (DAT), which assessed the effect on cognitive and psychomotor performance of LEM and supratherapeutic doses of active comparators, the z-drug, zolpidem (ZOL) 30 mg, and the DORA suvorexant (SUV) 40 mg compared with PBO. Suvorexant, as a DORA, was added to this study because it shares the same mechanism of pharmacologic action as LEM and has been previously studied for abuse potential.6
Cognitive assessments were also measured at preselected time points during the target therapeutic period (ie, 0.25 to 8 hours postdose), which is the timeframe where LEM is intended to exert a sleep-promoting effect, and in the posttarget or next-day period (8 hours to 24 hours postdose), where any residual drug-related effect is undesirable.
We report here these cognitive function and performance assessments following treatment with therapeutic LEM10 and supratherapeutic doses of LEM20 and LEM30 compared with PBO and supratherapeutic doses of ZOL and SUV in Study 103. Additional endpoints related to abuse potential were also examined in Study 103 and are reported elsewhere along with results from the primary endpoint of drug-liking.
METHODSThe overall design of Study 103 was consistent with the 2017 guidelines of the US FDA for the assessment of abuse liability of central nervous system active compounds in humans,4 the details of which have been previously described.7 The study protocol and informed consent form were approved by an institutional review board, and the study was conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki. All subjects provided written informed consent.
ObjectivesThe objective of these analyses was to evaluate the effects of therapeutic and supratherapeutic doses of LEM on cognition and performance compared with PBO and supratherapeutic doses of active comparators ZOL and SUV in healthy, nondependent, recreational sedative users. This analysis was an evaluation of key secondary endpoint results from Study 103 and was intended to aid in the understanding of the abuse potential of LEM.
SubjectsA description of subject demographics has been previously reported.7 Briefly, subjects were healthy males and females between 18 and 55 years of age who were current sedative users and had used sedatives (eg, ZOL, benzodiazepines) for recreational purposes (eg, nontherapeutic psychoactive effects) at least once in the 12 weeks before screening and ≥5 times during the previous year.
Subjects were screened for the ability to discriminate both SUV 40 mg and ZOL 30 mg from PBO on subjective drug measures and were able to tolerate study treatment during the qualification phase. Subjects were excluded if they met the criteria for substance or alcohol dependence in the past 2 years or had ever been in a program for substance or alcohol rehabilitation. A complete list of enrollment criteria is available on clinicaltrials.gov (NCT03158025).
Study Design and TreatmentStudy 103 was a single-center, single-dose, randomized, double-blind, PBO-controlled, 6-way crossover study with 3 phases: a qualification phase, a treatment phase, and a follow-up phase. The study was conducted from April 19, 2017, to July 4, 2018 in Toronto, Canada. Further details of the design of Study 103 have been previously described.
For the treatment of insomnia, maximum approved doses for SUV, ZOL immediate release, and LEM are 20 mg, 10 mg, and 10 mg, respectively. Human abuse potential studies typically include doses that are 2 to 3 times the therapeutic dose of test compounds. Therefore, treatments during the qualification and treatment phases (administered orally) were as follows: PBO; ZOL 30 mg; SUV 40 mg; and (in the treatment phase) LEM10, LEM20, and LEM30. Additional rationale for selecting the specific doses of LEM, ZOL, and SUV used in this abuse potential study has been previously described. The study drug was administered in the morning after an overnight fast of at least 8 hours.
During the qualification phase, subjects received a single oral dose of ZOL 30 mg, SUV 40 mg, or PBO in a randomized, double-dummy, double-blind, 3-period crossover manner under fasted conditions. A ≥15-point peak (Emax) increase on the bipolar “at this moment” drug-liking visual analog scale (VAS) in response to ZOL and SUV relative to PBO was used to confirm that subjects could distinguish ZOL 30 mg and SUV 40 mg from PBO after drug administration. Eligible subjects rated ZOL and SUV with a peak VAS score of ≥65 and PBO a peak VAS score of ≥40 and ≤60. Subjects were also required to demonstrate consistent responses on other subjective measures and ability to tolerate the treatments as well as demonstrate general behavior suggestive that the subject could successfully complete the study.
During the main treatment phase, study drug (PBO, ZOL, SUV, LEM10, LEM20, and LEM30) was administered in a triple-dummy fashion, and each treatment period was separated by a washout interval of at least 14 days. An approximate 14-day follow-up period occurred immediately after the final study drug administration and concluded with an end of study visit.
Cognitive Performance AssessmentsObjective cognitive performance of study subjects was assessed using the CRT task and the DAT, predose (baseline) and at prespecified time points from 0.25 to 24 hours after study drug administration as used in similar abuse studies.8–11 Choice reaction test is a metric of psychomotor performance and comprises the following measures: recognition reaction time (RRT), motor reaction time (MRT), and total reaction time (TRT). Recognition reaction time is defined as the time it takes for a subject to react to the illumination of a signal light by lifting their finger from a button, with higher scores (longer reaction times) indicating greater impairment. Motor reaction time is defined as the time between subject lifting their finger from the button and pressing a response button, with higher scores (longer reaction times) indicating greater impairment. Total reaction time is the sum of RRT and MRT, with higher scores indicating greater impairment. Maximum change from baseline (CFBmax) was assessed for MRT, RRT, and TRT. The minimum change from baseline (CFBmin) for the percentage of correct responses was also assessed.
During the CRT test, the subject is presented with an onscreen equivalent of the numeric keypad. The subject is asked to quickly press the buttons on a separate keypad that correspond to the keys illuminated on the screen. For a given trial, 4 to 8 numbered squares that correspond spatially to the response keys on the keypad are illuminated on the computer screen. The sequence of key illumination is random and follows a pattern that alternates between the center button and any button that was part of the stimuli set of buttons. The stimulus set size progresses from 4 to 6 to 8 during the test. The number of alternative choices increases over blocks of responses in each cycle.12
Divided attention test is a manual-tracking test with a simultaneous visual target detection component. During testing, the subject is presented with the image of an airplane, controlled by the subject with a joystick, and a randomly curving road. As the road moves down the screen, the subject is tasked to position the image of the airplane over the center of the road and to press a button on the joystick in response to randomly appearing targets.13
Divided attention test assessments included the percentage of target hits, with lower scores indicating greater impairment; the percentage of time over the road, with lower percentages indicating greater impairment; and the number of false alarms with the subject pressing the button when no target has appeared, with higher scores indicating greater impairment. Root mean square (RMS) distance from the center of the road (pixels) was assessed, with longer distances indicating greater impairment. Also assessed was greatest distance from the center of the road (pixels), with longer distances indicating greater impairment. Response latency of correct responses (milliseconds) was assessed, with longer response latencies indicating greater impairment. Minimum change from baseline was assessed for the percentage of time over the road and percentage of target hits, and CFBmax was assessed for RMS distance from center of the road, mean greatest distance from the center of the road, mean response latency of correct responses, and the number of false alarms.
Statistical AnalysesCognition endpoints were analyzed in the completer analysis set, defined as the group of subjects who received all study treatments and completed all treatment periods in the main treatment phase as well as had ≥1 primary endpoint assessment (“at this moment” drug-liking VAS score) within 2 hours of the estimated time to maximum plasma concentration (tmax) for each treatment, regardless of protocol deviations.
A mixed-effect model was used to analyze cognition endpoints. The model included treatment period, treatment sequence, and first-order carryover effect (where applicable) as fixed effects, baseline (predose) measurements as covariate (where applicable), and subject nested within treatment sequence as a random effect. Least squares means, 95% confidence intervals, standard error, and P values for treatment differences were derived from the mixed-effect model if the normality assumption of the model was met. If the normality assumption of the model was not met, the paired differences from each of the contrasts were tested using a t test (means) if the distribution of the paired differences was normal or by Wilcoxon signed rank test (medians) if the distribution of the paired differences was not normal. Overall treatment effects were assessed using Friedman test.
SafetySafety analyses were performed in the safety analysis set, defined as subjects who received ≥1 dose of study drug during the main treatment phase and had ≥1 postdose safety assessment as previously described.7 Treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, electrocardiograms, and physical examinations were assessed as part of Study 103 and have been previously described.7
RESULTS Subject Disposition and CharacteristicsA total of 225 subjects were screened, from which 107 were randomized to the qualification phase. Of these 107 subjects, 68 (63.6%) discontinued from the qualification phase with 43 of 107 (40.2%) not meeting qualification criteria. Twenty subjects (18.7%) could not discriminate SUV from PBO, and 7 (6.5%) could not discriminate ZOL from PBO; 7 subjects (6.5%) could not discriminate either SUV or ZOL from PBO. Twenty-five of 107 subjects (23.4%) discontinued for other reasons.
Thirty-nine subjects (safety analysis set) met the qualification criteria and were randomized into the main treatment phase; 32 subjects (7 discontinued) received and completed all treatments. Subjects in the safety analysis set had a median (range) age of 36.0 (18–50) years, were mostly male (30 of 39 [76.9%]), and White (29 of 39 [74.4%]). Additional details of subject disposition and characteristic have been previously reported.
Choice Reaction TestFor each of the 3 measures of the CRT task, each active agent (ZOL 30 mg, SUV 40 mg, and all doses of LEM) caused a significantly greater reduction in performance from baseline compared with PBO (Table 1). Based on MRT, TRT, and percentage correct, ZOL 30 mg caused a numerically greater reduction in performance compared with all doses of LEM. Based on percentage correct, all doses of LEM caused a greater reduction numerically in performance compared with SUV 40 mg. Findings for LEM versus SUV were generally nonsignificant for the other CRT measures.
TABLE 1 - Summary of Direction Between-Treatment Differences of Means for Cognitive Endpoints (Completer Analysis Set) ZOL– PBO SUV–PBO LEM10–PBO LEM20–PBO LEM30–PBO ZOL–LEM10 ZOL–LEM20 ZOL–LEM30 SUV–LEM10 SUV–LEM20 SUV–LEM30 Choice RT task Recognition RT* CFBmax > > > > > NS NS NS NS NS NS Motor RT* CFBmax > > > > > > > > NS NS NS Total RT* CFBmax > > > > > > > > NS NS < Percentage correct† CFBmin < < < < < < < < > > > Divided attention task RMS distance from center of road* CFBmax > > > > > > > > NS < < Greatest distance from center of road* CFBmax > > > > > > NS NS NS < < Response latency of correct responses* CFBmax > > > > > NS NS NS NS NS NS No. false alarms* CFBmax > NS NS NS NS > > > NS NS NS Percentage of time over road‡ CFBmin < < < < < < < < NS > > Percentage of target hits‡ CFBmin < < < < < < < < NS > >> indicates that between-treatment difference in means is positive and statistically significant; < indicates that between-treatment difference in means is negative and statistically significant; NS indicates difference is not statistically significant. For each endpoint, comparisons tested the null hypothesis that the difference of the means between treatment groups is zero.
*Smaller CFB is better.
†Less negative CFB (change in percentage correct closer to zero) is better. For example, reduction in percentage correct was less (CFBmin was less negative) for PBO versus active treatments.
‡Less negative CFB (closer to zero) is better.
CFB indicates change from baseline; LEM10, lemborexant 10 mg; LEM20, lemborexant 20 mg; LEM30, lemborexant 30 mg; NS, not significant; PBO, placebo; RT, reaction time; SUV, suvorexant 40 mg; ZOL, zolpidem 30 mg.
Mean CFBmax scores for RRT were significantly greater versus PBO for all LEM doses (all P < 0.001) and for ZOL (P < 0.001) and SUV (P = 0.004). For all doses, LEM was not significantly different compared with ZOL or SUV (Table 2). For MRT, mean CFBmax scores versus PBO were significantly greater for all LEM (all P < 0.001) and for ZOL (P < 0.001) and SUV (P < 0.001). Zolpidem showed statistically significantly greater mean CFBmax (larger mean increase in MRT) scores compared with all doses of LEM (all P < 0.001), but mean CFBmax scores for LEM and SUV were not significantly different (Table 2).
TABLE 2 - Findings for Cognitive Outcome Measure: Choice Reaction Time Mean Value and Difference (Tested Drug Less Comparator) Measure Value PBO (n = 32) ZOL (n = 32) SUV (n = 32) LEM10 (n = 32) LEM20 (n = 32) LEM30 (n = 32) Recognition RT, CFBmax*, ms*For between-treatment differences, LSM (SE) difference is presented.
†For between-treatment differences, if a paired t test was used to assess the difference, mean (SE) difference is presented. If the sign test was used, median (first and third quartile) difference is presented.
‡Indicates statistically significant difference versus comparator.
CFBmax, maximum change from baseline; CFBmin, minimum change from baseline; LEM10, lemborexant 10 mg; LEM20, lemborexant 20 mg; LEM30, lemborexant 30 mg; LSM, least squares mean; PBO, placebo; RT, reaction time; SE, standard error; SUV, suvorexant 40 mg; ZOL, zolpidem 30 mg.
Finally, for TRT, mean CFBmax scores versus PBO were significantly greater for LEM (all P < 0.001) and for ZOL (P < 0.001) and SUV (P < 0.001). Mean CFBmax score for LEM30 was significantly greater compared with SUV (P = 0.025). Zolpidem showed significantly greater mean CFBmax scores compared with all doses of LEM (all P < 0.001) (Table 2).
For the percentage of correct responses, mean CFBmin was significantly greater for all doses of LEM (all P < 0.01) and for ZOL (P < 0.001) and SUV (P < 0.05) compared with PBO. All LEM doses exhibited significantly higher mean CFBmin (smaller decrease in percentage correct) compared with ZOL (all P ≤ 0.001). All doses of LEM exhibited significantly lower mean CFBmin (greater decrease in percentage correct) compared with SUV (all P < 0.05). For LEM, SUV, and ZOL, CFBmax for RRT, MRT, and TRT was observed within 2 hours after drug administration with CFB for all cognitive performance measures and all treatment groups consistently returning to baseline by 8 hours after drug administration (Fig. 1).
FIGURE 1: Mean CRT over time. A, Recognition reaction time, (B) MRT, and (C) total response time. SUV indicates suvorexant 40 mg; ZOL, zolpidem 30 mg; CRT, Choice Reaction Time; LEM10, lemborexant 10 mg; LEM20, lemborexant 20 mg; LEM30, lemborexant 30 mg; PBO, placebo; SUV, suvorexant 40 mg; ZOL, zolpidem 30 mg.
Divided Attention TaskFor all measures of the DAT except for the number of false alarms, each active agent (ZOL 30 mg, SUV 40 mg, and all doses of LEM) exhibited a significantly greater reduction in performance from baseline compared with PBO (Table 1, Fig. 2). On 4 of the measures: RMS distance from the center of the road, percentage of time over the road, number of false alarms, and percentage of target hits, ZOL 30 mg showed reductions in performance compared with each dose of LEM (Table 1, Fig. 2). On the divided attention task measures, which are RMS distance from center of road, greatest distance from center of road, and percentage of time over road, both LEM20 and LEM30 caused significantly more loss of performance than SUV 40 mg (Table 1, Fig. 2).
FIGURE 2: Divided attention test over time. A, Root mean square distance and mean DAT over time, (B) greatest distance from center of the road, (C) percent time over road, (D) response latency: correct response, (E) number of false alarms, and (F) percentage of target hits. SUV indicates suvorexant 40 mg; ZOL, zolpidem 30 mg. DAT, divided attention test; LEM10, lemborexant 10 mg; LEM20, lemborexant 20 mg; LEM30, lemborexant 30 mg; PBO, placebo; SUV, suvorexant 40 mg; ZOL, zolpidem 30 mg.
For RMS, all doses of LEM exhibited statistically significantly lower mean CFBmax scores compared with ZOL (P = 0.001, P = 0.027, and P = 0.039 for LEM10, LEM20, and LEM30, respectively) indicative of improved motor control. Lemborexant (20 mg) and LEM30 showed significantly higher mean CFBmax scores compared with SUV (P = 0.007 and P = 0.004, respectively), indicative of reduced motor precision (Table 3). Mean CFBmax scores for LEM, ZOL, and SUV were significantly higher compared with PBO. Zolpidem exhibited the quickest and largest postdose increase in RMS distance (Fig. 2A).
TABLE 3 - Findings for Cognitive Outcome Measure: Divided Attention Task Mean Value and Difference (Tested Drug Less Comparator) Measure Value PBO (n = 32) ZOL (n = 32) SUV (n = 32) LEM10 (n = 32) LEM20 (n = 32) LEM30 (n = 32) Percentage of target hits, CFBmin*
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