A randomized placebo-controlled polysomnographic study of eszopiclone in Japanese patients with primary insomnia

Sleep Medicine 13 (2012) 1247–1253

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Original Article

A randomized placebo-controlled polysomnographic study of eszopiclone in Japanese patients with primary insomnia q Naohisa Uchimura a,⇑, Atsushi Kamijo b, Hiroo Kuwahara a, Makoto Uchiyama c, Tetsuo Shimizu d, Shigeru Chiba e, Yuichi Inoue f a

Department of Neuropsychiatry, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan Department of Psychiatry, Nihon University School of Medicine, 30-1 Oyaguchi Kamicho, Itabashi-ku, Tokyo 173-8610, Japan d Department of Neuropsychiatry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan e Department of Psychiatry and Neurology, School of Medicine, Asahikawa Medical University, 1-1-1 Midorigaoka Higashi 2-jo, Hokkaido 078-8510, Japan f Department of Somnology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan b c

a r t i c l e

i n f o

Article history: Received 23 March 2012 Received in revised form 6 August 2012 Accepted 6 August 2012 Available online 11 October 2012 Keywords: Eszopiclone Primary insomnia Japanese Polysomnography Sleep latency WASO

a b s t r a c t Objectives: To evaluate the efficacy and dose–response effect of eszopiclone on sleep latency and sleep maintenance in Japanese patients with primary insomnia. Methods: In this randomized, double-blind, five-way crossover study, 72 patients received placebo, eszopiclone 1 mg, 2 mg, and 3 mg, and zolpidem 10 mg in random order for two consecutive nights with a washout period between treatments. Objective sleep measures from polysomnography (PSG) and subjective patient reports were collected. Results: All active treatments produced significant improvement in objective and subjective sleep latency compared with placebo (P < 0.05 for all comparisons); linear dose–response relationships were observed for eszopiclone. PSG-determined wake time after sleep onset (WASO), sleep efficiency, and number of awakenings (NA), and patient-reported measures of WASO, NA, sleep quality, sleep depth, and daytime functioning significantly improved following treatment with eszopiclone 2 mg and 3 mg and zolpidem 10 mg versus placebo (P < 0.05). Eszopiclone at all doses increased total sleep time and stage 2 sleep time (P < 0.001 for both comparisons), but did not alter REM or slow-wave sleep. Eszopiclone was generally well tolerated; the most frequently reported adverse event was mild dysgeusia. Conclusions: In Japanese patients with primary insomnia, eszopiclone 2 mg and 3 mg significantly improved PSG-determined and patient-reported sleep latency and sleep maintenance relative to placebo. Ó 2012 Elsevier B.V. All rights reserved.

1. Introduction Nationwide epidemiology studies in Japan have estimated the prevalence of insomnia among adults to be between 17% and 22% [1]. In the US, a general consensus has emerged from population-based studies that 30% of adults have one or more symptoms of insomnia (difficulty initiating sleep, difficulty maintaining sleep, waking up too early, or poor quality of sleep) and 10% also have daytime symptoms associated with a diagnosis of insomnia [2,3]. A recent nationwide survey based on health care claims, with confirmatory evaluations by clinical sleep medicine experts, estimated the prevalence of insomnia among American adults to be 23% [4],

q Clinical Trial Information: A phase II/III study of SEP-190 (eszopiclone) in patients with primary insomnia; Registration #NCT00770510; http://www.clinicaltrials. gov/ct2/show/NCT00770510. ⇑ Corresponding author. Tel.: +81 942 35 3777; fax: +81 942 35 6041. E-mail address: [email protected] (N. Uchimura).

1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2012.08.015

remarkably similar to the prevalence in Japan. Insomnia has a substantial negative impact on work absenteeism, work productivity and performance, health care utilization and costs, and quality of life [4–8] and is also associated with medical and psychiatric comorbidities [3,7]. Relatively limited published research is available regarding the effects of insomnia in Japanese populations [8], but studies have shown an association between sleep disturbances and absenteeism, work performance, physical and psychological health, and quality of life [8–10]. High prevalence rates in combination with the associated personal and socioeconomic burdens make insomnia a significant public health issue. Eszopiclone is an S-isomer of racemic zopiclone; it is a nonbenzodiazepine cyclopyrrolone agent indicated for the treatment of insomnia in the US [11,12]. In studies of nonelderly adults with chronic primary insomnia, both short-term (6 weeks) and longterm (6–12 months) nightly treatment with 2–3 mg eszopiclone produced significant improvement in sleep latency, sleep maintenance, and daytime functioning compared with placebo [13–15].

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Similar benefits were observed in studies conducted in elderly patients with primary insomnia [11,16] and nonelderly patients with comorbid insomnia [17–19]. No signal for tolerance has been observed; rebound insomnia was rare, and when it did occur, was limited to the first night after discontinuation of medication [11,13,14]. A placebo-controlled, crossover study conducted in a US patient population with primary insomnia evaluated four doses of eszopiclone from 1 mg to 3 mg [20]. All doses were superior to placebo regarding measures of sleep latency and sleep efficiency. Treatment with 3 mg eszopiclone also provided greater improvement in sleep maintenance compared with placebo [20]. There are otherwise no previously published reports of eszopiclone in the treatment of Japanese patients with primary insomnia. In general, drug responses may vary depending on different ethnic groups [21–23]. We therefore, designed this study to evaluate the efficacy and safety in Japanese patients with primary insomnia. The current study evaluated the efficacy and safety of incremental doses of eszopiclone (1–3 mg) in a placebo-controlled crossover study of nonelderly Japanese patients with primary insomnia. Insomnia is a subjective complaint and is typically diagnosed and treated based on patient-reported symptoms; therefore, it is clinically relevant to include in a study not only polysomnography (PSG)-based objective assessments, but also patient-reported subjective assessments of sleep disturbance. The co-primary endpoints required that statistically significant changes in objective latency to persistent sleep (LPS) were also associated with significant improvement in the patients’ subjective estimate. The recommended dose for clinical use of eszopiclone in nonelderly patients in the US is 2–3 mg [12]; therefore, the primary objectives were to assess the dose–response relationship of eszopiclone and to evaluate the superiority of treatment with eszopiclone 2 mg and 3 mg compared with placebo for sleep latency based on both PSG-determined and subjective evaluations. The secondary objective of the present study were to evaluate the effects of eszopiclone on other PSG-determined sleep measures and patient-reported measures of sleep and daytime functioning.

2. Methods 2.1. Study design This was a randomized, double-blind, placebo-controlled, dose– response, five-way crossover study conducted at 21 sites in Japan between September 2008 and May 2010. The study consisted of a 2-week screening period, a treatment period that included five intervals of two consecutive nights, each of which was separated by a washout of approximately 5 days, and a follow-up period of 6 days. Placebo, eszopiclone 1 mg, 2 mg, and 3 mg, and zolpidem 10 mg were administered in random order. Zolpidem was included as an active reference to allow qualitative comparisons of eszopiclone. A third-party patient enrollment center generated the randomization table, enrolled patients in the study, and assigned each patient to one of 10 prespecified treatment sequence patterns using block randomization (18 blocks, each containing all 10 sequence patterns). A third-party drug randomization manager assigned study medication codes to drug boxes, confirmed the indistinguishable appearance of the study medication formulations at the time of allocation, and maintained sealed study medication codes until study completion, ensuring that patients and all other study personnel were blinded to the treatment sequence. PSG recordings and subjective sleep evaluations were conducted during the screening and treatment periods. The protocol and written patient information were approved by the Institutional Review Board at each site, patients provided written informed consent prior to

enrollment, and the study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Japan Good Clinical Practice guidelines. 2.2. Patients Japanese patients ages 21–64 years with a diagnosis of primary insomnia based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR; Japanese version) criteria were eligible for the study [24]. Additional key inclusion criteria were history of at least 4 weeks duration of sleep latency P30 min for at least 3 days per week and total sleep time 6390 min for at least 3 days per week. Eligible participants entered a screening period during which they were administered placebo 30 min prior to PSG recording on two consecutive nights in a single-blind manner. An LPS of P20 min for two consecutive nights based on PSG, and either objective total sleep time (TST) 6420 min or objective wake time after sleep onset (WASO) P20 min for two consecutive nights based on PSG were required for study entry. Exclusion criteria included comorbid primary sleep disorder other than primary insomnia (e.g., circadian rhythm disorder, restless leg syndrome, periodic limb movement disorder, sleep apnea), apnea–hypopnea index P15 for two consecutive nights during screening, periodic limb movement index P10 for two consecutive nights during screening, presence of DSM-IV-TR Axis I or Axis II psychiatric illness or personality disorder, and history of drug abuse or alcohol dependence. 2.3. Study medication Study medication was provided in identical blister cards containing eight tablets (four tablets per day for 2 days of treatment). During each treatment term, one tablet per day contained active medication (eszopiclone 1 mg, 2 mg, or 3 mg or zolpidem 10 mg depending on the randomly assigned treatment sequence) and the other tablets contained matching placebo; during treatment with placebo, no tablets contained active medication. In this manner, study medications for the five different treatments were indistinguishable to patients and study personnel. Each night, study personnel removed four tablets from the blister card and gave them to the patient for administration 30 min prior to starting PSG recording. During screening, treatment, and follow-up, the concomitant administration of sedative hypnotics, anxiolytics, antineurologic disease drugs, anticonvulsants, Parkinson’s disease medications, antihistamines, corticosteroids, melatonin, oriental medicines indicated for insomnia, or other medications that could influence sleep was prohibited. Medications known to be potent inhibitors or inducers of cytochrome P450 isoenzyme 3A4 were also prohibited. 2.4. Assessments The primary efficacy assessments were LPS based on PSG and sleep latency (SL) based on subjective evaluation. During the screening period, patients were provided a diary in which they recorded the time of lights out before bedtime for 1 week prior to PSG evaluations. PSG recording was performed according to a manual for overnight PSG. The start time for PSG recording was individualized and scheduled within ±30 min of the patient’s median bedtime as recorded in the sleep diary. PSG recording duration for scoring was 8 h. Assessments obtained from PSG during the screening and treatment periods were LPS, TST, and WASO. Sleep efficiency (SE; the ratio of total sleep time to the total time in bed of 8 h 100, expressed as a percent), objective number of awakenings (NA) during sleep, and sleep stages were also measured during the treatment

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period. PSG data recorded during treatment were centrally scored by a trained expert based on Rechtschaffen and Kales criteria (1968) [25]. Subjective estimates of SL, TST, WASO, NA, sleep quality, and sleep depth were obtained from patients’ responses to morning questionnaires. Patients rated their daytime sleepiness, physical well-being, and ability to function on evening questionnaires using a numeric rating scale (0–10 scale, with higher values indicating more positive outcomes). Questionnaires were administered during the screening period and at each visit during the treatment period. Adverse events were recorded throughout the study and assessed according to severity (mild, moderate, severe) and investigator attribution of the potential causal relationship to treatment. Clinical laboratory tests, blood pressure, heart rate, and electrocardiogram (ECG) were obtained, and neurologic examinations, including a toe-walking test, heel-walking test, and Romberg test were performed. 2.5. Statistical methods Based on the results from the US study of eszopiclone with similar design [20], a sample size of 60 patients was estimated to provide 90% or greater power to detect significant differences after treatment with 2 mg and 3 mg of eszopiclone versus placebo for each of the two primary efficacy assessments. Therefore, the intended sample size was 70 patients to allow for a 10–15% dropout rate. Efficacy analyses are reported for the full analysis set, which included randomized patients who were administered P1 dose of study medication and had evaluable data for the primary efficacy assessments (LPS and SL) from any of the 5 treatment intervals. Prior to the start of data analysis, it was determined that eszopiclone would be considered an efficacious treatment only if there was statistically significant improvement compared with placebo for eszopiclone 2 mg and 3 mg on both primary efficacy assessments. Efficacy analyses were performed using mean values of Day 1 and Day 2 measurements from each treatment term. Measurements of objective sleep parameters (LPS, WASO, NA, sleep stages) and subjective sleep parameters (SL, WASO, NA) were log-transformed; SE was logit-transformed. LPS, SL, and other PSG-based and subjective sleep parameters, including TST, WASO, NA, quality of sleep, and depth of sleep, were analyzed using a cross over analysis of variance (ANOVA) model with treatment, visit, and sequence as fixed effects and subject as a random effect. Each of the three eszopiclone groups and the zolpidem group were compared with the placebo group using pairwise contrasts from the ANOVA model. Subjective parameters of daytime functioning based on evening questionnaires (daytime sleepiness, daytime alertness, physical well-being and ability to function) were summarized using descriptive statistics for each night by treatment. For these measures, the cross over ANOVA with pairwise contrasts was conducted using measurement on evening 2 as a response variable and measurement on evening 1 as a covariate. Objective and subjective sleep parameters were summarized descriptively (e.g., number of subjects, mean, standard deviation [SD], median, and range). The level of statistical significance was 0.05 (two-sided) for all efficacy analyses. ANOVA contrasts were used to assess the dose–response relationship of eszopiclone for LPS and SL. The relationship between LPS and SL was evaluated using Pearson correlations and scatter plots. The safety population included randomized patients who were administered P1 dose of study medication and had any evaluable safety data. Adverse events were summarized by frequency and severity for each treatment. For continuous variables of laboratory parameters, measurements in the screening period and the follow up period (or discontinuation) and changes from the screening visit

were summarized using descriptive statistics. For categorical variables, data were summarized using numbers of subjects and percentages. For vital sign parameters (blood pressure and heart rate), summary statistics for each visit and changes from the first day of the screening period were calculated by treatment. ECG results were presented in cross tables with presence or absence of abnormality in the screening period and the follow up period (or discontinuation) for all patients. Neurologic examinations were summarized as number and percentage of patients with an abnormal result.

3. Results 3.1. Patients Of the 192 patients who entered the screening period, 72 were randomized to study medication (excluding 119 ineligible patients; one withdrawal of consent), and 67 of 72 patients (93.1%) completed the study (excluding five discontinued; Fig. 1). The full analysis set and safety analysis set consisted of 72 patients. The average age of patients was 39.4 years, and 59.7% of patients were men. During the screening period, PSG-determined median LPS was 60.0 min, median TST was 359.5 min, and median WASO was 56.3 min per night (Table 1). 3.2. Efficacy 3.2.1. Sleep latency Compared with placebo, treatment with eszopiclone 1 mg, 2 mg, and 3 mg and zolpidem 10 mg produced significant improvement in both primary efficacy assessments, LPS and SL (P < 0.001 for all comparisons, except eszopiclone 1 mg for SL [P < 0.05]; Fig. 2). There was a linear dose–response relationship for eszopiclone on both LPS and SL; greater efficacy was obtained as dose increased. The relationship between LPS and SL for each treatment shows a positive correlation between these sleep parameters. The correlation between LPS and SL in patients taking placebo was 0.649. The correlation ranged from 0.549 to 0.670 in patients taking eszopiclone and was 0.441 in those taking zolpidem.

Fig. 1. Patient disposition.

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Table 1 Patient demographic characteristics and baseline sleep characteristics. Characteristic

Randomized patients (N = 72b)

Age, years, mean (SD) Male sex, n (%) Body weight, kg, mean (SD) Body mass index, kg/m2, mean (SD)

39.4 (11.9) 43 (59.7) 62.7 (10.8) 23.2 (3.9)

Latency to persistent sleepa, min Median Range Mean (SD)

60.0 21.0–282.0 74.3 (51.9)

Total sleep timea, min Median Range Mean (SD)

359.5 81.5–432.8 338.9 (74.7)

Wake time after sleep onseta, min Median Range Mean (SD)

56.3 6.0–299.5 78.8 (61.5)

SD = standard deviation. a Objective measurements using polysomnography. b Screening period included a total of 192 patients.

3.3. Safety and tolerability Adverse events occurring in P2% of patients for any treatment are listed in Table 4. The proportion of patients experiencing any adverse event was 16.9% (placebo), 22.9%, 23.2%, and 26.5% (at 1 mg, 2 mg, and 3 mg of eszopiclone, respectively), and 18.6% (at 10 mg of zolpidem). The most common adverse events were dysgeusia and somnolence when taking eszopiclone and, dizziness and somnolence when taking zolpidem. All adverse events were rated as mild in severity, with the exception of one case of nasopharyngitis in a patient taking eszopiclone 2 mg that was deemed moderate. No deaths were reported. Furthermore, there were no reports of serious adverse events or adverse events resulting in discontinuation during the treatment period. There were no clinically relevant changes in laboratory tests or vital sign parameters across groups. An ECG revealed sinus bradycardia in one patient taking placebo and first-degree atrioventricular block in one patient taking zolpidem 10 mg; both ECG changes were considered by the investigator to be mild in severity. No abnormal changes in neurologic parameters were observed.

4. Discussion

Fig. 2. Median polysomnography-determined latency to persistent sleep (LPS) and patient-reported sleep latency (SL) following treatment with placebo, eszopiclone 1 mg, 2 mg, and 3 mg, and zolpidem 10 mg in patients with primary insomnia (full analysis set). ⁄P < 0.001 versus placebo;  P < 0.05 versus placebo.

3.2.2. Other sleep parameters PSG-determined WASO, SE, TST, and NA improved significantly following treatment with eszopiclone 2 mg and 3 mg and zolpidem 10 mg compared with placebo (Table 2), as did patient-reported WASO, NA, TST, sleep quality, and sleep depth (Table 3). Significant improvement was observed on next-day measures of daytime alertness, physical well-being, and daily ability to function following treatment with eszopiclone 2 mg and 3 mg compared with placebo (Table 3). Treatment with eszopiclone 1 mg did not significantly affect any of these next-day measures. Treatment with zolpidem 10 mg significantly improved daytime alertness and daily ability to function (Table 3). Sleep architecture was affected by treatment with eszopiclone 1 mg, 2 mg, and 3 mg, and zolpidem 10 mg (Table 2). Compared with placebo, treatment with eszopiclone at all doses and zolpidem 10 mg increased non-REM sleep (P < 0.001) and stage 2 sleep (P < 0.001), but not REM sleep. The amount of stage 1 and stage 3 or 4 sleep was not significantly altered by eszopiclone treatment; administration of zolpidem significantly increased stage 3 or 4 sleep compared with placebo (P < 0.01).

This was a randomized, placebo-controlled, dose–response, crossover study of eszopiclone, with zolpidem as an active reference treatment, in 72 nonelderly Japanese patients with primary insomnia. Treatment with eszopiclone produced significant decreases in objective and subjective sleep latency in a dose-related manner compared with placebo. PSG-determined SE and TST also were significantly improved at all doses. Compared with placebo, treatment with eszopiclone 2 mg and 3 mg produced significant decreases in PSG-determined and patient-reported WASO and NA. Thus, beneficial effects of eszopiclone 2 mg and 3 mg were shown for both sleep onset and sleep maintenance. Similar results have been reported in a US population of nonelderly patients with primary insomnia using a similar study design [20]. In the crossover study, eszopiclone 1–3 mg dose-dependently reduced PSG-determined sleep latency and SE compared with placebo. The only notable difference between the results of the US study and the current study regarding effect of treatment on sleep measures was that the US study did not show a significant effect for eszopiclone 2 mg on WASO and NA [20]. These findings indicate that the clinically effective dose of eszopiclone for nonelderly Japanese patients with insomnia is 2–3 mg, which is consistent with the recommended dose in the US [12]. The effects of eszopiclone treatment on PSG-determined LPS, SE, TST, and WASO are consistent with those reported in parallelgroup studies of nonelderly and elderly patients [13,16]. The present study also confirmed previous findings regarding the effects of eszopiclone treatment on sleep architecture, significantly increasing total sleep time and non-REM sleep without altering REM sleep or slow-wave sleep compared with placebo [13,16]. Daytime impairment is another important component of insomnia treatment. The current study showed significant benefits of eszopiclone 2 mg and 3 mg in patient reports of daytime alertness, sense of physical well-being, and daily ability to function that were generally consistent with findings in studies of eszopiclone involving nonelderly patients with primary insomnia [15,20,26] or comorbid insomnia [17–19]. The efficacy of eszopiclone was demonstrated consistently for both subjective and objective assessments of sleep disturbance in this study. PSG-determined and patient-reported measures of sleep latency were highly correlated, which supports the use of both objective and subjective outcome measures in studies of insomnia

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N. Uchimura et al. / Sleep Medicine 13 (2012) 1247–1253 Table 2 Polysomnography-determined objective measures of sleep maintenance and sleep architecture following treatment (full analysis set). Measurea

Placebo (n = 71)

Eszopiclone

Zolpidem

1 mg (n = 70)

2 mg (n = 69)

3 mg (n = 68)

10 mg (n = 70)

Latency to persistent sleep, min Median 22.8 Range 0.8–194.5 Mean (SD) 37.5 (37.8)

17.9b 0.5–88.8 24.4 (22.7)

11.3b 0.3–132.3 20.9 (24.3)

10.4b 0.0–59.3 12.8 (11.2)

7.0b 0.0–146.5 14.3 (22.6)

Wake time after sleep onset, min Median 26.3 Range 1.5–164.3

22.5 1.0–144.8

17.8b 0.5–176.0

18.8c 0.8–165.5

20.0b 1.5–139.5

Sleep efficiency, % Median Range

86.3 58.2–98.0

91.3c 60.9–97.6

94.3b 47.4–99.2

94.5b 65.3–98.9

93.5b 70.6–99.3

Number of awakenings, n Median Range

4.0 0.5–18.0

4.0 0.0–11.0

3.5d 0.0–10.0

2.8b 0.0–10.0

3.5d 0.5–14.0

Total sleep time, min Median Range

414.0 279.3–470.3

438.3b 292.3–468.5

452.5b 227.5–475.8

453.4b 313.5–474.5

448.6b 338.8–476.3

Non-REM sleep, min Median Range

317.3 188.0–371.0

340.1b 233.5–429.0

352.3b 196.3–396.3

358.6b 253.8–400.5

357.3b 240.5–406.0

Stage 2 sleep, min Median Range

182.8 69.0–274.5

208.5b 100.5–292.5

218.3b 58.5–322.3

224.5b 114.5–314.8

209.5b 132.0–333.0

Stage 3 or 4 sleep, min Median Range

79.1 0.0–169.0

76.9 0.0–167.8

74.5 0.0–169.3

78.8 0.0–178.8

86.5c 0.0–212.0

REM sleep, min Median Range

90.8 16.3–171.0

91.5 14.5–143.0

95.5 31.3–129.3

87.0 41.3–118.5

86.3 35.0–136.8

REM = rapid eye-movement. a Median values (range) presented for all measures. b P < 0.001 versus placebo. c P < 0.01 versus placebo. d P < 0.05 versus placebo.

and confirms the validity of the PSG recording and scoring procedures in this study. The finding that patients with insomnia tended to overestimate sleep latency is consistent with previous reports [27,28]. The correlation between objective and subjective sleep latency reported in the current study (with an observation of overestimated sleep latency), is also consistent with previous reports in patients with insomnia [27,28], patients with major depressive disorder [29], and healthy control subjects [29]. The correlations during eszopiclone treatment are also generally consistent with a previous report for zolpidem, although the correlation for zolpidem in the current study was somewhat lower [28]. In the current study, treatment with zolpidem 10 mg improved PSG-determined LPS, WASO, and NA. These results differ from previous studies in patients with primary insomnia that did not show a significant effect for zolpidem therapy on objective measures of sleep maintenance [20,30]. In contrast with a previous study of patients with insomnia that did not show changes in slow-wave sleep [30], treatment with zolpidem 10 mg in this study and a previous study in Japanese patients [31] increased slow-wave sleep without affecting REM sleep. To date, the reasons for these variant results have not been explained adequately. Eszopiclone and zolpidem bind with different affinity profiles to receptors bearing various a subunits of the c-aminobutyric acid type-A receptor (GABAA), the known site of action of benzodiazepine and non-benzodiazepine hypnotic agents [11,32]. Zolpidem preferentially binds to a1 subunit isoform-bearing receptors; eszopiclone binds predominantly to a2 and a3 bearing receptors,

although its affinity for a1 is also high, in absolute terms [11,33– 35]. It has been suggested that differences in receptor binding may be related to differences in clinical effects, but confirmatory research of GABAA subtype binding in humans is required [33,36]. As in previous studies, eszopiclone was well-tolerated at doses of 1–3 mg, with the most frequently observed adverse event being mild dysgeusia [20,13,15]. Dizziness and somnolence were reported in <6% of patients at any dose, were mild in severity, and occurred less frequently following treatment with eszopiclone in this study than in the US study of similar design [20]. However, differences between studies in the rates of occurrence of adverse events were small, and the safety profile of eszopiclone was generally comparable for Japanese and nonJapanese patients [20]. A study of eszopiclone (1–4 mg) in healthy Japanese and Caucasian adults showed comparable pharmacokinetics and safety profiles for both groups (unpublished data). The findings from this study suggest that treatment with eszopiclone does not result in substantial differences between Japanese and non-Japanese populations in terms of efficacy and tolerability. Because of its crossover design and short treatment duration, this study does not provide information about sustained treatment with eszopiclone, which is required for many patients. However, previous studies have demonstrated the long-term (6–12 month) efficacy and safety of nightly eszopiclone therapy in patients with primary insomnia [14,15]. Quantitative comparisons of the relative efficacy of eszopiclone and zolpidem were not possible because

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Table 3 Patient-reported measures of sleep parameters and daytime functioning following treatment (full analysis set). Placebo

Eszopiclone

Zolpidem

1 mg

2 mg

3 mg

10 mg

Sleep measure

n = 71

n = 70

n = 69

n = 68

n = 70

Sleep latency, min Median Range Mean (SD)

45.0 12.5–210.0 62.0 (47.8)

32.5c 10.0–202.5 45.5 (36.7)

25.0a 3.0–120.0 32.6 (26.4)

20.0a 3.0–142.5 28.4 (23.8)

22.5a 0.0–150.0 28.0 (24.6)

Wake time after sleep onset, min Median 75.0 Range 3.0–300.0

60.0 0.5–285.0

37.5b 0.0–255.0

40.0a 0.0–227.5

50.0a 0.0–285.0

Number of awakenings, n Median Range

3.0 0.0–11.0

3.0 0.5–8.0

2.5a 0.0–6.5

2.0a 0.0–8.0

2.0a 0.0–6.0

Total sleep time, min Median Range

360.0 90.0–452.5

390.0a 225.0–460.0

397.5a 225.0–478.5

420.0a 225.0–480.0

411.3a 195.0–480.0

Sleep qualityd Mean (SD)

5.2 (1.9)

5.8 (1.9)b

6.3 (1.8)a

6.7 (1.9)a

6.6 (2.0)a

5.2 (1.9)

5.8 (1.9)c

6.1 (1.9)a

6.7 (1.9)a

6.7 (1.9)a

n = 70

n = 68

n = 69

n = 67

n = 68

d

Sleep depth Mean (SD)

Daytime measured Daytime sleepiness Mean (SD)

a b c d

5.8 (2.3)

5.9 (2.3)

6.6 (2.3)b

6.3 (2.6)

6.3 (2.4)

Daytime alertness Mean (SD)

6.0 (2.2)

6.2 (2.2)

6.7 (2.1)a

6.5 (2.4)c

6.6 (2.1)b

Physical well-being Mean (SD)

6.1 (2.2)

6.3 (2.0)

6.6 (2.2)c

6.7 (2.3)c

6.5 (2.0)

Ability to function Mean (SD)

6.1 (2.1)

6.4 (2.0)

6.7 (2.2)b

6.5 (2.2)c

6.7 (1.9)b

P < 0.001 versus placebo. P < 0.01 versus placebo. P < 0.05 versus placebo. Numeric rating scale from 0 to 10 (higher values indicate more positive outcomes).

Table 4 Adverse events reported by P2% of patients in any treatment group (safety analysis set). Adverse event, n (%)

Any adverse event Dysgeusia Somnolence Dizziness Dermatitis contact Feeling abnormal

Placebo (n = 71)

Eszopiclone 1 mg (n = 70)

2 mg (n = 69)

3 mg (n = 68)

10 mg (n = 70)

12 (16.9) 1 (1.4) 2 (2.8) 0 (0) 2 (2.8) 0 (0)

16 (22.9) 4 (5.7) 1 (1.4) 0 (0) 2 (2.9) 3 (4.3)

16 (23.2) 6 (8.7) 3 (4.3) 0 (0) 1 (1.4) 0 (0)

18 (26.5) 11 (16.2) 4 (5.9) 2 (2.9) 0 (0) 0 (0)

13 (18.6) 1 (1.4) 3 (4.3) 3 (4.3) 1 (1.4) 0 (0)

this study was not statistically powered to detect differences between active treatments. In conclusion, treatment with eszopiclone 1 mg, 2 mg, and 3 mg produced dose-dependent improvement that was superior to placebo for both objective and subjective measures of sleep latency in nonelderly Japanese patients with primary insomnia. Substantial correlations between objective and subjective sleep latency measures were noted. At doses of 2 mg and 3 mg, eszopiclone treatment also resulted in greater improvement in objective and subjective measures of sleep maintenance compared with placebo. Overall, the effects of eszopiclone 2 mg and 3 mg were comparable to those of zolpidem 10 mg. Eszopiclone was an efficacious and generally well-tolerated treatment for both sleep onset and sleep maintenance in this population of nonelderly Japanese patients.

Zolpidem

Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2012.08.015.

Acknowledgments The authors would like to thank Dr. Chikuma Hamada for statistical advice. The authors would also like to acknowledge the study investigators for their participation: Drs. Yu Ariyoshi, Masahiko Fujita, Yuji Hashizume, Azusa Ikegami, Takashi Kanbayashi, Seiichi Kawada, Seiji Kawahara, Shigefumi Koike, Masako Kosaka, Kenji

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