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Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials
Accepted Manuscript Title: Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data From Phase-3 Randomized Controlled Clinical Trials Author: W. Joseph Herring, Kathryn M. Connor, Ellen Snyder, Duane B. Snavely, Ying Zhang, Jill Hutzelmann, Deborah Matzura-Wolfe, Ruth M. Benca, Andrew D. Krystal, James K. Walsh, Christopher Lines, Thomas Roth, David Michelson PII: DOI: Reference:
S1064-7481(17)30253-1 http://dx.doi.org/doi: 10.1016/j.jagp.2017.03.004 AMGP 808
To appear in:
The American Journal of Geriatric Psychiatry
Received date: Revised date: Accepted date:
13-9-2016 6-3-2017 6-3-2017
Please cite this article as: W. Joseph Herring, Kathryn M. Connor, Ellen Snyder, Duane B. Snavely, Ying Zhang, Jill Hutzelmann, Deborah Matzura-Wolfe, Ruth M. Benca, Andrew D. Krystal, James K. Walsh, Christopher Lines, Thomas Roth, David Michelson, Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data From Phase-3 Randomized Controlled Clinical Trials, The American Journal of Geriatric Psychiatry (2017), http://dx.doi.org/doi: 10.1016/j.jagp.2017.03.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Number of Words: 3812 Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase3 Randomized Controlled Clinical Trials
W. Joseph Herring, MD, PhDa; Kathryn M. Connor, MDa; Ellen Snyder, PhDa; Duane B. Snavely, MAa; Ying Zhang, PhDa; Jill Hutzelmann, MSa; Deborah Matzura-Wolfe, BSa; Ruth M. Benca, MDb; Andrew D. Krystal, MDc; James K. Walsh, PhDd; Christopher Lines, PhDa; Thomas Roth, PhDe; David Michelson, MDa
a
Merck & Co., Inc., Kenilworth, NJ, USA
b
c
University of California-Irvine, Irvine, CA USA
Department of Psychiatry and Behavioral Sciences, Duke University School of
Medicine, Durham, NC, USA d
Sleep Medicine and Research Center, St. Luke’s Hospital, St. Louis, MO, USA
e
Henry Ford Hospital Sleep Center, Detroit, MI, USA
*Address correspondence to W. Joseph Herring, Merck, UG 4C-13, PO Box 1000, North Wales, PA 19454-1099, USA. Tel.: 001 267 305 7933, Fax: 011 267 305 6390. E-mail: [email protected]
These studies were funded by Merck & Co., Inc., Kenilworth, NJ, USA.
Key Words: suvorexant; orexin; randomized clinical trial; efficacy; safety
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Previous presentation: These data were previously presented at SLEEP 2014, May 31June 4 2014, Minneapolis, MN, USA
Running head: Suvorexant in elderly insomnia patients
ACKNOWLEDGMENTS Mingqui Wu, formerly from Merck & Co., Inc., contributed to the statistical analysis. Sheila Erespe from Merck & Co., Inc. assisted with the submission.
Conflicts of Interest and Source of Funding: Dr. Herring, Dr. Connor, Dr. Snyder, Mr. Snavely, Dr. Zhang, Ms. Hutzelmann, Ms. Matzura-Wolfe, Dr. Lines and Dr. Michelson are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA and own or owned stock/stock options in Merck. Dr. Benca has served as a consultant to and receives research support from Merck, and has served as a consultant to Janssen and Jazz over the past 2 years. Dr. Krystal has received grants/research support from NIH, Teva, Sunovion, Astellas, Abbott, Neosync, Brainsway, Janssen, ANS St. Jude, Novartis. He has served as a consultant to: Abbott, Astellas, AstraZeneca, Attentiv, BMS, Teva, Eisai, Eli Lilly, GlaxoSmithKline, Jazz, Janssen, Merck, Neurocrine, Novartis, Otsuka, Lundbeck, Roche, Sanofi-Aventis, Somnus, Sunovion, Somaxon, Takeda, Transcept, Vantia. Dr. Walsh has received research support from the following in the past 2 years: Apnex, Merck, Novo Nordisk, Respironics, Vanda, and has provide consulting services to: Merck, Somnus, Transcept,
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Vanda, Ventus, and Vivus. Dr. Roth has received grants/research support from Aventis, Cephalon, GlaxoSmithKline, Neurocrine, Pfizer, Sanofi, Schering-Plough, Sepracor, Somaxon, Syrex, Takeda, TransOral, Wyeth and Xenoport; has acted as a consultant for Abbott, Acadia, Acoglix, Actelion, Alchemers, Alza, Ancil, Arena, AstraZeneca, Aventis, AVER, BMS, BTG, Cephalon, Cypress, Dove, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hypnion, Impax, Intec, Intra-Cellular, Jazz, Johnson – Johnson, King, Lundbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Prestwick, Procter – Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi, Schering-Plough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Vanda, Vivometrics, Wyeth, Yamanuchi, and Xenoport; and has participated in speaking engagements supported by Cephalon, Sanofi, and Takeda. These studies were funded by Merck & Co., Inc., Kenilworth, NJ, USA.
Author Contributions: Herring: Study concept and design, interpretation of data, preparation of manuscript. Connor, Krystal, Walsh: Study concept and design, interpretation of data, review of manuscript. Snyder: Study concept and design, analysis and interpretation of data, preparation of manuscript. Snavely, Zhang: Study concept and design, analysis and interpretation of data, review of manuscript. Hutzelmann: Study concept and design, review of manuscript. Matzura-Wolfe, Benca: Interpretation of data, review of manuscript. Lines: Interpretation of data, preparation of manuscript. Roth, Michelson: Study concept and design, interpretation of data, review of manuscript.
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Sponsor’s Role: The sponsor was involved in the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
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ABSTRACT Objective: Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10-20mg. Previously-reported phase-3 results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and non-elderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly. Design: Pre-specified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group, trials. Setting: Naturalistic outpatient use, sleep clinics, and laboratories. Participants: Elderly (≥65 years) patients with insomnia. Interventions: Suvorexant 30mg, suvorexant 15mg, placebo. By design, fewer patients were randomized to 15mg. Measurements: Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints. Results: Suvorexant 30mg (N=319) was effective compared to placebo (N=318) on patient-reported and polysomnographic sleep maintenance and onset endpoints at Night-1 (polysomnographic endpoints)/Week-1 (patient-reported endpoints), Month-1 and Month-3. Suvorexant 15mg (N=202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing due to adverse events over 3-months were 6.4% for 30mg (N=627 treated), 3.5% for 15mg (N=202 treated), and 5.5% for placebo (N=469 treated). Somnolence was the most common adverse event (8.8% for 30mg, 5.4% for 15mg, 3.2% for placebo).
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Conclusions: Suvorexant generally improved sleep maintenance and onset over 3months of nightly treatment and was well-tolerated in elderly patients with insomnia.
ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.
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INTRODUCTION The elderly constitute a large proportion of those with insomnia.1-3 As the sleep profile changes with aging, the elderly have been shown to have particular problems with sleep maintenance (disrupted sleep), and to shift to a pattern of earlier retiring and rising (“morning chronotype”) with increased napping during the day.1, 4-8 Most sleep medications used to treat insomnia (e.g. zolpidem, zaleplon, eszopiclone, temazepam) act by enhancing the broad central nervous system depressant effects of GABA inhibition via effects on the benzodiazepine receptor at the GABA-A complex.9 With this class, there are concerns that the elderly might be more sensitive to adverse drug effects (e.g., falls, residual effects) and/or show a differential efficacy response compared with non-elderly patients.10-14 Despite these concerns, there have been relatively few longer-term (>1 month) randomized controlled trials of sleep medications in the elderly. The orexin receptor antagonist suvorexant is a new first-in-class treatment for insomnia, approved in the US and Japan in 2014.15-17 Suvorexant provides a novel approach to treating insomnia by blocking orexin-mediated wake signaling.18, 19 The suvorexant phase-3 development program included both elderly and non-elderly insomnia patients. The program consisted of two 3-month pivotal trials, each of which evaluated two age-adjusted (non-elderly/elderly) suvorexant dose regimes of 40/30mg and 20/15mg ,20 and a 1-year trial of 40/30mg.21 In order to evaluate the clinical profile of suvorexant in elderly patients, a subgroup analysis of pooled elderly data from the phase-3 trials was pre-specified. We report the results of the analysis here.
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METHODS Overview The pooled efficacy elderly subgroup analyses included data from two phase-3 randomized, double-blind, placebo-controlled, parallel-group, 3-month efficacy and safety trials in non-elderly (18-64 years) and elderly (≥65 years) patients with primary insomnia (P028 and P029).20 P028 also included an optional randomized, double-blind, placebo-controlled, 3-month extension. The elderly comprised approximately 40% of those randomized in the trials. Suvorexant doses of 40/30mg (non-elderly/elderly) and 20/15mg (non-elderly/elderly) were evaluated, with fewer patients randomized to 20/15mg than 40/30mg or placebo. Efficacy data from a randomized, double-blind, placebo-controlled, parallel-group 1-year trial (P009)21 were not included in the pooled analysis as that trial was primarily a safety study and did not include polysomnography (PSG) assessments or the 20/15mg dose. The pooled safety elderly subgroup analyses included data from the two phase-3 3-month trials (P028 and P029) and also 3-month data on 30mg and placebo from the 1year trial (P009; 15 mg was not included in the trial). Each trial incorporated a 1-week, randomized, double-blind run-out after double-blind treatment (3 months in P029, 3 or 6 months in P028, 12 months in P009) to assess withdrawal and rebound insomnia.
Patients Non-elderly (18-64) and elderly (≥65) patients who met DSM-IV-TR criteria for primary insomnia22 and were otherwise in good physical and mental health were enrolled. All patients in the two pivotal efficacy studies provided subjective sleep estimates using
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an electronic sleep diary/questionnaire. Approximately 75% of those patients also underwent PSG over 8 hours. Patients who completed only self-report assessments are referred to as the questionnaire (Q)-cohort; those who completed self-report and PSG assessments are referred to as the PSG+questionnaire (PQ)-cohort. To enter the Qcohort, patients had to report a total sleep time (sTST) <6.5 hours and time to sleep onset (sTSO) ≥30 min, both on ≥4 of 7-nights during the last week of a 2-week placebo run-in before randomization. For the PQ-cohort, patients had to meet the following PSG criteria for screening and baseline PSG nights: latency to onset of persistent sleep (LPS) >20 min, and mean (across screening and baseline) wakefulness after persistent sleep onset (WASO) ≥60 min with neither night ≤45 min. They were not required to meet the Qcohort diary entry criteria.
Design and Procedure Patients were discontinued from existing hypnotic medications prior to entering the trials. Following a 2-week placebo run-in, patients were randomized to treatment with suvorexant 40/30mg, suvorexant 20/15mg, or placebo in a 3:2:3 ratio in P028, and a 1:1:1 ratio (Q-cohort) or a 2:1:2 ratio (PQ-cohort) in P029. In P009, patients were randomized to treatment with suvorexant 40/30mg or placebo in a 2:1 ratio. Doses differed by age to adjust for previously-observed plasma exposure differences (<65: 40mg or 20mg; ≥65: 30mg or 15mg). Randomization was stratified by age-category (non-elderly vs elderly) in all trials and also by cohort (Q vs PQ) in P028 and P029. For the run-out phase, patients initially assigned to suvorexant were randomized to either continue on the same dose of suvorexant (suvorexant→suvorexant) or to switch to placebo
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(suvorexant→placebo) in a 1:1 ratio, while patients initially assigned to placebo continued to receive placebo (placebo→placebo). Patients were assigned to treatment in a double-blind fashion according to a randomization schedule generated by a Merck statistician using a computerized allocation schedule system. Treatment assignment was implemented through an interactive voice response system. Study investigators, site staff, patients, PSG scorers, and Merck monitoring staff remained blinded to treatment allocation throughout the study. The trials were conducted in accordance with principles of Good Clinical Practice and were approved by the appropriate institutional review boards and regulatory agencies for each site. Informed consent was obtained from all patients. The trials were registered at ClinicalTrials.gov (NCT01097616, NCT01097629, NCT01021813).
Assessments Patients used an electronic diary each morning to report measures of the previous night’s sleep including sTST (min), sTSO (min), and wake after sleep onset (sWASO, min). PSG measures included LPS and WASO assessed at Night-1, Month-1, and Month3. Safety assessments included open-ended questioning for adverse events, the Columbia Suicidality Severity Rating Scale,23 and periodic physical, chemistry, hematology, and electrocardiogram assessments. A Motor-Vehicle-Accidents-andViolations questionnaire was administered during clinic visits or phone calls to assess the occurrence of traffic or motor vehicle accidents (and related injuries) or citations since the last visit when the patient was the driver.
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A program-wide guidance document containing definitions of adverse events prespecified as events of clinical interest was provided to investigators. A blinded independent committee comprised of 3 experts in neurology, psychiatry and sleep, respectively, adjudicated all events of clinical interest potentially suggestive of intrusion of REM into wakefulness (cataplexy) or at initiation of sleep (sleep-onset paralysis). Falls were also adjudicated to ascertain whether they were due to a possible episode of cataplexy. Residual effects were assessed in the PQ-cohort by the Digit Symbol Substitution Test (DSST) within 0.5-1 hour following lights-on on the morning after PSG. Potential withdrawal symptoms were assessed after completion of the doubleblind treatment period by the Tyrer Withdrawal Symptom Questionnaire24 administered prior to dosing on 3 consecutive evenings at the start of the run-out.
Efficacy Endpoints The primary efficacy endpoints in the original trials20 were change from baseline in sleep diary and PSG measures of sleep maintenance (sTST, WASO) and sleep onset (sTSO, LPS). Values for the self-report endpoints were the mean of the daily values for the first week (“Week-1”), the last week of the first month (“Month-1”), or the last 2weeks of the third month (“Month-3”). Change from baseline on sWASO was also assessed.
Statistical Analysis
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A pooled subgroup analysis of phase-3 elderly efficacy and safety data was prespecified, to allow a more robust evaluation than in each individual trial. The pooled efficacy analysis dataset included all patients in P028+P029 who took ≥1 dose of treatment, had ≥1 post-treatment efficacy measure, and had baseline data (for analyses requiring baseline data). Efficacy endpoints (i.e., change-from-baseline in sTST, WASO, sWASO, sTSO, LPS) were assessed using a mixed model repeated measures analysis with terms for study, baseline value, age category (<65, ≥65), region, gender, treatment, time point, treatment-by-time point and age category-by-treatment-by-time point interaction as covariates; cohort was also included in the models for sTST and sTSO and other subjective endpoints. The model assumed a different mean for each treatment at each of the repeated time points in the analysis. In the model, time was treated as a categorical variable so that no restriction was imposed on the trajectory of the means over time. Since the model allows the inclusion of patients who have missing data at certain time points, all efficacy data available during the 3-month treatment period were included in the analyses. An unstructured covariance matrix was used to model the correlation among repeated measurements. The present report focuses on results from the elderly subgroup. Least-squares mean estimates and comparisons of the treatment differences vs. placebo in elderly patients were obtained using appropriate contrasts of the age categoryby-treatment-by-time point interaction term which corresponds to a 2-sided t-test; Satterthwaite’s approximation was used to estimate the degrees of freedom.25 The pre-specified analysis plan for these pooled subgroup analyses did not include an adjustment for the multiple comparisons performed since the primary purpose was to provide improved precision in the estimates of the treatment group differences
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from placebo; note that nominal P-values for these treatment differences were computed as a measure of strength of evidence for the effect rather than a formal test of hypothesis. The safety analysis included all elderly patients in P028+P029+P009 who took ≥1 dose of treatment. The percentages of patients with adverse events, including prespecified events of clinical interest, were calculated. Rebound insomnia (worsening of sleep relative to baseline) for diary endpoints was assessed in elderly patients who entered the 1-week run-out at the end of treatment in P028+P029+P009 (3-months, 6-months or 12-months). The proportion of patients in each treatment group with lower sTST (or greater sTSO) relative to pretreatment baseline, regardless of the magnitude of the difference, was calculated for each of the first 3-nights of run-out as well as on any of the 3-nights. For PSG parameters (WASO and LPS), values during the first night of the run-out at the end of 3 months of treatment were compared to those obtained at pre-treatment baseline. The primary comparisons were between the suvorexant→placebo groups and the placebo→placebo group. Additionally, rebound effects were assessed by between group comparisons of the mean changes from pre-treatment baseline (in minutes) during the run-out for sTST, sTSO, WASO and LPS. To assess withdrawal symptoms, the proportion of elderly patients with ≥3 newlyemergent or worsened (compared to the last treatment measurement) symptoms on the 20-item Tyrer Withdrawal Symptom Questionnaire for each of the first 3-nights of runout as well as across all 3-nights in P028+P029+P009 was calculated. The primary comparisons were between the suvorexant→suvorexant groups and the suvorexant→placebo groups.
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Next-morning residual effects were assessed by the number of attempts and number of correct items on the DSST in the PQ-cohort of P028+P029.
Power No power calculations were made for this pooled elderly subgroup analysis. It should be noted that in in each of the primary studies (which included both non-elderly and elderly patients), there was greater power to declare all primary sleep maintenance measures significant as compared to sleep onset measures, and greater power for the higher 40/30mg (non-elderly/elderly) dose comparisons to placebo versus the 20/15mg (non-elderly/elderly) dose comparisons to placebo due to the smaller sample size allocated to the 20/15mg group.
RESULTS Patients The pooled efficacy dataset (P028+P029) included 839 treated patients; completion rates were high (88-90%) and similar among treatment groups (Fig. S1, Supplemental Digital Content 1). A similar pattern was evident for the pooled safety dataset (P028+P029+P009) which included 1,298 treated patients (Fig. S2, Supplemental Digital Content 1). Patient baseline characteristics and baseline symptom severity were generally similar among treatment groups and are summarized in Table 1 (efficacy dataset). At baseline, patients reported a mean sTST of ~5 hours and a mean sTSO of ~1
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hour. Patient baseline characteristics were also generally similar among treatment groups in the pooled safety dataset (Table S1, Supplemental Digital Content 1).
Efficacy Mean changes-from-baseline in each treatment group for diary and PSG sleep onset and maintenance measures are shown in Table S2 (Supplemental Digital Content 1). Suvorexant differences from placebo are summarized in Table 2. Suvorexant 30mg was effective on all measures at each timepoint. Suvorexant 15mg was also effective across multiple measures and time points, although there was a less robust onset effect at later time points and less precise 95% confidence intervals, possibly in part due to the smaller sample size compared with 30mg (Fig. 1).
Safety Adverse events over 3-months are summarized in Table 3. Patients treated with suvorexant had generally similar incidences of any adverse events or discontinuations due to adverse events compared with placebo. The proportion of patients with serious adverse events was similar among the treatment groups and there was no important difference between treatment groups in the specific types of serious adverse events that were reported. The proportion of patients that had drug-related adverse events was somewhat higher with suvorexant, but none of the suvorexant drug-related adverse events were serious. The most common adverse event that was increased for suvorexant versus placebo was next-day somnolence (Table 3), which was mostly mild or moderate in
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intensity (95% of reports for 30mg, 100% of reports for 15mg, and 93% of reports for placebo). The incidence of pre-defined events of clinical interest over 3-months is shown in Table 3. The most common category for both suvorexant and placebo was events where patient’s returned less study medication than expected and denied taking extra study medication. Although this was assessed as a means of detecting potential abuse, review of these cases suggested that the vast majority (94.7%) were isolated events and due to accidental loss of study medication. Other events of clinical interest reported in ≥1 patient on suvorexant but no patients on placebo included hypnagogic hallucination, hypnopompic hallucination, sleep paralysis, excessive daytime sleepiness, complex sleep-related behavior, and suicidal ideation (Table 3). No reported adverse events were adjudicated as cataplexy. The percentages of patients with falls were similar for suvorexant and placebo. The percentages with motor vehicle accident or violation events were small but numerically higher in the suvorexant 15mg group than the suvorexant 30mg or placebo groups (Table 3). One patient with a history of talking in his sleep who treated with suvorexant 30mg experienced two events of complex sleep-related behavior. The first was a parasomnia that occurred in the sleep laboratory; the patient was talking in his sleep and lunged out of bed and hit his head and face against a wall. The second event was sleep walking and occurred at the patient’s home after he had been off study medication for 2 weeks. Over 3 months, based on clinician’s assessments of adverse events and patient responses to the Columbia Suicide Severity Rating Scale, suicidal ideation was reported
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by 1 patient on suvorexant 30mg. The report was associated with clearly identified precipitating stressful life events, and no suicidal behavior was reported.
Rebound Insomnia Analyses of rebound insomnia (worsening of sleep relative to baseline) for selfreport endpoints during the first 3-nights of the run-out, and PSG endpoints on the first night, are summarized in Table S3 (Supplemental Digital Content 1). The suvorexant 15mg→placebo group showed an increase in the percentages of patients classified as having rebound on sTST across Nights 1, 2 or 3, on sTSO at Night 1, and on WASO at Night 1. The suvorexant 30mg→placebo group showed an increase in the percentages of patients classified as having rebound on sTST on Night 1, Night 2, Night 3, and across Nights 1, 2 or 3, as well as on WASO at Night 1. The supportive approach looking at mean changes from baseline in minutes showed that in all groups (suvorexant 15mg→placebo, suvorexant 30mg→placebo, and placebo→placebo) self-report and PSG endpoints either continued to be improved from baseline during the run-out nights or were comparable to baseline, except for sTSO at Night 1 in the suvorexant 15mg→placebo group (Table S4, Supplemental Digital Content 1).
Withdrawal Analyses of change in Tyrer Withdrawal Symptom Questionnaire scores during the first 3-nights of the run-out are summarized in Appendix Table S5. There were no significant differences in the numbers of patients meeting the pre-specified withdrawal
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criteria for the comparisons of the suvorexant →suvorexant groups versus the corresponding suvorexant→placebo groups.
Residual Effects No significant differences were observed between suvorexant and placebo in terms of baseline-adjusted number of correct responses or attempted responses on the DSST (Table S6, Supplemental Digital Content 1).
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DISCUSSION Although the elderly comprise a large percentage of those with insomnia, relatively few randomized controlled clinical trials have assessed the use of sleep medications in this population, especially in the setting of longer-term use and in the same study as younger patients. Our pre-specified analyses of pooled data from phase-3 randomized clinical trials showed that a 30mg dose of the novel orexin receptor antagonist suvorexant improved self-report and PSG measures of sleep onset and maintenance at the initiation of treatment and over 3 months of nightly use in elderly patients with insomnia. Suvorexant 15mg was also effective across measures, although the onset effect was less evident at later time points. The latter finding may be due in part to the reduced power for sleep onset versus sleep maintenance measures as well as the smaller sample size studied at the 15mg dose. Overall, these results are consistent with the previously observed profile of suvorexant’s more pronounced effects on sleep maintenance.15, 20, 21 This efficacy profile may be of particular benefit to older adults, who often report difficulty maintaining sleep as a sleep complaint.1 Our pooled analysis also showed that suvorexant 30mg and 15mg were generally well-tolerated over 3-months in elderly patients. The most common adverse event associated with suvorexant was somnolence which was mostly mild-to-moderate in intensity. Severe and impairing daytime somnolence, prospectively defined as ‘excessive daytime sleepiness’, occurred in more elderly patients on suvorexant than placebo but was infrequent (0.6% for 30mg, 0.5% for 15 mg, 0% for placebo). Falls are a particular concern in the elderly; in our analysis the percentage of patients with falls was similar for suvorexant versus placebo (0.6% for 30mg, 1.5% for 15 mg, 1.5% for placebo). Analysis
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of DSST scores suggested that suvorexant did not impair next-morning psychomotor function. The percentage of patients with motor vehicle accidents or violations was increased for 15mg versus placebo (2.8% vs 1.0%). This could be a chance finding given the relatively small sample size available for this evaluation and given that there was no increase with 30mg versus placebo (0.9% vs 1.0%). A dedicated on-the-road driving study in healthy elderly men and women found that suvorexant 15mg and 30mg did not produce an impairment in next-morning driving performance as assessed by overall group mean changes in deviation from lane position or in terms of the percentage of subjects who showed a clinically meaningful impairment relative to placebo.26 There is a theoretical concern that antagonism of orexin receptors could mimic signs or symptoms of narcolepsy, particularly cataplexy (sudden intrusion of REM into the waking state associated with sudden loss of muscle tone), given that patients with narcolepsy have a progressive degeneration of orexin neurons.27, 28 No events, including falls, were adjudicated as cataplexy in the suvorexant phase-3 trials in either elderly or non-elderly patients. However, patients known to have narcolepsy were excluded from the phase-3 trials, and suvorexant is not indicated for use in these patients. With regard to sleep-specific adverse events, suvorexant was associated with a small number of reports of sleep-related hallucinations (n=3) and sleep paralysis (n=1) whereas there were no such reports for placebo. Given that both sleep-related hallucinations and sleep paralysis occur spontaneously in the general population it is unknown whether the observed events are specifically related to antagonism of orexin receptors. There was 1 report of a complex sleep behavior for suvorexant 30mg, which
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appeared qualitatively similar to the types of events that have been reported for other sleep medications. The pooled analysis evaluated abrupt suvorexant discontinuation after periods of 3, 6 or 12 months. There was minor evidence of rebound insomnia (worsening of any sleep parameter relative to baseline) when looking at the percentages of patients classified as having rebound, particularly for sleep maintenance measures. However, when looking at mean changes from baseline in minutes, the evaluated sleep endpoints either continued to be improved from baseline during the run-out nights or were comparable to baseline. Thus, the effects observed following suvorexant discontinuation had the characteristics of a loss of therapeutic effect and did not appear to be consistent with rebound insomnia in the majority of patients. Overall, these results suggest that following abrupt termination of suvorexant 30mg after 3-12 months, and suvorexant 15mg after 3-6 months, there is a loss of treatment efficacy, but not a worsening of insomnia compared to the pre-treatment condition, in most elderly insomnia patients. There was no evidence of withdrawal symptoms following abrupt suvorexant discontinuation. Several factors limit the interpretation of our data. The elderly patients included in the trials were usually in good general health and the results may differ in the general elderly population which includes frail elderly. The pooled sample also comprised mostly younger elderly patients 65-74 years of age, with a smaller percentage of patients (<20%) age 75 years or older. The trials were conducted in patients with DSM-IV criteria primary insomnia, and results could differ in patients with co-morbidities. Patients with major depression, which shows a high co-morbidity with insomnia, were excluded and
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suvorexant effects in this population have not been evaluated. In terms of suicidality, in the present pooled analysis suicidal ideation was reported for 1 elderly patient on suvorexant 30mg. Given the sample size of approximately 800 elderly participants receiving suvorexant, it is possible that serious but rarer adverse effects (e.g., with an incidence of less than 1/1000) would likely be missed. Patients with sleep related breathing disorders were also excluded. Phase 1 studies of patients with mild to moderate obstructive sleep apnea (mean age = 49 years, range = 30 to 64) or chronic obstructive pulmonary disease (mean age = 58 years, range = 39 to 72) found that a 40/30mg dose of suvorexant does not have clinically meaningful effects on mean changes in sleep apnea frequency or oxygenation level during sleep.29,30 Because there is inter- and intra-individual variability in respiratory effects, suvorexant should be used with caution in patients with compromised respiratory function. Finally, we note that in the suvorexant phase 3 trials an elderly dose adjustment was made based on available pharmacokinetic data at the time the trials were initiated (elderly patients received 30mg versus 40mg for non-elderly, and 15mg versus 20mg for non-elderly). Based on review of the totality of the pharmacokinetic data subsequently available at the time the marketing application package was submitted, and included in a population pharmacokinetic model, it was determined that age was unlikely to have an effect on suvorexant pharmacokinetics. Therefore, the US dosing recommendations for the elderly follow those for the non-elderly (the recommended dose is 10mg which may be increased to a maximum of 20mg). The US dosing recommendations are based on the FDA’s perspective that the lowest effective dose of insomnia treatments should be used. Consequently, the 15mg data presented in this paper are of most clinical relevance.
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Cox CD, Breslin MJ, Whitman DB, et al: Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1yl][5-methyl-2-(2H -1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 2010;53:5320-5332.
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FIGURE 1. Effect of suvorexant on (A) sleep maintenance measures and (B) sleep onset measures in elderly patients in P028+P029: estimate (95% CI) of difference in least squares means for suvorexant versus placebo
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TABLE 1. Baseline Characteristics of Treated Elderly Patients for P028+P029 (Efficacy Population) Demographics Age Mean (SD), years 65 to 74 years, n (%) ≥75 years, n (%) Gender, n (%) Female Male Body mass index Mean (SD), kg/m2 Underweight <18.5, n (%) Normal 18.5-25, n (%) Overweight 25-30, n (%) Obese >30, n (%) Race, n (%) White Black Asian Other Ethnicity, n (%) Non-Hispanic/Latino Hispanic/Latino Region, n (%) North America Europe Japan Asia Pacific Central/South America Middle East/Africa Central/Eastern Europe Cohort, n (%) Q (Diary only) PQ (Diary plus PSG)
Suvorexant 15mg (N = 202)
Suvorexant 30 mg (N = 319)
Placebo (N = 318)
70 (4) 170 (84.2) 32 (15.8)
71 (4) 264 (82.8) 55 (17.2)
71 (5) 255 (80.2) 63 (19.8)
133 (65.8) 69 (34.2)
199 (62.4) 120 (37.6)
213 (67.0) 105 (33.0)
25.8 (3.9) 4 (2.0) 84 (41.6) 87 (43.1) 27 (13.4)
26.2 (4.0) 4 (1.3) 125 (39.2) 144 (45.1) 46 (14.4)
25.8 (3.8) 3 (0.9) 136 (42.8) 134 (42.1) 45 (14.2)
155 (76.7) 6 (3.0) 32 (15.8) 9 (4.5)
239 (74.9) 14 (4.4) 49 (15.4) 17 (5.3)
243 (76.4) 15 (4.7) 40 (12.6) 20 (6.3)
173 (85.6) 29 (14.4)
272 (85.3) 47 (14.7)
273 (85.8) 45 (14.2)
87 (43.1) 72 (35.6) 25 (12.4) 6 (3.0) 10 (5.0) 0 (0.0) 2 (1.0)
157 (49.2) 96 (30.1) 38 (11.9) 6 (1.9) 20 (6.3) 0 (0.0) 2 (0.6)
139 (43.7) 108 (34.0) 36 (11.3) 2 (0.6) 22 (6.9) 2 (0.6) 9 (2.8)
56 (27.7) 146 (72.3)
69 (21.6) 250 (78.4)
66 (20.8) 252 (79.2)
Mean (SD) baseline scores# Diary measures sTST, min 314.1 (69.2) 313.2 (66.3) 315.1 (60.3) sTSO, min 67.0 (45.9) 69.1 (49.4) 66.1 (39.2) sWASO, min 85.1 (53.3) 89.5 (54.4) 86.7 (52.0) PSG measures (PQ-Cohort) LPS, min 66.5 (49.8) 64.6 (43.1) 67.5 (49.1) WASO, min 133.5 (49.8) 130.3 (52.6) 127.1 (50.5) # Ns were slightly smaller for some baseline diary measure and rating scale scores due to missing data; Ns for PSG measures were smaller because PSG was assessed only in the PQ-Cohort. sTST = subjective total sleep time, sTSO = subjective time to sleep onset, sWASO = subjective wake after sleep onset, LPS = latency to persistent sleep, WASO = wake after sleep onset.
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TABLE 2. Summary of Efficacy for Suvorexant in Elderly Patients over 3 Months for P028+P029: Difference (95% CI) between Suvorexant and Placebo in Least Squares Mean Change from Baseline Suvorexant 15 mg Week 1 (Diary)/ Night 1 (PSG)/
Month 1
Diary measures sTST, min t (df) sTSO, min t (df) sWASO, min t (df)
16.7 (8.8, 24.6)*** 4.17 (1965) -6.5 (-12.1, -1.0)* -2.32 (1918) -9.3 (-14.7, -3.8) *** -3.35 (1905)
PSG measures LPS, min t (df) WASO, min t (df)
-10.0 (-17.3, -2.6)** -2.65 (1475) -39.3 (-47.2, -31.3)*** -9.65 (1474)
Suvorexant 30 mg Month 3
Week 1 (Diary)/ Night 1 (PSG)/
Month 1
Month 3
15.5 (5.8, 25.2) ** 3.13 (1922) -3.6 (-10.4, 3.2) -1.04 (1842) -10.8 (-17.1, -4.4)*** -3.34 (1872)
18.9 (8.3, 29.5)*** 3.51 (1814) -6.5 (-13.2, 0.1) -1.93 (1564) -10.8 (-17.2, -4.3)** -3.26 (1732)
24.9 (18.0, 31.8)*** 7.05 (1964) -9.6 (-14.5, -4.8)*** -3.88 (1917) -10.3 (-15.1, -5.6)*** -4.25 (1905)
20.6 (12.0, 29.1)*** 4.72 (1917) -8.7 (-14.6, -2.7)** -2.86 (1837) -10.4 (-15.9, -4.8)*** -3.65 (1867)
20.4 (11.0, 29.7)*** 4.29 (1811) -9.2 (-15.0, -3.3)** -3.08 (1560) -9.4 (-15.1, -3.7)** -3.24 (1729)
-5.0 (-11.9, 1.8) -1.44 (1416) -26.9 (-35.9, -17.9)*** -5.86 (1415)
-6.2 (-13.5, 1.0) -1.69 (1327) -23.4 (-32.7, -14.2)*** -4.98 (1337)
-17.5 (-23.9, -11.2)*** -5.43 (1477) -49.4 (-56.3, -42.6)*** -14.10 (1477)
-6.7 (-12.6, -0.9)* -2.26 (1415) -31.6 (-39.3, -23.9)*** -8.06 (1411)
-7.7 (-14.0, -1.4)* -2.41 (1332) -24.7 (-32.7, -16.7)*** -6.06 (1345)
Results based on a repeated measures ANCOVA model with terms for study, baseline value, age category (<65, ≥65), region, gender, treatment, time point, treatment-by-time point and age category-by-treatment by-time point interaction as covariates; cohort was also included in the model for Diary measures. sTST = subjective total sleep time, sTSO = subjective time to sleep onset, sWASO = subjective wake after sleep onset, LPS = latency to persistent sleep, WASO = wake after sleep onset. *** p< 0.001, ** p<0.01, *p<0.05, based upon 2-sided t-test (t) with Satterthwaite’s approximation for degrees of freedom (df).
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TABLE 3. Summary of Adverse Events in Elderly Patients over 3 Months for P028+P029+P009: Number (%) of Patients Suvorexant 15mg N=202
Suvorexant 30mg N=627
Placebo N=469
General categories of events ≥1 adverse event ≥1 drug-related adverse event ≥1 serious adverse event ≥1 serious drug-related adverse event Discontinued due to adverse event Death
99 42 3 0 7 0
(49.0) (20.8) (1.5) (0.0) (3.5) (0.0)
316 149 12 0 40 0
(50.4) (23.8) (1.9) (0.0) (6.4) (0.0)
232 69 11 0 26 0
(49.5) (14.7) (2.3) (0.0) (5.5) (0.0)
Specific events ≥2% in any group Somnolence Headache Fatigue Dry mouth Nasopharyngitis Upper respiratory tract infection Dizziness Diarrhea Abnormal dreams Urinary tract infection Drug administration error Back pain Cough Nausea Pruritis Gastroenteritis
11 14 3 5 7 6 8 8 5 6 1 4 5 4 4 4
(5.4) (6.9) (1.5) (2.5) (3.5) (3.0) (4.0) (4.0) (2.5) (3.0) (0.5) (2.0) (2.5) (2.0) (2.0) (2.0)
55 35 24 18 18 16 14 14 10 8 8 7 7 7 2 2
(8.8) (5.6) (3.8) (2.9) (2.9) (2.6) (2.2) (2.2) (1.6) (1.3) (1.3) (1.1) (1.1) (1.1) (0.3) (0.3)
15 25 8 8 19 6 23 7 4 11 10 13 5 6 4 3
(3.2) (5.3) (1.7) (1.7) (4.1) (1.3) (4.9) (1.5) (0.9) (2.3) (2.1) (2.8) (1.1) (1.3) (0.9) (0.6)
Pre-specified events of clinical interest Suicidal ideation and/or behavior 0 (0.0) 1 (0.2) 0 (0.0) Events suggestive of abuse potentiala 1 (0.5) 8 (1.3) 10 (2.1) Complex sleep-related behaviors 0 (0.0) 1 (0.2) 0 (0.0) Hypnagogic hallucination 0 (0.0) 2 (0.3) 0 (0.0) Hypnopompic hallucination 1 (0.5) 0 (0.0) 0 (0.0) Excessive daytime sleepinessb 1 (0.5) 4 (0.6) 0 (0.0) Sleep paralysis 0 (0.0) 1 (0.2) 0 (0.0) Sleep onset paralysis (confirmed by 0 (0.0) 1 (0.2) 0 (0.0) adjudication) Cataplexy (confirmed by adjudication) 0 (0.0) 0 (0.0) 0 (0.0) Fallsc 3 (1.5) 4 (0.6) 7 (1.5) Motor vehicle accidents/violationsd 4 ( 2.8) 2 (0.9) 2 (1.0) Determined by the investigator to be related to the drug (determination made while blinded). 95% CI of comparison to placebo excluded zero a All were events of drug maladministration. Most events were isolated and associated with loss of study medication or patients denying taking additional study medication. b Excessive daytime sleepiness was defined as a more persistent daytime sleepiness than typical next-day residual somnolence; patients were not evaluated by ICSD criteria for the excessive daytime sleepiness symptom diagnosis. c Falls were adjudicated to determine whether they were suggestive of cataplexy. d Includes spontaneously reported events when the patients was the driver and events elicited via a Motor Vehicle Accidents and Violations Questionnaire. Only patients who treated and drove during the treatment phase of the study were included: N=142 for suvorexant 15mg, N=224 for suvorexant 30mg, N=209 for placebo. The counts for discontinuations due to adverse events are based on the period in which the adverse event started.
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S1064-7481(17)30253-1 http://dx.doi.org/doi: 10.1016/j.jagp.2017.03.004 AMGP 808
To appear in:
The American Journal of Geriatric Psychiatry
Received date: Revised date: Accepted date:
13-9-2016 6-3-2017 6-3-2017
Please cite this article as: W. Joseph Herring, Kathryn M. Connor, Ellen Snyder, Duane B. Snavely, Ying Zhang, Jill Hutzelmann, Deborah Matzura-Wolfe, Ruth M. Benca, Andrew D. Krystal, James K. Walsh, Christopher Lines, Thomas Roth, David Michelson, Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data From Phase-3 Randomized Controlled Clinical Trials, The American Journal of Geriatric Psychiatry (2017), http://dx.doi.org/doi: 10.1016/j.jagp.2017.03.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Number of Words: 3812 Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase3 Randomized Controlled Clinical Trials
W. Joseph Herring, MD, PhDa; Kathryn M. Connor, MDa; Ellen Snyder, PhDa; Duane B. Snavely, MAa; Ying Zhang, PhDa; Jill Hutzelmann, MSa; Deborah Matzura-Wolfe, BSa; Ruth M. Benca, MDb; Andrew D. Krystal, MDc; James K. Walsh, PhDd; Christopher Lines, PhDa; Thomas Roth, PhDe; David Michelson, MDa
a
Merck & Co., Inc., Kenilworth, NJ, USA
b
c
University of California-Irvine, Irvine, CA USA
Department of Psychiatry and Behavioral Sciences, Duke University School of
Medicine, Durham, NC, USA d
Sleep Medicine and Research Center, St. Luke’s Hospital, St. Louis, MO, USA
e
Henry Ford Hospital Sleep Center, Detroit, MI, USA
*Address correspondence to W. Joseph Herring, Merck, UG 4C-13, PO Box 1000, North Wales, PA 19454-1099, USA. Tel.: 001 267 305 7933, Fax: 011 267 305 6390. E-mail: [email protected]
These studies were funded by Merck & Co., Inc., Kenilworth, NJ, USA.
Key Words: suvorexant; orexin; randomized clinical trial; efficacy; safety
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Previous presentation: These data were previously presented at SLEEP 2014, May 31June 4 2014, Minneapolis, MN, USA
Running head: Suvorexant in elderly insomnia patients
ACKNOWLEDGMENTS Mingqui Wu, formerly from Merck & Co., Inc., contributed to the statistical analysis. Sheila Erespe from Merck & Co., Inc. assisted with the submission.
Conflicts of Interest and Source of Funding: Dr. Herring, Dr. Connor, Dr. Snyder, Mr. Snavely, Dr. Zhang, Ms. Hutzelmann, Ms. Matzura-Wolfe, Dr. Lines and Dr. Michelson are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA and own or owned stock/stock options in Merck. Dr. Benca has served as a consultant to and receives research support from Merck, and has served as a consultant to Janssen and Jazz over the past 2 years. Dr. Krystal has received grants/research support from NIH, Teva, Sunovion, Astellas, Abbott, Neosync, Brainsway, Janssen, ANS St. Jude, Novartis. He has served as a consultant to: Abbott, Astellas, AstraZeneca, Attentiv, BMS, Teva, Eisai, Eli Lilly, GlaxoSmithKline, Jazz, Janssen, Merck, Neurocrine, Novartis, Otsuka, Lundbeck, Roche, Sanofi-Aventis, Somnus, Sunovion, Somaxon, Takeda, Transcept, Vantia. Dr. Walsh has received research support from the following in the past 2 years: Apnex, Merck, Novo Nordisk, Respironics, Vanda, and has provide consulting services to: Merck, Somnus, Transcept,
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Vanda, Ventus, and Vivus. Dr. Roth has received grants/research support from Aventis, Cephalon, GlaxoSmithKline, Neurocrine, Pfizer, Sanofi, Schering-Plough, Sepracor, Somaxon, Syrex, Takeda, TransOral, Wyeth and Xenoport; has acted as a consultant for Abbott, Acadia, Acoglix, Actelion, Alchemers, Alza, Ancil, Arena, AstraZeneca, Aventis, AVER, BMS, BTG, Cephalon, Cypress, Dove, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hypnion, Impax, Intec, Intra-Cellular, Jazz, Johnson – Johnson, King, Lundbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Prestwick, Procter – Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi, Schering-Plough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Vanda, Vivometrics, Wyeth, Yamanuchi, and Xenoport; and has participated in speaking engagements supported by Cephalon, Sanofi, and Takeda. These studies were funded by Merck & Co., Inc., Kenilworth, NJ, USA.
Author Contributions: Herring: Study concept and design, interpretation of data, preparation of manuscript. Connor, Krystal, Walsh: Study concept and design, interpretation of data, review of manuscript. Snyder: Study concept and design, analysis and interpretation of data, preparation of manuscript. Snavely, Zhang: Study concept and design, analysis and interpretation of data, review of manuscript. Hutzelmann: Study concept and design, review of manuscript. Matzura-Wolfe, Benca: Interpretation of data, review of manuscript. Lines: Interpretation of data, preparation of manuscript. Roth, Michelson: Study concept and design, interpretation of data, review of manuscript.
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Sponsor’s Role: The sponsor was involved in the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
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ABSTRACT Objective: Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10-20mg. Previously-reported phase-3 results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and non-elderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly. Design: Pre-specified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group, trials. Setting: Naturalistic outpatient use, sleep clinics, and laboratories. Participants: Elderly (≥65 years) patients with insomnia. Interventions: Suvorexant 30mg, suvorexant 15mg, placebo. By design, fewer patients were randomized to 15mg. Measurements: Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints. Results: Suvorexant 30mg (N=319) was effective compared to placebo (N=318) on patient-reported and polysomnographic sleep maintenance and onset endpoints at Night-1 (polysomnographic endpoints)/Week-1 (patient-reported endpoints), Month-1 and Month-3. Suvorexant 15mg (N=202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing due to adverse events over 3-months were 6.4% for 30mg (N=627 treated), 3.5% for 15mg (N=202 treated), and 5.5% for placebo (N=469 treated). Somnolence was the most common adverse event (8.8% for 30mg, 5.4% for 15mg, 3.2% for placebo).
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Conclusions: Suvorexant generally improved sleep maintenance and onset over 3months of nightly treatment and was well-tolerated in elderly patients with insomnia.
ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.
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INTRODUCTION The elderly constitute a large proportion of those with insomnia.1-3 As the sleep profile changes with aging, the elderly have been shown to have particular problems with sleep maintenance (disrupted sleep), and to shift to a pattern of earlier retiring and rising (“morning chronotype”) with increased napping during the day.1, 4-8 Most sleep medications used to treat insomnia (e.g. zolpidem, zaleplon, eszopiclone, temazepam) act by enhancing the broad central nervous system depressant effects of GABA inhibition via effects on the benzodiazepine receptor at the GABA-A complex.9 With this class, there are concerns that the elderly might be more sensitive to adverse drug effects (e.g., falls, residual effects) and/or show a differential efficacy response compared with non-elderly patients.10-14 Despite these concerns, there have been relatively few longer-term (>1 month) randomized controlled trials of sleep medications in the elderly. The orexin receptor antagonist suvorexant is a new first-in-class treatment for insomnia, approved in the US and Japan in 2014.15-17 Suvorexant provides a novel approach to treating insomnia by blocking orexin-mediated wake signaling.18, 19 The suvorexant phase-3 development program included both elderly and non-elderly insomnia patients. The program consisted of two 3-month pivotal trials, each of which evaluated two age-adjusted (non-elderly/elderly) suvorexant dose regimes of 40/30mg and 20/15mg ,20 and a 1-year trial of 40/30mg.21 In order to evaluate the clinical profile of suvorexant in elderly patients, a subgroup analysis of pooled elderly data from the phase-3 trials was pre-specified. We report the results of the analysis here.
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METHODS Overview The pooled efficacy elderly subgroup analyses included data from two phase-3 randomized, double-blind, placebo-controlled, parallel-group, 3-month efficacy and safety trials in non-elderly (18-64 years) and elderly (≥65 years) patients with primary insomnia (P028 and P029).20 P028 also included an optional randomized, double-blind, placebo-controlled, 3-month extension. The elderly comprised approximately 40% of those randomized in the trials. Suvorexant doses of 40/30mg (non-elderly/elderly) and 20/15mg (non-elderly/elderly) were evaluated, with fewer patients randomized to 20/15mg than 40/30mg or placebo. Efficacy data from a randomized, double-blind, placebo-controlled, parallel-group 1-year trial (P009)21 were not included in the pooled analysis as that trial was primarily a safety study and did not include polysomnography (PSG) assessments or the 20/15mg dose. The pooled safety elderly subgroup analyses included data from the two phase-3 3-month trials (P028 and P029) and also 3-month data on 30mg and placebo from the 1year trial (P009; 15 mg was not included in the trial). Each trial incorporated a 1-week, randomized, double-blind run-out after double-blind treatment (3 months in P029, 3 or 6 months in P028, 12 months in P009) to assess withdrawal and rebound insomnia.
Patients Non-elderly (18-64) and elderly (≥65) patients who met DSM-IV-TR criteria for primary insomnia22 and were otherwise in good physical and mental health were enrolled. All patients in the two pivotal efficacy studies provided subjective sleep estimates using
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an electronic sleep diary/questionnaire. Approximately 75% of those patients also underwent PSG over 8 hours. Patients who completed only self-report assessments are referred to as the questionnaire (Q)-cohort; those who completed self-report and PSG assessments are referred to as the PSG+questionnaire (PQ)-cohort. To enter the Qcohort, patients had to report a total sleep time (sTST) <6.5 hours and time to sleep onset (sTSO) ≥30 min, both on ≥4 of 7-nights during the last week of a 2-week placebo run-in before randomization. For the PQ-cohort, patients had to meet the following PSG criteria for screening and baseline PSG nights: latency to onset of persistent sleep (LPS) >20 min, and mean (across screening and baseline) wakefulness after persistent sleep onset (WASO) ≥60 min with neither night ≤45 min. They were not required to meet the Qcohort diary entry criteria.
Design and Procedure Patients were discontinued from existing hypnotic medications prior to entering the trials. Following a 2-week placebo run-in, patients were randomized to treatment with suvorexant 40/30mg, suvorexant 20/15mg, or placebo in a 3:2:3 ratio in P028, and a 1:1:1 ratio (Q-cohort) or a 2:1:2 ratio (PQ-cohort) in P029. In P009, patients were randomized to treatment with suvorexant 40/30mg or placebo in a 2:1 ratio. Doses differed by age to adjust for previously-observed plasma exposure differences (<65: 40mg or 20mg; ≥65: 30mg or 15mg). Randomization was stratified by age-category (non-elderly vs elderly) in all trials and also by cohort (Q vs PQ) in P028 and P029. For the run-out phase, patients initially assigned to suvorexant were randomized to either continue on the same dose of suvorexant (suvorexant→suvorexant) or to switch to placebo
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(suvorexant→placebo) in a 1:1 ratio, while patients initially assigned to placebo continued to receive placebo (placebo→placebo). Patients were assigned to treatment in a double-blind fashion according to a randomization schedule generated by a Merck statistician using a computerized allocation schedule system. Treatment assignment was implemented through an interactive voice response system. Study investigators, site staff, patients, PSG scorers, and Merck monitoring staff remained blinded to treatment allocation throughout the study. The trials were conducted in accordance with principles of Good Clinical Practice and were approved by the appropriate institutional review boards and regulatory agencies for each site. Informed consent was obtained from all patients. The trials were registered at ClinicalTrials.gov (NCT01097616, NCT01097629, NCT01021813).
Assessments Patients used an electronic diary each morning to report measures of the previous night’s sleep including sTST (min), sTSO (min), and wake after sleep onset (sWASO, min). PSG measures included LPS and WASO assessed at Night-1, Month-1, and Month3. Safety assessments included open-ended questioning for adverse events, the Columbia Suicidality Severity Rating Scale,23 and periodic physical, chemistry, hematology, and electrocardiogram assessments. A Motor-Vehicle-Accidents-andViolations questionnaire was administered during clinic visits or phone calls to assess the occurrence of traffic or motor vehicle accidents (and related injuries) or citations since the last visit when the patient was the driver.
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A program-wide guidance document containing definitions of adverse events prespecified as events of clinical interest was provided to investigators. A blinded independent committee comprised of 3 experts in neurology, psychiatry and sleep, respectively, adjudicated all events of clinical interest potentially suggestive of intrusion of REM into wakefulness (cataplexy) or at initiation of sleep (sleep-onset paralysis). Falls were also adjudicated to ascertain whether they were due to a possible episode of cataplexy. Residual effects were assessed in the PQ-cohort by the Digit Symbol Substitution Test (DSST) within 0.5-1 hour following lights-on on the morning after PSG. Potential withdrawal symptoms were assessed after completion of the doubleblind treatment period by the Tyrer Withdrawal Symptom Questionnaire24 administered prior to dosing on 3 consecutive evenings at the start of the run-out.
Efficacy Endpoints The primary efficacy endpoints in the original trials20 were change from baseline in sleep diary and PSG measures of sleep maintenance (sTST, WASO) and sleep onset (sTSO, LPS). Values for the self-report endpoints were the mean of the daily values for the first week (“Week-1”), the last week of the first month (“Month-1”), or the last 2weeks of the third month (“Month-3”). Change from baseline on sWASO was also assessed.
Statistical Analysis
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A pooled subgroup analysis of phase-3 elderly efficacy and safety data was prespecified, to allow a more robust evaluation than in each individual trial. The pooled efficacy analysis dataset included all patients in P028+P029 who took ≥1 dose of treatment, had ≥1 post-treatment efficacy measure, and had baseline data (for analyses requiring baseline data). Efficacy endpoints (i.e., change-from-baseline in sTST, WASO, sWASO, sTSO, LPS) were assessed using a mixed model repeated measures analysis with terms for study, baseline value, age category (<65, ≥65), region, gender, treatment, time point, treatment-by-time point and age category-by-treatment-by-time point interaction as covariates; cohort was also included in the models for sTST and sTSO and other subjective endpoints. The model assumed a different mean for each treatment at each of the repeated time points in the analysis. In the model, time was treated as a categorical variable so that no restriction was imposed on the trajectory of the means over time. Since the model allows the inclusion of patients who have missing data at certain time points, all efficacy data available during the 3-month treatment period were included in the analyses. An unstructured covariance matrix was used to model the correlation among repeated measurements. The present report focuses on results from the elderly subgroup. Least-squares mean estimates and comparisons of the treatment differences vs. placebo in elderly patients were obtained using appropriate contrasts of the age categoryby-treatment-by-time point interaction term which corresponds to a 2-sided t-test; Satterthwaite’s approximation was used to estimate the degrees of freedom.25 The pre-specified analysis plan for these pooled subgroup analyses did not include an adjustment for the multiple comparisons performed since the primary purpose was to provide improved precision in the estimates of the treatment group differences
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from placebo; note that nominal P-values for these treatment differences were computed as a measure of strength of evidence for the effect rather than a formal test of hypothesis. The safety analysis included all elderly patients in P028+P029+P009 who took ≥1 dose of treatment. The percentages of patients with adverse events, including prespecified events of clinical interest, were calculated. Rebound insomnia (worsening of sleep relative to baseline) for diary endpoints was assessed in elderly patients who entered the 1-week run-out at the end of treatment in P028+P029+P009 (3-months, 6-months or 12-months). The proportion of patients in each treatment group with lower sTST (or greater sTSO) relative to pretreatment baseline, regardless of the magnitude of the difference, was calculated for each of the first 3-nights of run-out as well as on any of the 3-nights. For PSG parameters (WASO and LPS), values during the first night of the run-out at the end of 3 months of treatment were compared to those obtained at pre-treatment baseline. The primary comparisons were between the suvorexant→placebo groups and the placebo→placebo group. Additionally, rebound effects were assessed by between group comparisons of the mean changes from pre-treatment baseline (in minutes) during the run-out for sTST, sTSO, WASO and LPS. To assess withdrawal symptoms, the proportion of elderly patients with ≥3 newlyemergent or worsened (compared to the last treatment measurement) symptoms on the 20-item Tyrer Withdrawal Symptom Questionnaire for each of the first 3-nights of runout as well as across all 3-nights in P028+P029+P009 was calculated. The primary comparisons were between the suvorexant→suvorexant groups and the suvorexant→placebo groups.
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Next-morning residual effects were assessed by the number of attempts and number of correct items on the DSST in the PQ-cohort of P028+P029.
Power No power calculations were made for this pooled elderly subgroup analysis. It should be noted that in in each of the primary studies (which included both non-elderly and elderly patients), there was greater power to declare all primary sleep maintenance measures significant as compared to sleep onset measures, and greater power for the higher 40/30mg (non-elderly/elderly) dose comparisons to placebo versus the 20/15mg (non-elderly/elderly) dose comparisons to placebo due to the smaller sample size allocated to the 20/15mg group.
RESULTS Patients The pooled efficacy dataset (P028+P029) included 839 treated patients; completion rates were high (88-90%) and similar among treatment groups (Fig. S1, Supplemental Digital Content 1). A similar pattern was evident for the pooled safety dataset (P028+P029+P009) which included 1,298 treated patients (Fig. S2, Supplemental Digital Content 1). Patient baseline characteristics and baseline symptom severity were generally similar among treatment groups and are summarized in Table 1 (efficacy dataset). At baseline, patients reported a mean sTST of ~5 hours and a mean sTSO of ~1
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hour. Patient baseline characteristics were also generally similar among treatment groups in the pooled safety dataset (Table S1, Supplemental Digital Content 1).
Efficacy Mean changes-from-baseline in each treatment group for diary and PSG sleep onset and maintenance measures are shown in Table S2 (Supplemental Digital Content 1). Suvorexant differences from placebo are summarized in Table 2. Suvorexant 30mg was effective on all measures at each timepoint. Suvorexant 15mg was also effective across multiple measures and time points, although there was a less robust onset effect at later time points and less precise 95% confidence intervals, possibly in part due to the smaller sample size compared with 30mg (Fig. 1).
Safety Adverse events over 3-months are summarized in Table 3. Patients treated with suvorexant had generally similar incidences of any adverse events or discontinuations due to adverse events compared with placebo. The proportion of patients with serious adverse events was similar among the treatment groups and there was no important difference between treatment groups in the specific types of serious adverse events that were reported. The proportion of patients that had drug-related adverse events was somewhat higher with suvorexant, but none of the suvorexant drug-related adverse events were serious. The most common adverse event that was increased for suvorexant versus placebo was next-day somnolence (Table 3), which was mostly mild or moderate in
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intensity (95% of reports for 30mg, 100% of reports for 15mg, and 93% of reports for placebo). The incidence of pre-defined events of clinical interest over 3-months is shown in Table 3. The most common category for both suvorexant and placebo was events where patient’s returned less study medication than expected and denied taking extra study medication. Although this was assessed as a means of detecting potential abuse, review of these cases suggested that the vast majority (94.7%) were isolated events and due to accidental loss of study medication. Other events of clinical interest reported in ≥1 patient on suvorexant but no patients on placebo included hypnagogic hallucination, hypnopompic hallucination, sleep paralysis, excessive daytime sleepiness, complex sleep-related behavior, and suicidal ideation (Table 3). No reported adverse events were adjudicated as cataplexy. The percentages of patients with falls were similar for suvorexant and placebo. The percentages with motor vehicle accident or violation events were small but numerically higher in the suvorexant 15mg group than the suvorexant 30mg or placebo groups (Table 3). One patient with a history of talking in his sleep who treated with suvorexant 30mg experienced two events of complex sleep-related behavior. The first was a parasomnia that occurred in the sleep laboratory; the patient was talking in his sleep and lunged out of bed and hit his head and face against a wall. The second event was sleep walking and occurred at the patient’s home after he had been off study medication for 2 weeks. Over 3 months, based on clinician’s assessments of adverse events and patient responses to the Columbia Suicide Severity Rating Scale, suicidal ideation was reported
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by 1 patient on suvorexant 30mg. The report was associated with clearly identified precipitating stressful life events, and no suicidal behavior was reported.
Rebound Insomnia Analyses of rebound insomnia (worsening of sleep relative to baseline) for selfreport endpoints during the first 3-nights of the run-out, and PSG endpoints on the first night, are summarized in Table S3 (Supplemental Digital Content 1). The suvorexant 15mg→placebo group showed an increase in the percentages of patients classified as having rebound on sTST across Nights 1, 2 or 3, on sTSO at Night 1, and on WASO at Night 1. The suvorexant 30mg→placebo group showed an increase in the percentages of patients classified as having rebound on sTST on Night 1, Night 2, Night 3, and across Nights 1, 2 or 3, as well as on WASO at Night 1. The supportive approach looking at mean changes from baseline in minutes showed that in all groups (suvorexant 15mg→placebo, suvorexant 30mg→placebo, and placebo→placebo) self-report and PSG endpoints either continued to be improved from baseline during the run-out nights or were comparable to baseline, except for sTSO at Night 1 in the suvorexant 15mg→placebo group (Table S4, Supplemental Digital Content 1).
Withdrawal Analyses of change in Tyrer Withdrawal Symptom Questionnaire scores during the first 3-nights of the run-out are summarized in Appendix Table S5. There were no significant differences in the numbers of patients meeting the pre-specified withdrawal
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criteria for the comparisons of the suvorexant →suvorexant groups versus the corresponding suvorexant→placebo groups.
Residual Effects No significant differences were observed between suvorexant and placebo in terms of baseline-adjusted number of correct responses or attempted responses on the DSST (Table S6, Supplemental Digital Content 1).
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DISCUSSION Although the elderly comprise a large percentage of those with insomnia, relatively few randomized controlled clinical trials have assessed the use of sleep medications in this population, especially in the setting of longer-term use and in the same study as younger patients. Our pre-specified analyses of pooled data from phase-3 randomized clinical trials showed that a 30mg dose of the novel orexin receptor antagonist suvorexant improved self-report and PSG measures of sleep onset and maintenance at the initiation of treatment and over 3 months of nightly use in elderly patients with insomnia. Suvorexant 15mg was also effective across measures, although the onset effect was less evident at later time points. The latter finding may be due in part to the reduced power for sleep onset versus sleep maintenance measures as well as the smaller sample size studied at the 15mg dose. Overall, these results are consistent with the previously observed profile of suvorexant’s more pronounced effects on sleep maintenance.15, 20, 21 This efficacy profile may be of particular benefit to older adults, who often report difficulty maintaining sleep as a sleep complaint.1 Our pooled analysis also showed that suvorexant 30mg and 15mg were generally well-tolerated over 3-months in elderly patients. The most common adverse event associated with suvorexant was somnolence which was mostly mild-to-moderate in intensity. Severe and impairing daytime somnolence, prospectively defined as ‘excessive daytime sleepiness’, occurred in more elderly patients on suvorexant than placebo but was infrequent (0.6% for 30mg, 0.5% for 15 mg, 0% for placebo). Falls are a particular concern in the elderly; in our analysis the percentage of patients with falls was similar for suvorexant versus placebo (0.6% for 30mg, 1.5% for 15 mg, 1.5% for placebo). Analysis
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of DSST scores suggested that suvorexant did not impair next-morning psychomotor function. The percentage of patients with motor vehicle accidents or violations was increased for 15mg versus placebo (2.8% vs 1.0%). This could be a chance finding given the relatively small sample size available for this evaluation and given that there was no increase with 30mg versus placebo (0.9% vs 1.0%). A dedicated on-the-road driving study in healthy elderly men and women found that suvorexant 15mg and 30mg did not produce an impairment in next-morning driving performance as assessed by overall group mean changes in deviation from lane position or in terms of the percentage of subjects who showed a clinically meaningful impairment relative to placebo.26 There is a theoretical concern that antagonism of orexin receptors could mimic signs or symptoms of narcolepsy, particularly cataplexy (sudden intrusion of REM into the waking state associated with sudden loss of muscle tone), given that patients with narcolepsy have a progressive degeneration of orexin neurons.27, 28 No events, including falls, were adjudicated as cataplexy in the suvorexant phase-3 trials in either elderly or non-elderly patients. However, patients known to have narcolepsy were excluded from the phase-3 trials, and suvorexant is not indicated for use in these patients. With regard to sleep-specific adverse events, suvorexant was associated with a small number of reports of sleep-related hallucinations (n=3) and sleep paralysis (n=1) whereas there were no such reports for placebo. Given that both sleep-related hallucinations and sleep paralysis occur spontaneously in the general population it is unknown whether the observed events are specifically related to antagonism of orexin receptors. There was 1 report of a complex sleep behavior for suvorexant 30mg, which
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appeared qualitatively similar to the types of events that have been reported for other sleep medications. The pooled analysis evaluated abrupt suvorexant discontinuation after periods of 3, 6 or 12 months. There was minor evidence of rebound insomnia (worsening of any sleep parameter relative to baseline) when looking at the percentages of patients classified as having rebound, particularly for sleep maintenance measures. However, when looking at mean changes from baseline in minutes, the evaluated sleep endpoints either continued to be improved from baseline during the run-out nights or were comparable to baseline. Thus, the effects observed following suvorexant discontinuation had the characteristics of a loss of therapeutic effect and did not appear to be consistent with rebound insomnia in the majority of patients. Overall, these results suggest that following abrupt termination of suvorexant 30mg after 3-12 months, and suvorexant 15mg after 3-6 months, there is a loss of treatment efficacy, but not a worsening of insomnia compared to the pre-treatment condition, in most elderly insomnia patients. There was no evidence of withdrawal symptoms following abrupt suvorexant discontinuation. Several factors limit the interpretation of our data. The elderly patients included in the trials were usually in good general health and the results may differ in the general elderly population which includes frail elderly. The pooled sample also comprised mostly younger elderly patients 65-74 years of age, with a smaller percentage of patients (<20%) age 75 years or older. The trials were conducted in patients with DSM-IV criteria primary insomnia, and results could differ in patients with co-morbidities. Patients with major depression, which shows a high co-morbidity with insomnia, were excluded and
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suvorexant effects in this population have not been evaluated. In terms of suicidality, in the present pooled analysis suicidal ideation was reported for 1 elderly patient on suvorexant 30mg. Given the sample size of approximately 800 elderly participants receiving suvorexant, it is possible that serious but rarer adverse effects (e.g., with an incidence of less than 1/1000) would likely be missed. Patients with sleep related breathing disorders were also excluded. Phase 1 studies of patients with mild to moderate obstructive sleep apnea (mean age = 49 years, range = 30 to 64) or chronic obstructive pulmonary disease (mean age = 58 years, range = 39 to 72) found that a 40/30mg dose of suvorexant does not have clinically meaningful effects on mean changes in sleep apnea frequency or oxygenation level during sleep.29,30 Because there is inter- and intra-individual variability in respiratory effects, suvorexant should be used with caution in patients with compromised respiratory function. Finally, we note that in the suvorexant phase 3 trials an elderly dose adjustment was made based on available pharmacokinetic data at the time the trials were initiated (elderly patients received 30mg versus 40mg for non-elderly, and 15mg versus 20mg for non-elderly). Based on review of the totality of the pharmacokinetic data subsequently available at the time the marketing application package was submitted, and included in a population pharmacokinetic model, it was determined that age was unlikely to have an effect on suvorexant pharmacokinetics. Therefore, the US dosing recommendations for the elderly follow those for the non-elderly (the recommended dose is 10mg which may be increased to a maximum of 20mg). The US dosing recommendations are based on the FDA’s perspective that the lowest effective dose of insomnia treatments should be used. Consequently, the 15mg data presented in this paper are of most clinical relevance.
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FIGURE 1. Effect of suvorexant on (A) sleep maintenance measures and (B) sleep onset measures in elderly patients in P028+P029: estimate (95% CI) of difference in least squares means for suvorexant versus placebo
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TABLE 1. Baseline Characteristics of Treated Elderly Patients for P028+P029 (Efficacy Population) Demographics Age Mean (SD), years 65 to 74 years, n (%) ≥75 years, n (%) Gender, n (%) Female Male Body mass index Mean (SD), kg/m2 Underweight <18.5, n (%) Normal 18.5-25, n (%) Overweight 25-30, n (%) Obese >30, n (%) Race, n (%) White Black Asian Other Ethnicity, n (%) Non-Hispanic/Latino Hispanic/Latino Region, n (%) North America Europe Japan Asia Pacific Central/South America Middle East/Africa Central/Eastern Europe Cohort, n (%) Q (Diary only) PQ (Diary plus PSG)
Suvorexant 15mg (N = 202)
Suvorexant 30 mg (N = 319)
Placebo (N = 318)
70 (4) 170 (84.2) 32 (15.8)
71 (4) 264 (82.8) 55 (17.2)
71 (5) 255 (80.2) 63 (19.8)
133 (65.8) 69 (34.2)
199 (62.4) 120 (37.6)
213 (67.0) 105 (33.0)
25.8 (3.9) 4 (2.0) 84 (41.6) 87 (43.1) 27 (13.4)
26.2 (4.0) 4 (1.3) 125 (39.2) 144 (45.1) 46 (14.4)
25.8 (3.8) 3 (0.9) 136 (42.8) 134 (42.1) 45 (14.2)
155 (76.7) 6 (3.0) 32 (15.8) 9 (4.5)
239 (74.9) 14 (4.4) 49 (15.4) 17 (5.3)
243 (76.4) 15 (4.7) 40 (12.6) 20 (6.3)
173 (85.6) 29 (14.4)
272 (85.3) 47 (14.7)
273 (85.8) 45 (14.2)
87 (43.1) 72 (35.6) 25 (12.4) 6 (3.0) 10 (5.0) 0 (0.0) 2 (1.0)
157 (49.2) 96 (30.1) 38 (11.9) 6 (1.9) 20 (6.3) 0 (0.0) 2 (0.6)
139 (43.7) 108 (34.0) 36 (11.3) 2 (0.6) 22 (6.9) 2 (0.6) 9 (2.8)
56 (27.7) 146 (72.3)
69 (21.6) 250 (78.4)
66 (20.8) 252 (79.2)
Mean (SD) baseline scores# Diary measures sTST, min 314.1 (69.2) 313.2 (66.3) 315.1 (60.3) sTSO, min 67.0 (45.9) 69.1 (49.4) 66.1 (39.2) sWASO, min 85.1 (53.3) 89.5 (54.4) 86.7 (52.0) PSG measures (PQ-Cohort) LPS, min 66.5 (49.8) 64.6 (43.1) 67.5 (49.1) WASO, min 133.5 (49.8) 130.3 (52.6) 127.1 (50.5) # Ns were slightly smaller for some baseline diary measure and rating scale scores due to missing data; Ns for PSG measures were smaller because PSG was assessed only in the PQ-Cohort. sTST = subjective total sleep time, sTSO = subjective time to sleep onset, sWASO = subjective wake after sleep onset, LPS = latency to persistent sleep, WASO = wake after sleep onset.
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TABLE 2. Summary of Efficacy for Suvorexant in Elderly Patients over 3 Months for P028+P029: Difference (95% CI) between Suvorexant and Placebo in Least Squares Mean Change from Baseline Suvorexant 15 mg Week 1 (Diary)/ Night 1 (PSG)/
Month 1
Diary measures sTST, min t (df) sTSO, min t (df) sWASO, min t (df)
16.7 (8.8, 24.6)*** 4.17 (1965) -6.5 (-12.1, -1.0)* -2.32 (1918) -9.3 (-14.7, -3.8) *** -3.35 (1905)
PSG measures LPS, min t (df) WASO, min t (df)
-10.0 (-17.3, -2.6)** -2.65 (1475) -39.3 (-47.2, -31.3)*** -9.65 (1474)
Suvorexant 30 mg Month 3
Week 1 (Diary)/ Night 1 (PSG)/
Month 1
Month 3
15.5 (5.8, 25.2) ** 3.13 (1922) -3.6 (-10.4, 3.2) -1.04 (1842) -10.8 (-17.1, -4.4)*** -3.34 (1872)
18.9 (8.3, 29.5)*** 3.51 (1814) -6.5 (-13.2, 0.1) -1.93 (1564) -10.8 (-17.2, -4.3)** -3.26 (1732)
24.9 (18.0, 31.8)*** 7.05 (1964) -9.6 (-14.5, -4.8)*** -3.88 (1917) -10.3 (-15.1, -5.6)*** -4.25 (1905)
20.6 (12.0, 29.1)*** 4.72 (1917) -8.7 (-14.6, -2.7)** -2.86 (1837) -10.4 (-15.9, -4.8)*** -3.65 (1867)
20.4 (11.0, 29.7)*** 4.29 (1811) -9.2 (-15.0, -3.3)** -3.08 (1560) -9.4 (-15.1, -3.7)** -3.24 (1729)
-5.0 (-11.9, 1.8) -1.44 (1416) -26.9 (-35.9, -17.9)*** -5.86 (1415)
-6.2 (-13.5, 1.0) -1.69 (1327) -23.4 (-32.7, -14.2)*** -4.98 (1337)
-17.5 (-23.9, -11.2)*** -5.43 (1477) -49.4 (-56.3, -42.6)*** -14.10 (1477)
-6.7 (-12.6, -0.9)* -2.26 (1415) -31.6 (-39.3, -23.9)*** -8.06 (1411)
-7.7 (-14.0, -1.4)* -2.41 (1332) -24.7 (-32.7, -16.7)*** -6.06 (1345)
Results based on a repeated measures ANCOVA model with terms for study, baseline value, age category (<65, ≥65), region, gender, treatment, time point, treatment-by-time point and age category-by-treatment by-time point interaction as covariates; cohort was also included in the model for Diary measures. sTST = subjective total sleep time, sTSO = subjective time to sleep onset, sWASO = subjective wake after sleep onset, LPS = latency to persistent sleep, WASO = wake after sleep onset. *** p< 0.001, ** p<0.01, *p<0.05, based upon 2-sided t-test (t) with Satterthwaite’s approximation for degrees of freedom (df).
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TABLE 3. Summary of Adverse Events in Elderly Patients over 3 Months for P028+P029+P009: Number (%) of Patients Suvorexant 15mg N=202
Suvorexant 30mg N=627
Placebo N=469
General categories of events ≥1 adverse event ≥1 drug-related adverse event ≥1 serious adverse event ≥1 serious drug-related adverse event Discontinued due to adverse event Death
99 42 3 0 7 0
(49.0) (20.8) (1.5) (0.0) (3.5) (0.0)
316 149 12 0 40 0
(50.4) (23.8) (1.9) (0.0) (6.4) (0.0)
232 69 11 0 26 0
(49.5) (14.7) (2.3) (0.0) (5.5) (0.0)
Specific events ≥2% in any group Somnolence Headache Fatigue Dry mouth Nasopharyngitis Upper respiratory tract infection Dizziness Diarrhea Abnormal dreams Urinary tract infection Drug administration error Back pain Cough Nausea Pruritis Gastroenteritis
11 14 3 5 7 6 8 8 5 6 1 4 5 4 4 4
(5.4) (6.9) (1.5) (2.5) (3.5) (3.0) (4.0) (4.0) (2.5) (3.0) (0.5) (2.0) (2.5) (2.0) (2.0) (2.0)
55 35 24 18 18 16 14 14 10 8 8 7 7 7 2 2
(8.8) (5.6) (3.8) (2.9) (2.9) (2.6) (2.2) (2.2) (1.6) (1.3) (1.3) (1.1) (1.1) (1.1) (0.3) (0.3)
15 25 8 8 19 6 23 7 4 11 10 13 5 6 4 3
(3.2) (5.3) (1.7) (1.7) (4.1) (1.3) (4.9) (1.5) (0.9) (2.3) (2.1) (2.8) (1.1) (1.3) (0.9) (0.6)
Pre-specified events of clinical interest Suicidal ideation and/or behavior 0 (0.0) 1 (0.2) 0 (0.0) Events suggestive of abuse potentiala 1 (0.5) 8 (1.3) 10 (2.1) Complex sleep-related behaviors 0 (0.0) 1 (0.2) 0 (0.0) Hypnagogic hallucination 0 (0.0) 2 (0.3) 0 (0.0) Hypnopompic hallucination 1 (0.5) 0 (0.0) 0 (0.0) Excessive daytime sleepinessb 1 (0.5) 4 (0.6) 0 (0.0) Sleep paralysis 0 (0.0) 1 (0.2) 0 (0.0) Sleep onset paralysis (confirmed by 0 (0.0) 1 (0.2) 0 (0.0) adjudication) Cataplexy (confirmed by adjudication) 0 (0.0) 0 (0.0) 0 (0.0) Fallsc 3 (1.5) 4 (0.6) 7 (1.5) Motor vehicle accidents/violationsd 4 ( 2.8) 2 (0.9) 2 (1.0) Determined by the investigator to be related to the drug (determination made while blinded). 95% CI of comparison to placebo excluded zero a All were events of drug maladministration. Most events were isolated and associated with loss of study medication or patients denying taking additional study medication. b Excessive daytime sleepiness was defined as a more persistent daytime sleepiness than typical next-day residual somnolence; patients were not evaluated by ICSD criteria for the excessive daytime sleepiness symptom diagnosis. c Falls were adjudicated to determine whether they were suggestive of cataplexy. d Includes spontaneously reported events when the patients was the driver and events elicited via a Motor Vehicle Accidents and Violations Questionnaire. Only patients who treated and drove during the treatment phase of the study were included: N=142 for suvorexant 15mg, N=224 for suvorexant 30mg, N=209 for placebo. The counts for discontinuations due to adverse events are based on the period in which the adverse event started.
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