A 2-Night, 3-Period, Crossover Study of Ramelteon’s Efficacy and Safety in Older Adults With Chronic Insomnia

By Roth, Thomas Seiden, David; Wang-Weigand, Sherry; Zhang, Jeffrey

Key words: Chronic insomnia – Elderly – Melatonin – MT^sub 1^/ MT^sub 2^-receptor agonists ABSTRACT

Objective: To assess the efficacy and safety of ramelteon, a selective melatonin MT^sub 1^/MT^sub 2^-receptor agonist, for Insomnia treatment in older adults.

Methods: In a randomized, 9-week, 3-period crossover trial conducted at 17 sleep centers, older adults (N = 100) with chronic primary insomnia (37 men, 63 women; mean age [range], 70.7 [65-83] years) were administered placebo, ramelteon 4mg, and ramelteon 8 mg in three treatment phases for two consecutive nights. Each phase was separated by 5-to 12-day washout periods. Sleep was monitored via polysomnography. Subjective sleep parameters, using a Postsleep Questionnaire, were recorded, and residual pharmacologie effects were assessed.

Results: Statistically significant reductions in latency to persistent sleep were observed with both ramelteon 4mg and 8mg compared to placebo (28.7 min vs. 38.4 min, p < 0.001; 30.8 min vs. 38.4 min, p = 0.005, respectively). Total sleep time (p = 0.036 and p = 0.007, respectively) and sleep efficiency (p= 0.037 and p = 0.007, respectively) were also significantly improved with ramelteon 4 mg and 8 mg compared to placebo. Statistically significant reductions in subjective sleep latency on a Postsleep Questionnaire were reported with ramelteon 4 mg versus placebo (p = 0.037), but not ramelteon 8 mg (p = 0.120); no significant differences on other subjective sleep assessments were reported. A lack of power limits interpretation of self-reported sleep parameters. Incidences of adverse events considered treatment related were placebo (7%), ramelteon 4 mg (11%), and ramelteon 8 mg (5%). No residual pharmacologic effects were observed via Digit Symbol Substitution Test, memory recall tests (immediate and delayed), visual analog scales (feelings and mood), and Postsleep Questionnaire (level of alertness and ability to concentrate).

Conclusions: In older adults with chronic primary insomnia, ramelteon produced significant reductions in latency to persistent sleep and increases in total sleep time and sleep efficacy, and showed no evidence of adverse next-day psychomotor or cognitive effects.

Introduction

Insomnia is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality of sleep (DSM-IV-TR). Epidemiologie reports of disturbed sleep vary considerably as a result of differing evaluation criteria and populations studied, although estimates suggest that insomnia affects approximately 10% of the general population1-4. These prevalence rates increase noticeably among older adults, with reports ranging anywhere from 10% to 40%5″7. According to the Established Populations for Epidemiologie Studies of the Elderly (EPESE), the annual incidence of insomnia is approximately 5% in adults over 65 years of age. This percentage translates to eight million older adults with insomnia at any given time and over one million new cases each year6.

A number of medications have been used to treat insomnia, including sedative-hypnotics (e.g., benzodiazepine receptor agonists), sedating antidepressants, dietary supplements, and over- the-counter antihistamines. Unfortunately, many of these medications may produce adverse effects, particularly in older adults. In contrast to these traditional insomnia treatments, receptor- specific agents are being developed that promote sleep by targeting sleep-wake modulators (e.g., melatonin receptors in the suprachiasmatic nuclei [SCN] in the brain)89. The SCN regulates the Orcadian rhythm that underlies the normal sleep-wake cycle10.

Ramelteon is a novel insomnia medication that has a higher affinity and selectivity for MT^sub 1^/MT^sub 2^ receptors than melatonin11. MT^sub 1^/MT^sub 2^ receptors have been implicated in the effect of melatonin on sleep initiation and circadian rhythms12,13. Because of this mechanism of action, ramelteon has been referred to as a chronohypnotic agent. It shows no significant affinity for a large number of binding sites, including benzodiazepine, dopamine, and opiate receptors, which are known to affect cognitive function and abuse potential11. Due to its receptor binding properties, ramelteon is not considered to be a sedative- hypnotic. Even at peak plasma levels, ramelteon shows no sedative effect and no psychomotor memory impairment14. Additionally, in abuse liability paradigms, ramelteon has shown no potential for abuse15. It is the only prescription insomnia medication not classified as a controlled substance by the Drug Enforcement Administration (DEA)16. Ramelteon has been shown to reduce sleep latency with no evidence of psychomotor or memory effects in younger adults (aged 18-64 years) with chronic or transient insomnia17’18. Thus, ramelteon offers the potential for sleep promotion without unwanted residual or other adverse pharmacologie effects in older adults – a population particularly susceptible to adverse effects. The current study was designed to evaluate the efficacy and safety of ramelteon 4 mg and 8 mg in older adults (65 years or older) with chronic primary insomnia.

Methods

Subject sample

Eligible subjects were 65 years of age or older, had a diagnosis of chronic (recurring for at least 3 months, a minimum of 3-4 nights per week), primary insomnia (DSM-IV-TR), and daytime impairment or distress associated with disturbed sleep. Subjects were required to have a body mass index between 18 and 34 (inclusive) and a self- reported habitual bedtime between 8:30 p.m. and 12:00 a.m.

Subjects were prohibited from study entry if they had any of the following: significant psychiatric or medical illness as determined by the investigator within 1 year of baseline; use of any medications or supplements known to affect the sleep-wake cycle within 5 days of baseline (or five half-lives of the drug); use of any other CNS active medications (other than ramelteon), including sleep aids and herbal preparations with CNS effects, within 3 weeks of baseline; or use of tobacco products within 90 days of baseline. Subjects who had a substantial change in diet or exercise or an employment-related shift in sleep-wake schedule within 3 months of baseline, or who had flown across more than three time zones within 7 days of screening were not enrolled.

Subjects meeting the above criteria underwent polysomnographic (PSG) screening for 8 h on two consecutive nights; subjects were randomized to double-blind treatment if they had a mean latency to persistent sleep (LPS) >/= 20 min on two nights with neither night < 15 min, and a mean wake time after sleep onset (WASO) >/= 60 min with a wake time >/= 45 min on each of the two nights. Subjects with an apnea-hypopnea index > 15 or periodic leg movements with arousal index > 20 on the PSG could not participate.

Procedure

This study used a double-blind, placebo-controlled, randomized, 3- period crossover design. At PSG screening visits, subjects practiced the Digit Symbol Substitution Test (DSST) and Memory Recall Tests to reduce the impact of learning effects, and completed the visual analog scales (VAS) of Mood and of Feelings and a Presleep and Postsleep Questionnaire.

Following screening, eligible subjects were randomly assigned a 3- period treatment sequence of placebo, ramelteon 4 mg, and ramelteon 8 mg. There were six unique treatment sequences to which subjects could be randomized; each sequence presented the three study drugs in a different order. Each of the three treatment phases was 2 days in duration separated by a 5- to 12-day washout. A variable duration for the washout period was incorporated to allow some flexibility in scheduling return visits. Subjects arrived on Day 1 approximately 2.0-2.5 h before their habitual bedtime and completed the cognitive assessments and a Presleep Questionnaire. Each subject was administered a single dose of study medication 30 min before the PSG, which was performed uninterrupted for 8 h with lights out. The use of alcohol and caffeine was prohibited 10h prior to dosing. On the morning of Day 2, subjects completed cognitive assessments and a Postsleep Questionnaire before being discharged. Subjects returned the evening of Day 2 to repeat the procedures.

This study was conducted in accordance with applicable US Food and Drug Administration Code of Federal Regulations, the World Medical Association Declaration of Helsinki (1989), and the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice. The institutional review board at each investigative site approved the protocol. Before enrollment, participants provided written informed consent. Subjects were compensated for their participation.

Efficacy measures

The primary efficacy measure was the mean LPS for each 2-day treatment period, defined as the time from PSG recording initiation to onset of the first 10 min of continuous sleep (i.e., total number of epochs before the first 20 consecutive non-wake epochs, divided by 2) of two consecutive PSG recordings. PSG was also used to measure the following secondary efficacy measures: total sleep time (TST), sleep efficiency (TST divided by total time-in-bed, multiplied by 100), number of nighttime awakenings (NAW), and wake time after sleep onset (WASO). Self-reported efficacy was assessed by a Postsleep Questionnaire, which evaluated sSL, sTST, subjective NAW (sNAW), subjective WASO (sWASO), degree of difficulty in falling back to sleep, and subjective sleep quality (evaluated on a 7-point Likert scale on which 1 = excellent and 7 = extremely poor). Residual pharmacologie effects measures

The Postsleep Questionnaire was also used to evaluate morning level of alertness and ability to concentrate.

The DSST is a measure in which subjects were given a set of symbols with corresponding single-digit numbers and were asked to make as many symbolfor-digit substitutions as possible, working from left to right without skipping any boxes within a 90-s period. The number of correct substitutions in the 90-s period was recorded.

The Memory Recall Test consisted of a list of 16 words, which were read to the subjects. Immediately after the reading, subjects recorded as many words as they remembered (Immediate Recall). The next morning, subjects attempted to recall as many words as possible from the night before (Delayed Recall).

The VAS for Mood consisted of 12 scales: Drowsy, Slowed Down, Sleepy, Sedated, Tired, Worn Out, Listless, Fatigued, Exhausted, Sluggish, Weary, and Bushed. Subjects were asked to place a vertical mark on a 100-mm horizontal line, corresponding with their mood (Omm equals a little and 100mm equals a lot). The distance from Omm to the subject’s mark was recorded in mm.

The VAS for Feelings consisted of eight evaluated scales: Calm/ Anxious, Energetic/Fatigued, Thinking Slowed Down/Thinking Speeded Up, Peaceful/Tense, Normal/Spacey, At ease/Nervous, Relaxed/ Excited, and Normal/Easily Irritated. The measure was identical to the procedure used for the Mood scales where, for example, Calm was at Omm and Anxious at 100mm.

Sleep architecture

Sleep architecture was evaluated by the percentage of time spent in each stage (Stage 1, Stage 2, Stage 3/4, and rapid eye movement [REM]), which was calculated by taking the total amount of time (min) in that stage, divided by the TST, then multiplied by 100.

Safety measures

Adverse events (AEs) and serious adverse events (SAEs) were recorded at each visit. Investigators assessed and rated the severity of AEs and SAEs based on their judgement as mild (transient and easily tolerated), moderate (causing discomfort and interrupted normal activities), or severe (causing considerable interference with normal activities and could be incapacitating or life threatening), and determined relatedness of each event to the study drug. Before leaving the clinic, the Romberg Test (to assess the subjects’ ability to maintain truncal stability) was performed every 15 min until the test was negative. A complete medical history, laboratory evaluations, vital signs, 12-lead electrocardiogram (ECG), and physical exam were performed at screening and the final visit.

Statistical analyses

All statistical analyses were 2-sided and performed at the 0.05 significance level using SAS version 8.2. The planned sample size for this study was 100 randomized subjects. Based on the primary efficacy variable (LPS), a standard deviation of 25 min, a 2-sided paired f-test, a significance level of 0.05 adjusted for two comparisons between ramelteon and placebo using the Bonferroni Procedure, and 15% missing observations, 100 subjects were to provide more than 90% power to detect a difference of 12 min between each ramelteon dose and placebo. This sample size was to also provide approximately 80% power to detect a 12-min difference in TST and sSL between each ramelteon treatment and placebo.

PSG data from two consecutive nights were averaged for each subject; if only one night was available, those data were used. The efficacy of ramelteon 4 mg and 8 mg compared to placebo was evaluated using analysis of variance (ANOVA). Fisher’s protected LSD was used to test pairwise comparisons for the primary variable of LPS in order to control the error level at 5%. The secondary efficacy variables, TST and sleep quality, were evaluated in the same manner as the primary variable. In addition, interpretation of results for TST was contingent upon observing significance from the overall F-test of LPS. Likewise, interpretation of results for subjective sleep quality was contingent upon observing significance from the overall F-test of TST. However, no adjustments were made for the testing of the multiple variables or for testing within the other secondary variables. All treatment group comparisons were based on least-squares (LS) means +- standard errors.

Results

A total of 100 subjects with chronic primary insomnia (37 men, 63 women; mean age [range], 70.7 [6583] years) participated in the study. All 100 subjects completed this crossover study. A total of 87 subjects (out of 100) were taking concomitant medications during the study. The most common medications were vitamins (n = 39), antithrombotics (n = 26), serum lipid-reducing agents (n = 25), anti- inflammatories/ anti-rheumatics (n = 24), and mineral supplements (n = 23).There were no statistically significant differences among the treatment sequences for any demographic or baseline characteristics at study entry, including various PSG parameters (Table 1). Overall, mean (SD) PSG values at screening were as follows: LPS= 54.4 (33.18)min, TST= 327.4 (48.47)min, sleep efficiency= 68.3% (10.11), WASO= 103.6 (38.53)min, and NAW= 10.6 (3.46).

Efficacy

Statistically significant reductions in LPS were observed with ramelteon 4mg (28.7 min, p < 0.001) and 8mg (30.8 min, p = 0.005) compared with placebo (38.4 min) (Figure 1). Improvements in TST (359.4min and 362.0min vs. 350.4min) and sleep efficiency (74.9% and 75.5% vs. 73.1%) were also statistically significant following ramelteon 4 mg and ramelteon 8 mg versus placebo (Table 2). Subjects in the ramelteon 4mg group exhibited a slight but statistically significant increase in the NAW compared to placebo (10.9 vs. 10.1 awakenings, respectively; p= 0.016); however, this was not dose dependent, as the higher dose (8mg) did not show this effect (10.7 awakenings, p = 0.080). No statistically significant differences for WASO were observed with ramelteon 4mg (95.9 min, p = 0.874) or ramelteon 8mg (91.8 min, p = 0.204) compared to placebo (96.5).

Ramelteon 4 mg significantly reduced sSL, based on the Postsleep Questionnaire; however, there was no overall treatment effect (Table 2). No significant differences in sTST or subjective sleep quality were reported between ramelteon 4 mg or ramelteon 8 mg and placebo. Ramelteon and placebo also produced comparable results for other self-reported sleep parameters: sNAW, sWASO, and degree of difficulty in falling back to sleep.

Table 1. Summary of demographic and baseline characteristics

Sleep architecture

A statistically significant difference in percentage of TST spent in Stage 1 sleep was observed with both ramelteon 4mg (13.8% vs. 12.9%, p = 0.014) and 8mg (14.1% vs. 12.9%, p < 0.001) compared to placebo (Table 3). Conversely, a significantly lower percentage of TST was spent in Stage 3/4 sleep with ramelteon 4mg (9.3% vs. 11.2%, p < 0.001) or 8mg (8.1% vs. 11.2%, p < 0.001) versus placebo. Only the ramelteon 8 mg group showed significant increases in percentage of TST spent in Stage 2 sleep (placebo, 55.7%; ramelteon 8mg, 57.6%; p = 0.003). Compared to placebo (20.1%), there were no statistically significant differences in percent of TST spent in REM sleep with ramelteon 4mg (20.1%, p = 0.999) or 8mg (20.2%, p = 0.931).

Table 2. Summary of objective and subjective sleep parameters

Figure 1. LS Mean (SE) latency to persistent sleep (LPS) unth placebo, ramelteon 4mg, and ramelteon 8mg administration as measured by polysomnography (PSG). *p

Residual pharmacologie effects

No next-day residual pharmacologie effects were observed, as assessed by DSST, Memory Recall Test (Immediate), Memory Recall Test (Delayed), and Postsleep Questionnaire (levels of alertness and ability to concentrate) for ramelteon or placebo (Table 4).

Additionally, no statistically significant differences between ramelteon and placebo were observed for any item on the VAS for Mood. The VAS for Feeling showed a statistically significant overall treatment difference (p = 0.027), with the ramelteon 8mg group producing lower ratings (i.e., ratings were closer to 0 mm on a 100mm scale, where 0 mm represents Normal and 100mm represents Easily Irritated) on the Normal/Easily Irritated item versus placebo (17.7 vs. 20.1, p = 0.007, respectively). On the Calm/Anxious item, there was a statistically significant lower score with ramelteon 4mg compared to placebo (16.1 vs. 18.0, p = 0.023), although there was no difference overall (p = 0.069). The mean ratings between ramelteon and placebo were similar for the other six analyzed items on the VAS for Feeling.

Table 3. Sleep architecture

Table 4. Summary of residual pharmacologie effect measures

Safety

A total of 25 of the 100 subjects experienced at least one AE. The overall incidence of AEs was slightly higher in the ramelteon 4mg group (14%) compared with placebo (9%) and ramelteon 8mg (7%). Headache and nausea were the only AEs occurring in three or more subjects (Table 5). A slightly higher incidence of AEs considered potentially related to study medication was also observed with ramelteon 4mg (11%) compared with placebo (7%) and ramelteon 8mg (5%).

All but one AE were rated as mild or moderate in severity; one subject in the placebo group experienced an AE (sinus headache) considered severe. No subject withdrew from the study due to an AE, and no SAEs were reported.

Several subjects showed fluctuations in laboratory parameters, vital signs, and ECG results; however, no trends were noted. No subject experienced a change in laboratory values, vital signs, or ECG parameters that was reported as an AE or that caused a subject to discontinue from the study. Discussion

Older adults are particularly prone to developing sleep disorders, such as insomnia, which may be related to a variety of conditions and circumstances. For instance, co-morbid illnesses, such as congestive heart failure or chronic obstructive pulmonary disease, may precipitate sleeping difficulties2,19-21. Some medications may promote daytime napping (e.g., sedative-hypnotics), which is associated with impaired nocturnal sleep, while other medications are stimulating (e.g., beta-blockers and some antidepressants)2,22-24. Regardless of cause, the high prevalence of insomnia among older adults is of clinical importance. Decrements in quality of life, increased risk of falls, memory and concentration impairments, slowed response times, and attention deficits are all potentially caused or exacerbated by insomnia2,20,25-28.

The high incidence of insomnia among older adults and the associated impact on quality of life, cognitive impairment, and motor function are of concern not only for the patients and their families, but for health care providers and payers as well. Unfortunately, commonly used treatments for insomnia, such as benzodiazepine-receptor agonists (BzRAs) (e.g., triazolam, zolpidem, eszopiclone, zaleplon), low-dose sedating antidepressants (e.g., trazodone), or over-thecounter medications (e.g., diphenhydramine) may be undesirable for many older adults due to the potential for adverse events, such as postural hypotension and amnesia, and possible residual pharmacologie effects26-33. This could lead to medical compromise and put this patient population at risk of injury. For example, although trazodone is commonly used for sleep promotion in older adults, it is associated with risk for orthostatic hypotension, cardiac rhythm disturbance, and significant next-day sedation29,33. Diphenhydramine carries a risk of psychomotor impairment30 and anticholinergic effects32,34 (e.g., delirium, behavioral disturbance, memory deficit, confusion, disorientation, constipation, urinary retention, and blurred vision). BzRAs have been associated with amnesia and an increased risk of falls and fractures26,35-39. Added complications of co- morbid disease, such as chronic obstructive pulmonary disease, and concomitant medications are also of concern.

Table 5. Summary of adverse events

The present study was designed to examine the sleep-promoting efficacy and tolerability of a novel compound, ramelteon, in older adult subjects. Ramelteon’s efficacy was previously demonstrated by PSG in adults (18-64 years) with chronic insomnia18’40. Consistent with these findings, the current trial demonstrated significant improvements in LPS, TST, and sleep efficiency in older adults. Improvements in sleep initiation, as suggested by reduced LPS and increases in TST, have also been demonstrated with ramelteon in a model of transient insomnia”. Together these studies suggest that ramelteon promotes sleep onset in individuals with chronic or transient insomnia.

In the present study, LPS decreased by about 2 5 min relative to placebo baseline and was about 10 min shorter than the placebo condition. Although it is difficult to compare across studies, these decreases appear somewhat smaller than the changes reported in some, but not all, BzRA studies in the elderly41-43. To understand the results of this study, it is important to recognize that the mean response reported in this study reflects the average of responders and non-responders. In a 35-night, PSG study, 60-70% of subjects on ramelteon responded with a 50% or greater reduction in LPS44. There is also some evidence to suggest that subjective measures of sleep latency may increase over time with ramelteon treatment45’46. If these observations are confirmed in prospective studies, it will be important for physicians treating insomnia to understand that drugs having different mechanisms of action may have different patterns of efficacy.

The self-reported sleep measures evaluated in this trial showed a trend consistent with the LPS reductions, although no significant treatment effect was found. Like all PSG studies, this study was not powered to detect subjective responses. In the literature it is clear that larger samples are needed in self-report studies than in PSG studies to statistically differentiate drug from placebo47. Postsleep Questionnaires are generally included in PSG studies to determine whether selfreport data parallel PSG data. This was the case in the present study. In a larger study of ramelteon (n = 829), older adult subjects with chronic primary insomnia reported statistically significant reductions in sSL and sTST with ramelteon 4mg and 8mg compared to placebo when subjective assessments were explicitly measured as primary endpoints48. Also, bearing in mind the age of the study population and the chronic nature of their sleeping problems, this population may have had considerable experience with medications that have a pronounced sedative effect. It has been shown that ramelteon lacks these sedative effects even at 20 times the therapeutic dose, which is likely due to its unique mechanism of action15. Thus, subjective reports in the current trial may be influenced by the absence of previously experienced sedative cues. This finding may be particularly true for short treatment periods, where only acute differences are likely to be observed.

Administration of ramelteon 4 mg or 8 mg resulted in PSG- recorded improvements in sleep without impairing memory or psychomotor functioning, and did not produce next-day residual pharmacologie effects. There were no differences in scores of the DSST, no effects on short-term memory and fine motor skills, and no effects on word list memory tests (both of immediate and delayed recall). These data are also consistent with the findings of earlier studies, which have demonstrated a lack of residual pharmacologie effects, including no rebound insomnia, with ramelteon17,18,40,48.

In addition to a lack of residual pharmacologie effects, no significant safety concerns were identified in this study. Ramelteon treatment was associated with a relatively low incidence of AEs, and laboratory and ECG parameters showed no clinically significant shifts from baseline. AEs were reported in similar proportions for placebo, ramelteon 4 mg, and ramelteon 8 mg, the majority of which were rated as mild or moderate in severity. Headache and nausea were the most frequently reported AEs; no other AEs were reported in >/= 3% of subjects. These findings suggest that both the 4 mg and 8 mg doses of ramelteon are well tolerated in older adult subjects with chronic insomnia.

Alterations in sleep architecture with either dose of ramelteon did not appear to be clinically meaningful given that the magnitude of the change was very small (less than 3%). These findings are consistent with previous ramelteon studies17,18. Clearly, a change in Stage 3/4 sleep, either an increase or decrease, is difficult to interpret. Even so, changes of this magnitude are not likely to have clinical implications.

In this study, the sleep-promoting efficacy and tolerability of ramelteon had no uniform pattern of effect size with ramelteon 4 mg or 8 mg. These findings are consistent with previous studies, which have demonstrated a flat dose-response curve with ramelteon doses of 4mg and higher on measures of efficacy17,18,40,48 and tolerability49. This lack of a dose response has clear implications in the management of insomnia in different age groups. Unlike all other sleep-promoting agents, the approved dose of ramelteon is the same for adult and older adult populations. Ramelteon’s doseindependent effects suggest that it promotes sleep in a unique manner, possibly through action on endogenous sleep-modulating systems in the SCN50. However, the dose-independent nature of ramelteon is not currently understood and requires further research.

Conclusion

In this study of older adult subjects with chronic primary insomnia, ramelteon 4 mg and 8 mg produced significant sleep- promoting activity as indicated by PSG-recorded reductions of LPS, prolongation of TST, and improvements in sleep efficiency. Based on the Postsleep Questionnaire of sleep latency, ramelteon 4 mg was also perceived by subjects as significantly more effective than placebo. These improvements were achieved without evidence of next- morning residual effects. Additionally, the incidences of AEs were low with no difference among treatment groups. Thus, ramelteon appears to be an effective and well-tolerated treatment for older adult subjects with chronic insomnia, and may be a particularly good option for older adults with sleep initiation difficulties.

Acknowledgments

Declaration of interest: This research was supported by funding from Takeda Pharmaceutical Company Limited as was preparation of this manuscript. Takeda Global Research & Development participated in the study design and methods, review of data analysis, and manuscript preparation. TR was involved in the study concept and design, data interpretation, and manuscript preparation. He has received grants and is a Consultant for Takeda Pharmaceuticals North America, Inc. DS was a study investigator who collected data, assisted in data interpretation, and was involved in preparation of the manuscript. He has nothing to disclose. SW-W and JZ are employees of Takeda Global Research & Development Center. SW-W was involved in interpretation of data and preparation of the manuscript. JZ provided review of data analysis and was involved in the preparation of the manuscript.

This study was presented at the New Clinical Drug Evaluation Unit Annual Meeting on June 8, 2005 in Boca Raton, FL, USA; the American Association for Geriatric Psychiatry Annual Meeting on March 12, 2006 in San Juan, Puerto Rico; and the Associated Professional Sleep Societies Annual Meeting on June 20, 2006 in Salt Lake City, UT, USA. References

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3783_3, Accepted for publication: 09 February 2007

Published Online: 21 March 2007

doi:10.1185/030079907X178874

Thomas Roth(a), David Seiden(b), Sherry Wang-Weigand(c) and Jeffrey Zhang(c)

a Sleep Disorders and Research Center, Detroit, Ml, USA

b Broward Research Group & Sleep Wake Disorders Center of South Florida, Pembroke Pines, FL, USA

c Takeda Global Research and Development Center, Deerfield, IL, USA

Address for correspondence: Thomas Roth, PhD, Henry Ford Hospital, Sleep Disorders and Research Center, 2799 West Grand Blvd, CFP-3, Detroit, MI48202, USA. Tel: +1 313 916 5171; Fax: +1 313 916 5167; email: trothl@hfhs.org

Copyright Librapharm May 2007

(c) 2007 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.