Current Medical Research & Opinion
Article RT-0304.R1/884490 All rights reserved: reproduction in whole or part not permitted
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Original article The impact of shift duration on the efficacy and tolerability of armodafinil in patients with excessive sleepiness associated with shift work disorder Abstract
John Harsh
The Center for Sleep Medicine, Hattiesburg, MS, USA
Ronghua Yang
Teva Pharmaceuticals, Frazer, PA, USA
Steven G. Hull
Vince and Associates Clinical Research, Overland Park, KS, USA
Address for correspondence: John Harsh PhD DABSM, The University of Southern Mississippi, Department of Psychology, Southern Station Box 5025, Hattiesburg, MS 39406, USA. Tel: +1 601 266 4612; Fax: +1 601 266 5580; [email protected] Keywords: Armodafinil – Shift duration – Shift work disorder – Sleep disorder
Co
Accepted: 27 December 2013; published online: 4 February 2014 Citation: Curr Med Res Opin 2014; 30:945–51
No
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0300-7995 doi:10.1185/03007995.2014.884490
Vol. 30, No. 5, 2014, 945–951
Objective: To examine the impact of night-shift duration (9 hours or 49 hours) on efficacy and tolerability of armodafinil in patients with shift work disorder (SWD). Methods: This was a post hoc analysis of a 6 week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Shift workers with diagnosed SWD and late-in-shift sleepiness (between 4 AM and 8 AM, including the commute home) received armodafinil 150 mg or placebo before their night shift. Results: Proportion of patients with at least minimal improvement in late-in-shift sleepiness, late-in-shift Clinical Global Impressions–Change (CGI-C) rating and Karolinska Sleepiness Scale (KSS), as well as overall Global Assessment of Functioning (GAF) scale and modified Sheehan Disability Scale (SDS-M), were assessed at baseline and final visit. Results: Of the 383 patients enrolled, 279 (73%) worked shifts 9 hours and 104 (27%) worked shifts 49 hours. A greater percentage of patients receiving armodafinil had at least minimal improvement in late-in-shift CGI-C (9 hours: 78% vs 60%, P ¼ 0.0017; 49 hours: 77% vs 46%, P ¼ 0.0020) regardless of shift duration. Armodafinil patients also demonstrated significantly greater improvements in GAF score (9 hours: 9.5 vs 5.4, P50.0001; 49 hours: 9.6 vs 4.3, P ¼ 0.0019) and KSS score (9 hours: 2.9 vs 1.9, P ¼ 0.0002;49 hours: 2.8 vs 1.6, P ¼ 0.00 28). Improvement in SDS-M composite score was significantly greater for armodafinil patients working49 hours (6.8 vs 2.7, P ¼ 0.0086). Headache was the most frequent adverse event in all treatment groups. Conclusions: Patients receiving armodafinil had significantly greater improvements in late-in-shift clinical condition and in wakefulness and overall global functioning than did placebo-treated patients, regardless of shift duration. Prospectively designed, randomized clinical trials that include objective measures of sleepiness are needed to support these findings.
Introduction An estimated 21 million people in the United States, or nearly one in six members of the labor force, work shifts outside the daytime hours of 6 AM to 6 PM1. ! 2014 Informa UK Ltd www.cmrojournal.com
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Among such shift workers, excessive sleepiness, insomnia, or both, occur at significantly higher rates than among daytime workers2. The constant disruption of the sleep– wake cycle in shift workers places them at a greater risk of developing shift work disorder (SWD), a circadian rhythm sleep disorder in which misalignment of the circadian rhythm results in excessive sleepiness during work hours and/or insomnia during sleep onset and sleep maintenance. SWD is associated with significant impairment in social, occupational, or other areas of functioning3,4. Shift workers with symptoms of SWD are more likely than day workers to experience negative work outcomes, including falling asleep at work, absenteeism, and occupational accidents5. They are also at increased risk for ulcers and depression2, have impaired quality of life with respect to missed family and social activities2, and are more likely to avoid contact with coworkers5. Currently, there are only two FDA-approved therapies for the treatment of excessive sleepiness associated with SWD: modafinil (R- and S-modafinil) and armodafinil (R-modafinil). The exact mechanism by which these agents promote their wakefulness effect is not yet known. Armodafinil has a half-life of approximately 16.5 hours, which is similar to that of racemic modafinil (14.4 hours), but systemic exposure to armodafinil is greater than that for modafinil and the two are not bioequivalent6. Armodafinil is well absorbed, with peak plasma concentrations occurring approximately 2 hours after oral administration in a fasted state7. Armodafinil has been shown to improve wakefulness in patients with SWD in two randomized, multicenter, placebo-controlled studies8,9. In a 12 week study conducted in permanent or rotating night-shift workers experiencing excessive sleepiness associated with SWD, armodafinil improved mean nighttime sleep latency, measures of overall clinical condition, long-term memory, and attention8. Likewise, in a 6 week study of patients with SWD and late-in-shift sleepiness (between 4 AM and 8 AM, including the commute home), armodafinil significantly improved late-in-shift clinical condition and wakefulness, as well as overall global functioning9. Armodafinil also significantly improved self-reported disability and, among patients who completed the 6 week study, daily quality of life10. Individuals who work extended shift durations across a variety of occupations are at a particular risk for severe sleepiness11,12. Harma et al. noted that the risk of severe sleepiness (defined as a score of 7 on the Karolinska Sleepiness Scale [KSS]) increases by 15% for each hour increase in shift length12. Studies also have shown that individuals who work extended hours are at an increased risk for occupational accidents and motor vehicle accidents during the commute home13–16. For example, medical interns working extended shift durations had a 16.2% increased risk of motor vehicle accidents during 946
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the commute home compared with those not working extended shift durations17. In addition, they experienced almost twice as many percutaneous injuries, which were more likely to occur during the nighttime13. The impact of shift duration on the clinical efficacy of armodafinil has not previously been described. The current report therefore examines the impact of night-shift duration (9 hours or 49 hours) on the efficacy and tolerability of armodafinil among patients with SWD. This was a post hoc analysis of data from a previously described 6 week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of armodafinil in patients with SWD9,10.
Patients and methods The primary study, which was approved by the institutional review board for each study site, was conducted in men and women aged 18 to 65 years who provided written informed consent. To be eligible for the study, patients had to work five or more 6 to 12 hour night shifts (between 10 PM and 8 AM) per month and have a diagnosis of SWD (1 month) according to both International Classification of Sleep Disorders, 2nd edition (ICSD-2)3 and Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM IV-TR)4 criteria. In addition, they were to be at least ‘moderately ill’ for excessive sleepiness (i.e., a score of 4 on the Clinical Global Impression of Severity of Illness [CGI-SI] scale18) assessed late-in-shift (between 4 AM and 8 AM), including the commute home; have impaired function (i.e., a score 570 on the Global Assessment of Functioning [GAF] from the DSM IV-TR4); and have at least ‘some signs of sleepiness’ (i.e., an average score 6 on the KSS, based on three assessments within 15 minutes of 4, 6, and 8 AM at screening)19. Patients with even mild obstructive sleep apnea, as assessed by daytime polysomnography, or any history of medical/psychiatric disorder causing excessive sleepiness were excluded, as were any patients who, within 7 days of screening, had used any medications that could contribute to excessive sleepiness, wakefulness, or functional impairment (including modafinil, armodafinil, caffeine [4600 mg/day], amphetamines, melatonin, sedating antidepressants). Women of childbearing potential were required to use a medically accepted method of contraception; for those using steroidal contraceptives, a barrier method was required as well. Eligible patients were randomly allocated to receive armodafinil 150 mg or placebo. Armodafinil (or placebo) was titrated from 50 mg (1 tablet) to 150 mg (3 tablets) over the first 4 nights of the 6 week double-blind treatment period; thereafter, patients took 3 tablets orally once nightly, 30 to 60 minutes before the start of the night shift, but no later than 11 PM (only on nights worked). www.cmrojournal.com ! 2014 Informa UK Ltd
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The 150 mg dose and 4 day titration schedule referenced in the primary analysis were selected based on an earlier phase 3 clinical trial of armodafinil in patients with SWD8. For the purposes of this post hoc analysis, patients in each treatment group were further stratified into one of two groups based on the duration of their night shift (9 hours or 49 hours). Clinician assessments (Clinical Global Impressions– Change [CGI-C] ratings and GAF score) and patient assessments (KSS and modified Sheehan Disability Scale [SDS-M]) were conducted at the study site at baseline and at Weeks 3 and 6 (or final post-baseline visit for those who discontinued early) as previously described9,10. The primary efficacy measure was the proportion of patients with at least minimal improvement of clinical condition, as related to late-in-shift sleepiness, including the commute home (4 AM to 8 AM), measured immediately after the shift by the CGI-C at the final visit. The CGI-C is a clinician-rated measure of change in disease severity ranging from ‘very much improved’ to ‘very much worse’18. For this post hoc analysis, the Pearson’s chisquare test was used to assess the percentage of patients with at least minimal improvement in CGI-C rating at final visit for each shift duration group compared with placebo. Secondary efficacy assessments included change from baseline in GAF score at the final visit. The GAF is a clinician-rated scale (0–100) from Axis V of the DSM-IV Multiaxial Assessment that assesses overall psychological, social, and occupational functioning, with higher scores indicating better functioning20. Additional secondary measures included mean change from baseline in latein-shift KSS scores on the last night worked (average of scores conducted within 15 minutes of 4, 6, and 8 AM) to final visit; and mean change from baseline SDS-M scores to final visit. The KSS is a patient-rated scale of sleepiness ranging from 1 (‘very alert’) to 9 (‘very sleepy, fighting sleep’)19, while the SDS-M is an assessment of disability across the three domains of work, social life, and family life, which was modified to determine the impact of shift
work on a scale of 0 (‘not at all’) to 10 (‘extremely’)21. Analysis of variance was used to assess the change from baseline in GAF, KSS, and SDS-M scores for armodafinil compared with placebo within each shift duration group, with treatment as a factor. The efficacy analyses included all patients who received at least one dose of study drug and had at least one post-baseline CGI-C assessment. All test comparisons were two tailed, with a significance level of 0.05. Final visit data included study completers and last observation carried forward for non-completers. The effect of shift duration (9 hours or 49 hours) on tolerability (adverse events) was also assessed using descriptive statistics, with the tolerability analysis including all patients who received at least one dose of study drug.
Results Of the 383 patients who were enrolled in this study, 371 were evaluated for safety, and 359 were evaluated for efficacy. In all, 279 of the 383 patients (73%) enrolled worked shifts 9 hours; of these, 132 were randomized to receive armodafinil and 147 to receive placebo. The remaining 104 patients (27%) worked shifts 49 hours; of these, 61 received armodafinil and 43 received placebo. Discontinuations due to adverse events occurred in nine patients receiving armodafinil and one patient receiving placebo. Overall, mean age, weight and body mass index (BMI) among patients in each shift duration and treatment group were similar. The percentage of men in each shift duration and treatment group ranged between 51% and 61%, and most patients were white (Table 1). A significantly greater proportion of patients treated with armodafinil showed at least minimal improvement in late-in-shift CGI-C compared with placebo patients at final visit, regardless of whether they worked 9 hours (78% vs 60%; P ¼ 0.0017) or 49 hours (77% vs 46%; P ¼ 0.0020) (Figure 1).
Table 1. Baseline demographics and characteristics. Shift 9 hours
Characteristic
Age, years (SD) Male, n (%) Race, n (%) White Black Asian Other Mean body weight, kg (SD) Mean BMI, kg/m2 (SD)
Shift 49 hours
Placebo n ¼ 147
Armodafinil n ¼ 132
Total n ¼ 279
Placebo n ¼ 43
Armodafinil n ¼ 61
Total n ¼ 104
35.6 (10.7) 75 (51)
36.9 (10.8) 71 (54)
36.2 (10.8) 146 (52)
37.9 (10.9) 25 (58)
36.4 (10.5) 37 (61)
37.0 (10.6) 62 (60)
102 (69) 39 (27) 4 (3) 2 (1) 83.1 (18.1) 28.2 (5.38)
82 (62) 41 (31) 9 (7) 0 (0) 84.1 (18.6) 28.7 (5.74)
184 (66) 80 (29) 13 (5) 2 (1) 83.6 (18.3) 28.4 (5.55)
39 (91) 3 (7) 0 (0) 1 (2) 83.3 (17.0) 28.4 (4.77)
46 (75) 9 (15) 6 (10) 0 (0) 83.6 (16.4) 28.4 (5.74)
85 (82) 12 (12) 6 (6) 1 (51) 83.5 (16.6) 28.4 (5.33)
BMI, body mass index; SD, standard deviation.
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Percentage of Patients with Improved CGI-C Score
100 80
Armodafinil Placebo
*
†
60 40 20 0
(n=121) (n=141)
(n=56)
(n=41)
>9 hrs
Figure 1. The percentage of patients with at least minimal improvement in late-in-shift rating on the CGI-C (4 AM to 8 AM) from baseline to final visit. *P ¼ 0.0017 vs placebo; yP ¼ 0.0020 vs placebo. CGI-C, Clinical Global Impressions–Change.
Change in GAF Score
12 10
*
Armodafinil Placebo
†
8 6 4 2
n=121 n=141
n=56
n=41
0 ≤9 hrs
Change in KSS Score
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≤9 hrs
0
n=120 n=140
>9 hrs n=56
n=40
−1 −2 −3 ‡ −4
≤9 hrs
§ >9 hrs
Figure 2. Change from baseline in mean GAF and KSS scores (SEM). Upper panel: GAF score. Lower panel: KSS score. *P50.0001, yP ¼ 0.0019, z P ¼ 0.0002, xP ¼ 0.0028 for change from baseline compared with placebo. GAF, Global Assessment of Functioning; KSS, Karolinska Sleepiness Scale; SEM, standard error of the mean.
With respect to clinician assessment of global functioning, there was a significantly greater improvement from baseline to final visit in the GAF score for armodafinil patients compared with placebo patients working shifts 9 hours (þ9.5 vs þ5.4; P50.0001; 95% confidence interval [CI] 2.15, 6.02). A similar significant improvement was observed among patients who worked shifts 49 hours (þ9.6 vs þ4.3; P ¼ 0.0019; 95% CI 2.01, 8.56) (Figure 2). The changes from baseline to final visit in mean latein-shift KSS scores also showed significantly greater 948
improvement in patients treated with armodafinil for both shift durations. In patients who worked 9 hours, the mean improvement from baseline to final visit in the KSS score was 2.9 points for patients treated with armodafinil, compared with 1.9 points for patients treated with placebo (P ¼ 0.0002; 95% CI 1.50, 0.48). Among patients who worked shifts 49 hours, the mean decreases were 2.8 and 1.6 points, respectively (P ¼ 0.0028; 95% CI 1.99, 0.42) (Figure 2). The effects of armodafinil compared to placebo on selfreported overall functioning, as measured by the SDS-M, were different among the two shift duration populations. The mean improvement in the SDS-M composite score was not significantly different between the armodafinil and placebo groups among patients working shifts 9 hours (6.8 vs 5.0; P ¼ 0.0536; 95% CI 3.72, 0.03). However, among patients working shifts 49 hours, the mean decrease in SDS-M composite score was significantly greater in the armodafinil group compared with the placebo group (6.8 vs 2.7; P ¼ 0.0086; 95% CI 7.15, 1.07) (Figure 3). Patients working 49 hour shifts who received armodafinil also had significantly greater improvement in the SDS-M work subscore at the final visit (P ¼ 0.0025; 95% CI 3.22, 0.71). There were no significant differences between armodafinil and placebo groups in changes in SDS-M work subscores for shifts 9 hours, nor in social life or family life scales for either shift duration (Figure 3). Adverse events are presented in Table 2. The most common adverse events among patients in both shifts were headache, nausea, insomnia, and dry mouth; the highest incidence of each was in patients treated with armodafinil working shifts 49 hours. The safety findings in this analysis were similar to previous studies with armodafinil.
Armodafinil in patients with shift work disorder Harsh et al.
Discussion Extended duration work shifts are associated with increased risk for motor vehicle crashes as well as workrelated accidents and occupational illnesses13–15. The risk may also extend to those sharing the roadways with, working alongside, or receiving care or services from individuals working longer shift durations, making this a greater societal concern. The economic burden of motor vehicle accidents related to excessive sleepiness alone is substantial, with estimated costs reported between $53 billion and $69 billion, adjusted for 2009 values22. Armodafinil has previously been shown to improve wakefulness and overall clinical condition in patients with SWD8. Importantly, armodafinil significantly improves wakefulness and clinical condition late in the shift, including the commute home, during the critical circadian nadir period (4 AM to 8 AM)9,10. The present analysis extends www.cmrojournal.com ! 2014 Informa UK Ltd
Change in SDS-M Social Life Score from Baseline to Final Visit
0 −2 −4 −6 −8
*
0
−1
−2
−3
† >9 hrs
≤9 hrs
Change in SDS-M Family Life Score
Change in SDS-M Social Life Score
Change in Composite SDS-M from Baseline to Final Visit ≤9 hrs >9 hrs
Change in SDS-M Work Score from Baseline to Final Visit Change in SDS-M Work Score
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Change in Composite SDS-M Score
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≤9 hrs
>9 hrs
0
−1
−2
−3
Armodafinil Placebo Change in SDS-M Family Life Score from Baseline to Final Visit
0
−1
−2
−3
≤9 hrs
>9 hrs
Figure 3. Change from baseline in mean composite and subscores of the SDS-M (SEM). Upper left: composite score; lower left: work score; upper right: social life score; lower right: family life score. *P ¼ 0.0086, yP ¼ 0.0025 for change from baseline compared with placebo. SDS-M, modified Sheehan Disability Scale; SEM, standard error of the mean. Table 2. Adverse events in 45% armodafinil-treated patients. Adverse event, n (%)
1 Adverse event Headache Nausea Insomnia Dry mouth
Shift 9 hours
Shift 49 hours
Placebo n ¼ 146
Armodafinil n ¼ 126
Placebo n ¼ 41
Armodafinil n ¼ 58
38 (26)
49 (39)
11 (27)
35 (60)
10 (7) 6 (4) 3 (2) 1 (51)
16 (13) 10 (8) 6 (5) 3 (2)
3 (7) 1 (2) 0 (0) 2 (5)
12 (21) 10 (17) 6 (10) 5 (9)
those findings by showing that armodafinil maintains its beneficial effects on late-in-shift clinical condition, global functioning, and late-in-shift sleepiness in patients with SWD who work shifts longer than 9 hours, as well as in those who work shifts of shorter duration (9 hours). In fact, the magnitude of effect for armodafinil for each measure at final visit was similar in both populations, although there appeared to be a less robust placebo effect in the 49 hour group, suggesting that those patients were more impaired at baseline. The clinical efficacy of armodafinil late-in-shift during longer shift durations is consistent with its ! 2014 Informa UK Ltd www.cmrojournal.com
pharmacokinetic and pharmacodynamic profile. When compared on a milligram-to-milligram basis, late-day plasma concentrations of armodafinil are higher than those of modafinil6. In terms of clinical effects, armodafinil 200 mg has been shown to produce longer wake-promoting and attention-sustaining effects compared with modafinil 200 mg starting approximately 6–8 hours after dose administration in a population of healthy adults undergoing a period of acute sleep loss23. Furthermore, the application of a pharmacokinetic/pharmacodynamic model based on pooled data from two clinical studies of armodafinil and modafinil in patients with SWD determined that when administered at the same doses, armodafinil consistently increased wakefulness more than modafinil, including times late in an 8 hour shift24. According to the model, armodafinil 200 mg was estimated to produce a better response than modafinil 200 mg throughout the shift despite both armodafinil (150 and 200 mg) and modafinil 200 mg demonstrating significant improvement in multiple sleep latency test times compared with placebo24. This present analysis is the first to show a clinical benefit of armodafinil treatment specifically in SWD patients working longer shift durations (49 hours). In our study, 27% of patients with SWD worked shifts49 hours. While Armodafinil in patients with shift work disorder Harsh et al.
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the percentage of US workers who work shifts49 hours is not known, US Department of Labor statistics indicate approximately 25% of the US population works 441 hours a week, with approximately 7% working 460 hours a week25, indicating that a significant proportion of US workers may work shifts 49 hours. This is important, given that extended duration work shifts are associated with increased risk for motor vehicle crashes as well as work-related accidents and occupational illnesses13–15. Studies have shown that the risk of work-related accidents increases exponentially after the eighth or ninth hour at work26, with the relative accident risk increasing in an approximately linear fashion for shifts starting later in the day (i.e., 18.3% for the afternoon shift and 30.4% for the night shift, relative to that for the morning shift)27. In our study, patients taking armodafinil and working longer shifts (49 hours) as well as those working shorter shifts (9 hours) demonstrated improvements in sleepiness and overall clinical condition late-in-shift, including the commute home – a time when these patients may be most vulnerable to the symptoms of SWD. Of note, significantly greater overall improvement in functional impairment, including the work-related domain of the SDS-M, was demonstrated among SWD patients working 49 hours. In addition, although patients working49 hours who received armodafinil experienced a higher incidence of adverse events, most adverse events, as noted in the primary analysis, were mild or moderate in severity9. The incidence of headache in the49 hours per shift group was similar to what has been reported in previous trials of armodafinil 150 to 250 mg, suggesting that armodafinil continues to be generally well tolerated among patients with SWD8,9,28,29. The current study results further support the use of armodafinil in a variety of patients with SWD as part of an overall treatment regimen that may include pharmacological, as well as nonpharmacological, treatment options to help address the various symptoms associated with the disorder. The fact that the results were assessed by a post hoc analysis based on prospectively collected data is a limitation to the present analysis, and as a result of the post hoc design, the shift worker populations (9 hours vs 49 hours) were not balanced. Furthermore, with the exception of polysomnography that was used to rule out obstructive sleep apnea, no objective or subjective assessments of patients’ daytime sleep were performed. Patients with SWD often experience insomnia during the daytime sleep period; however, an assessment of patient daytime sleep architecture was not a goal of the primary study9. In addition, subjective rather than objective efficacy measures of excessive sleepiness were used in this study, although both patient- and clinician-rated measures were included, which enhances the generalizability of these results. 950
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Conclusion Overall, these data suggest that the improved clinical condition, functioning, and wakefulness observed with armodafinil can benefit a variety of patients with SWD and that efficacy and safety were maintained regardless of shift duration. These results will need to be confirmed in a prospectively designed randomized trial.
Transparency Declaration of funding This study was sponsored by Cephalon Inc. (now doing business as Teva Pharmaceuticals), a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd (Petah Tikva, Israel). Funding for the preparation of this manuscript was provided by Teva Pharmaceuticals. Declaration of financial/other relationships R.Y. has disclosed that he is an employee of Teva Pharmaceuticals. J.H. and S.G.H. have disclosed that they received sponsorship from Teva for their role in developing this study. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships. Acknowledgments The authors thank Joyce Willets PhD and Sarah Mizne PharmD of MedVal Scientific Information Services LLC for providing medical writing and editorial assistance. This manuscript was prepared according to the International Society for Medical Publication Professionals’ ‘Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP2 Guidelines’. Previous presentations: American Psychiatric Association 165th Annual Meeting, Philadelphia, PA, USA, 5–9 May 2012; Associated Professional Sleep Societies SLEEP 2012 Meeting, Boston, MA, USA, 9–13 June 2012.
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6. Darwish M, Kirby M, D’Andrea DM, et al. Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: a randomized, open-label, crossover study. Clin Ther 2010;32:2074-87 7. Darwish M, Kirby M, Hellriegel ET, et al. Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studies. Clin Drug Invest 2009;29:87-100 8. Czeisler CA, Walsh JK, Wesnes KA, et al. Armodafinil for treatment of excessive sleepiness associated with shift work disorder: a randomized controlled study. Mayo Clin Proc 2009;84:958-72 9. Erman MK, Seiden DJ, Yang R, et al. Efficacy and tolerability of armodafinil: effect on clinical condition late in the shift and overall functioning of patients with excessive sleepiness associated with shift work disorder. J Occup Environ Med 2011;53:1460-5 10. Erman MK, Yang R, Seidan DJ. The effect of armodafinil on patient-reported functioning and quality of life in patients with excessive sleepiness associated with shift work disorder: a randomized, double-blind, placebo-controlled trial. Prim Care Companion CNS Disord 2012;14. doi: 10.4088/PCC.12m01345 11. Son M, Kong JO, Koh SB, et al. Effects of long working hours and the night shift on severe sleepiness among workers with 12-hour shift systems for 5 to 7 consecutive days in the automobile factories of Korea. J Sleep Res 2008;17:385-94 12. Harma M, Sallinen M, Ranta R, et al. The effect of an irregular shift system on sleepiness at work in train drivers and railway traffic controllers. J Sleep Res 2002;11:141-51 13. Ayas NT, Barger LK, Cade BE, et al. Extended work duration and the risk of self-reported percutaneous injuries in interns. JAMA 2006;296:1055-62 14. Dembe AE, Erickson JB, Delbos RG, et al. The impact of overtime and long work hours on occupational injuries and illnesses: new evidence from the United States. Occup Environ Med 2005;62:588-97 15. Lombardi DA, Folkard S, Willetts JL, Smith GS. Daily sleep, weekly working hours, and risk of work-related injury: US National Health Interview Survey (2004–2008). Chronobiol Int 2010;27:1013-30 16. Akerstedt T, Peters B, Anund A, et al. Impaired alertness and performance driving home from the night shift: a driving simulator study. J Sleep Res 2005;14:17-20 17. Barger LK, Cade BE, Ayas NT, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med 2005;352:125-34
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18. Guy W. 028 CGI clinical global impressions. ECDEU Assessment Manual for Psychopharmacology Revised, 1976. DHEW Publication No. 1976:217-22 19. Kaida K, Takahashi M, Akerstedt T, et al. Validation of the Karolinska sleepiness scale against performance and EEG variables. Clin Neurophysiol 2006;117:1574-81 20. American Psychiatric Association. Global Assessment of Functioning (GAF) scale. In: First MB, ed. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. Washington, DC: American Psychiatric Association, 2000:34 21. Sheehan DV. Sheehan disability scale. In: Rush AJ, First MB, Blacker D, eds. Handbook of Psychiatric Measures. Washington, DC: American Psychiatric Publishing Inc., 2008:100-2 22. Culpepper L. The social and economic burden of shift-work disorder. J Fam Pract 2010;59(1 Suppl):S3-11 23. Dinges DF, Arora S, Darwish M, et al. Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Curr Med Res Opin 2006;22:159-67 24. Darwish M, Bond M, Ezzet F. Armodafinil and modafinil in patients with excessive sleepiness associated with shift work disorder: a pharmacokinetic/pharmacodynamic model for predicting and comparing their concentration–effect relationships. J Clin Pharmacol 2012;52:1328-42 25. United States Department of Labor. Bureau of Labor Statistics labor force statistics from the current population survey. Washington, DC: Bureau of Labor Statistics, 2012 26. Hanecke K, Tiedemann S, Nachreiner F, et al. Accident risk as a function of hour at work and time of day as determined from accident data and exposure models for the German working population. Scand J Work Environ Health 1998;24(Suppl 3):43-8 27. Folkard S, Tucker P. Shift work, safety and productivity. Occup Med (London) 2003;53:95-101 28. Black JE, Hull SG, Tiller J, et al. The long-term tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea, shift work disorder, or narcolepsy: an open-label extension study. J Clin Sleep Med 2010;6:458-66 29. Schwartz JR, Khan A, McCall WV, et al. Tolerability and efficacy of armodafinil in naive patients with excessive sleepiness associated with obstructive sleep apnea, shift work disorder, or narcolepsy: a 12-month, open-label, flexible-dose study with an extension period. J Clin Sleep Med 2010;6:450-7
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Article RT-0304.R1/884490 All rights reserved: reproduction in whole or part not permitted
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Original article The impact of shift duration on the efficacy and tolerability of armodafinil in patients with excessive sleepiness associated with shift work disorder Abstract
John Harsh
The Center for Sleep Medicine, Hattiesburg, MS, USA
Ronghua Yang
Teva Pharmaceuticals, Frazer, PA, USA
Steven G. Hull
Vince and Associates Clinical Research, Overland Park, KS, USA
Address for correspondence: John Harsh PhD DABSM, The University of Southern Mississippi, Department of Psychology, Southern Station Box 5025, Hattiesburg, MS 39406, USA. Tel: +1 601 266 4612; Fax: +1 601 266 5580; [email protected] Keywords: Armodafinil – Shift duration – Shift work disorder – Sleep disorder
Co
Accepted: 27 December 2013; published online: 4 February 2014 Citation: Curr Med Res Opin 2014; 30:945–51
No
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0300-7995 doi:10.1185/03007995.2014.884490
Vol. 30, No. 5, 2014, 945–951
Objective: To examine the impact of night-shift duration (9 hours or 49 hours) on efficacy and tolerability of armodafinil in patients with shift work disorder (SWD). Methods: This was a post hoc analysis of a 6 week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Shift workers with diagnosed SWD and late-in-shift sleepiness (between 4 AM and 8 AM, including the commute home) received armodafinil 150 mg or placebo before their night shift. Results: Proportion of patients with at least minimal improvement in late-in-shift sleepiness, late-in-shift Clinical Global Impressions–Change (CGI-C) rating and Karolinska Sleepiness Scale (KSS), as well as overall Global Assessment of Functioning (GAF) scale and modified Sheehan Disability Scale (SDS-M), were assessed at baseline and final visit. Results: Of the 383 patients enrolled, 279 (73%) worked shifts 9 hours and 104 (27%) worked shifts 49 hours. A greater percentage of patients receiving armodafinil had at least minimal improvement in late-in-shift CGI-C (9 hours: 78% vs 60%, P ¼ 0.0017; 49 hours: 77% vs 46%, P ¼ 0.0020) regardless of shift duration. Armodafinil patients also demonstrated significantly greater improvements in GAF score (9 hours: 9.5 vs 5.4, P50.0001; 49 hours: 9.6 vs 4.3, P ¼ 0.0019) and KSS score (9 hours: 2.9 vs 1.9, P ¼ 0.0002;49 hours: 2.8 vs 1.6, P ¼ 0.00 28). Improvement in SDS-M composite score was significantly greater for armodafinil patients working49 hours (6.8 vs 2.7, P ¼ 0.0086). Headache was the most frequent adverse event in all treatment groups. Conclusions: Patients receiving armodafinil had significantly greater improvements in late-in-shift clinical condition and in wakefulness and overall global functioning than did placebo-treated patients, regardless of shift duration. Prospectively designed, randomized clinical trials that include objective measures of sleepiness are needed to support these findings.
Introduction An estimated 21 million people in the United States, or nearly one in six members of the labor force, work shifts outside the daytime hours of 6 AM to 6 PM1. ! 2014 Informa UK Ltd www.cmrojournal.com
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Among such shift workers, excessive sleepiness, insomnia, or both, occur at significantly higher rates than among daytime workers2. The constant disruption of the sleep– wake cycle in shift workers places them at a greater risk of developing shift work disorder (SWD), a circadian rhythm sleep disorder in which misalignment of the circadian rhythm results in excessive sleepiness during work hours and/or insomnia during sleep onset and sleep maintenance. SWD is associated with significant impairment in social, occupational, or other areas of functioning3,4. Shift workers with symptoms of SWD are more likely than day workers to experience negative work outcomes, including falling asleep at work, absenteeism, and occupational accidents5. They are also at increased risk for ulcers and depression2, have impaired quality of life with respect to missed family and social activities2, and are more likely to avoid contact with coworkers5. Currently, there are only two FDA-approved therapies for the treatment of excessive sleepiness associated with SWD: modafinil (R- and S-modafinil) and armodafinil (R-modafinil). The exact mechanism by which these agents promote their wakefulness effect is not yet known. Armodafinil has a half-life of approximately 16.5 hours, which is similar to that of racemic modafinil (14.4 hours), but systemic exposure to armodafinil is greater than that for modafinil and the two are not bioequivalent6. Armodafinil is well absorbed, with peak plasma concentrations occurring approximately 2 hours after oral administration in a fasted state7. Armodafinil has been shown to improve wakefulness in patients with SWD in two randomized, multicenter, placebo-controlled studies8,9. In a 12 week study conducted in permanent or rotating night-shift workers experiencing excessive sleepiness associated with SWD, armodafinil improved mean nighttime sleep latency, measures of overall clinical condition, long-term memory, and attention8. Likewise, in a 6 week study of patients with SWD and late-in-shift sleepiness (between 4 AM and 8 AM, including the commute home), armodafinil significantly improved late-in-shift clinical condition and wakefulness, as well as overall global functioning9. Armodafinil also significantly improved self-reported disability and, among patients who completed the 6 week study, daily quality of life10. Individuals who work extended shift durations across a variety of occupations are at a particular risk for severe sleepiness11,12. Harma et al. noted that the risk of severe sleepiness (defined as a score of 7 on the Karolinska Sleepiness Scale [KSS]) increases by 15% for each hour increase in shift length12. Studies also have shown that individuals who work extended hours are at an increased risk for occupational accidents and motor vehicle accidents during the commute home13–16. For example, medical interns working extended shift durations had a 16.2% increased risk of motor vehicle accidents during 946
Armodafinil in patients with shift work disorder Harsh et al.
the commute home compared with those not working extended shift durations17. In addition, they experienced almost twice as many percutaneous injuries, which were more likely to occur during the nighttime13. The impact of shift duration on the clinical efficacy of armodafinil has not previously been described. The current report therefore examines the impact of night-shift duration (9 hours or 49 hours) on the efficacy and tolerability of armodafinil among patients with SWD. This was a post hoc analysis of data from a previously described 6 week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of armodafinil in patients with SWD9,10.
Patients and methods The primary study, which was approved by the institutional review board for each study site, was conducted in men and women aged 18 to 65 years who provided written informed consent. To be eligible for the study, patients had to work five or more 6 to 12 hour night shifts (between 10 PM and 8 AM) per month and have a diagnosis of SWD (1 month) according to both International Classification of Sleep Disorders, 2nd edition (ICSD-2)3 and Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM IV-TR)4 criteria. In addition, they were to be at least ‘moderately ill’ for excessive sleepiness (i.e., a score of 4 on the Clinical Global Impression of Severity of Illness [CGI-SI] scale18) assessed late-in-shift (between 4 AM and 8 AM), including the commute home; have impaired function (i.e., a score 570 on the Global Assessment of Functioning [GAF] from the DSM IV-TR4); and have at least ‘some signs of sleepiness’ (i.e., an average score 6 on the KSS, based on three assessments within 15 minutes of 4, 6, and 8 AM at screening)19. Patients with even mild obstructive sleep apnea, as assessed by daytime polysomnography, or any history of medical/psychiatric disorder causing excessive sleepiness were excluded, as were any patients who, within 7 days of screening, had used any medications that could contribute to excessive sleepiness, wakefulness, or functional impairment (including modafinil, armodafinil, caffeine [4600 mg/day], amphetamines, melatonin, sedating antidepressants). Women of childbearing potential were required to use a medically accepted method of contraception; for those using steroidal contraceptives, a barrier method was required as well. Eligible patients were randomly allocated to receive armodafinil 150 mg or placebo. Armodafinil (or placebo) was titrated from 50 mg (1 tablet) to 150 mg (3 tablets) over the first 4 nights of the 6 week double-blind treatment period; thereafter, patients took 3 tablets orally once nightly, 30 to 60 minutes before the start of the night shift, but no later than 11 PM (only on nights worked). www.cmrojournal.com ! 2014 Informa UK Ltd
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The 150 mg dose and 4 day titration schedule referenced in the primary analysis were selected based on an earlier phase 3 clinical trial of armodafinil in patients with SWD8. For the purposes of this post hoc analysis, patients in each treatment group were further stratified into one of two groups based on the duration of their night shift (9 hours or 49 hours). Clinician assessments (Clinical Global Impressions– Change [CGI-C] ratings and GAF score) and patient assessments (KSS and modified Sheehan Disability Scale [SDS-M]) were conducted at the study site at baseline and at Weeks 3 and 6 (or final post-baseline visit for those who discontinued early) as previously described9,10. The primary efficacy measure was the proportion of patients with at least minimal improvement of clinical condition, as related to late-in-shift sleepiness, including the commute home (4 AM to 8 AM), measured immediately after the shift by the CGI-C at the final visit. The CGI-C is a clinician-rated measure of change in disease severity ranging from ‘very much improved’ to ‘very much worse’18. For this post hoc analysis, the Pearson’s chisquare test was used to assess the percentage of patients with at least minimal improvement in CGI-C rating at final visit for each shift duration group compared with placebo. Secondary efficacy assessments included change from baseline in GAF score at the final visit. The GAF is a clinician-rated scale (0–100) from Axis V of the DSM-IV Multiaxial Assessment that assesses overall psychological, social, and occupational functioning, with higher scores indicating better functioning20. Additional secondary measures included mean change from baseline in latein-shift KSS scores on the last night worked (average of scores conducted within 15 minutes of 4, 6, and 8 AM) to final visit; and mean change from baseline SDS-M scores to final visit. The KSS is a patient-rated scale of sleepiness ranging from 1 (‘very alert’) to 9 (‘very sleepy, fighting sleep’)19, while the SDS-M is an assessment of disability across the three domains of work, social life, and family life, which was modified to determine the impact of shift
work on a scale of 0 (‘not at all’) to 10 (‘extremely’)21. Analysis of variance was used to assess the change from baseline in GAF, KSS, and SDS-M scores for armodafinil compared with placebo within each shift duration group, with treatment as a factor. The efficacy analyses included all patients who received at least one dose of study drug and had at least one post-baseline CGI-C assessment. All test comparisons were two tailed, with a significance level of 0.05. Final visit data included study completers and last observation carried forward for non-completers. The effect of shift duration (9 hours or 49 hours) on tolerability (adverse events) was also assessed using descriptive statistics, with the tolerability analysis including all patients who received at least one dose of study drug.
Results Of the 383 patients who were enrolled in this study, 371 were evaluated for safety, and 359 were evaluated for efficacy. In all, 279 of the 383 patients (73%) enrolled worked shifts 9 hours; of these, 132 were randomized to receive armodafinil and 147 to receive placebo. The remaining 104 patients (27%) worked shifts 49 hours; of these, 61 received armodafinil and 43 received placebo. Discontinuations due to adverse events occurred in nine patients receiving armodafinil and one patient receiving placebo. Overall, mean age, weight and body mass index (BMI) among patients in each shift duration and treatment group were similar. The percentage of men in each shift duration and treatment group ranged between 51% and 61%, and most patients were white (Table 1). A significantly greater proportion of patients treated with armodafinil showed at least minimal improvement in late-in-shift CGI-C compared with placebo patients at final visit, regardless of whether they worked 9 hours (78% vs 60%; P ¼ 0.0017) or 49 hours (77% vs 46%; P ¼ 0.0020) (Figure 1).
Table 1. Baseline demographics and characteristics. Shift 9 hours
Characteristic
Age, years (SD) Male, n (%) Race, n (%) White Black Asian Other Mean body weight, kg (SD) Mean BMI, kg/m2 (SD)
Shift 49 hours
Placebo n ¼ 147
Armodafinil n ¼ 132
Total n ¼ 279
Placebo n ¼ 43
Armodafinil n ¼ 61
Total n ¼ 104
35.6 (10.7) 75 (51)
36.9 (10.8) 71 (54)
36.2 (10.8) 146 (52)
37.9 (10.9) 25 (58)
36.4 (10.5) 37 (61)
37.0 (10.6) 62 (60)
102 (69) 39 (27) 4 (3) 2 (1) 83.1 (18.1) 28.2 (5.38)
82 (62) 41 (31) 9 (7) 0 (0) 84.1 (18.6) 28.7 (5.74)
184 (66) 80 (29) 13 (5) 2 (1) 83.6 (18.3) 28.4 (5.55)
39 (91) 3 (7) 0 (0) 1 (2) 83.3 (17.0) 28.4 (4.77)
46 (75) 9 (15) 6 (10) 0 (0) 83.6 (16.4) 28.4 (5.74)
85 (82) 12 (12) 6 (6) 1 (51) 83.5 (16.6) 28.4 (5.33)
BMI, body mass index; SD, standard deviation.
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Percentage of Patients with Improved CGI-C Score
100 80
Armodafinil Placebo
*
†
60 40 20 0
(n=121) (n=141)
(n=56)
(n=41)
>9 hrs
Figure 1. The percentage of patients with at least minimal improvement in late-in-shift rating on the CGI-C (4 AM to 8 AM) from baseline to final visit. *P ¼ 0.0017 vs placebo; yP ¼ 0.0020 vs placebo. CGI-C, Clinical Global Impressions–Change.
Change in GAF Score
12 10
*
Armodafinil Placebo
†
8 6 4 2
n=121 n=141
n=56
n=41
0 ≤9 hrs
Change in KSS Score
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≤9 hrs
0
n=120 n=140
>9 hrs n=56
n=40
−1 −2 −3 ‡ −4
≤9 hrs
§ >9 hrs
Figure 2. Change from baseline in mean GAF and KSS scores (SEM). Upper panel: GAF score. Lower panel: KSS score. *P50.0001, yP ¼ 0.0019, z P ¼ 0.0002, xP ¼ 0.0028 for change from baseline compared with placebo. GAF, Global Assessment of Functioning; KSS, Karolinska Sleepiness Scale; SEM, standard error of the mean.
With respect to clinician assessment of global functioning, there was a significantly greater improvement from baseline to final visit in the GAF score for armodafinil patients compared with placebo patients working shifts 9 hours (þ9.5 vs þ5.4; P50.0001; 95% confidence interval [CI] 2.15, 6.02). A similar significant improvement was observed among patients who worked shifts 49 hours (þ9.6 vs þ4.3; P ¼ 0.0019; 95% CI 2.01, 8.56) (Figure 2). The changes from baseline to final visit in mean latein-shift KSS scores also showed significantly greater 948
improvement in patients treated with armodafinil for both shift durations. In patients who worked 9 hours, the mean improvement from baseline to final visit in the KSS score was 2.9 points for patients treated with armodafinil, compared with 1.9 points for patients treated with placebo (P ¼ 0.0002; 95% CI 1.50, 0.48). Among patients who worked shifts 49 hours, the mean decreases were 2.8 and 1.6 points, respectively (P ¼ 0.0028; 95% CI 1.99, 0.42) (Figure 2). The effects of armodafinil compared to placebo on selfreported overall functioning, as measured by the SDS-M, were different among the two shift duration populations. The mean improvement in the SDS-M composite score was not significantly different between the armodafinil and placebo groups among patients working shifts 9 hours (6.8 vs 5.0; P ¼ 0.0536; 95% CI 3.72, 0.03). However, among patients working shifts 49 hours, the mean decrease in SDS-M composite score was significantly greater in the armodafinil group compared with the placebo group (6.8 vs 2.7; P ¼ 0.0086; 95% CI 7.15, 1.07) (Figure 3). Patients working 49 hour shifts who received armodafinil also had significantly greater improvement in the SDS-M work subscore at the final visit (P ¼ 0.0025; 95% CI 3.22, 0.71). There were no significant differences between armodafinil and placebo groups in changes in SDS-M work subscores for shifts 9 hours, nor in social life or family life scales for either shift duration (Figure 3). Adverse events are presented in Table 2. The most common adverse events among patients in both shifts were headache, nausea, insomnia, and dry mouth; the highest incidence of each was in patients treated with armodafinil working shifts 49 hours. The safety findings in this analysis were similar to previous studies with armodafinil.
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Discussion Extended duration work shifts are associated with increased risk for motor vehicle crashes as well as workrelated accidents and occupational illnesses13–15. The risk may also extend to those sharing the roadways with, working alongside, or receiving care or services from individuals working longer shift durations, making this a greater societal concern. The economic burden of motor vehicle accidents related to excessive sleepiness alone is substantial, with estimated costs reported between $53 billion and $69 billion, adjusted for 2009 values22. Armodafinil has previously been shown to improve wakefulness and overall clinical condition in patients with SWD8. Importantly, armodafinil significantly improves wakefulness and clinical condition late in the shift, including the commute home, during the critical circadian nadir period (4 AM to 8 AM)9,10. The present analysis extends www.cmrojournal.com ! 2014 Informa UK Ltd
Change in SDS-M Social Life Score from Baseline to Final Visit
0 −2 −4 −6 −8
*
0
−1
−2
−3
† >9 hrs
≤9 hrs
Change in SDS-M Family Life Score
Change in SDS-M Social Life Score
Change in Composite SDS-M from Baseline to Final Visit ≤9 hrs >9 hrs
Change in SDS-M Work Score from Baseline to Final Visit Change in SDS-M Work Score
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Change in Composite SDS-M Score
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≤9 hrs
>9 hrs
0
−1
−2
−3
Armodafinil Placebo Change in SDS-M Family Life Score from Baseline to Final Visit
0
−1
−2
−3
≤9 hrs
>9 hrs
Figure 3. Change from baseline in mean composite and subscores of the SDS-M (SEM). Upper left: composite score; lower left: work score; upper right: social life score; lower right: family life score. *P ¼ 0.0086, yP ¼ 0.0025 for change from baseline compared with placebo. SDS-M, modified Sheehan Disability Scale; SEM, standard error of the mean. Table 2. Adverse events in 45% armodafinil-treated patients. Adverse event, n (%)
1 Adverse event Headache Nausea Insomnia Dry mouth
Shift 9 hours
Shift 49 hours
Placebo n ¼ 146
Armodafinil n ¼ 126
Placebo n ¼ 41
Armodafinil n ¼ 58
38 (26)
49 (39)
11 (27)
35 (60)
10 (7) 6 (4) 3 (2) 1 (51)
16 (13) 10 (8) 6 (5) 3 (2)
3 (7) 1 (2) 0 (0) 2 (5)
12 (21) 10 (17) 6 (10) 5 (9)
those findings by showing that armodafinil maintains its beneficial effects on late-in-shift clinical condition, global functioning, and late-in-shift sleepiness in patients with SWD who work shifts longer than 9 hours, as well as in those who work shifts of shorter duration (9 hours). In fact, the magnitude of effect for armodafinil for each measure at final visit was similar in both populations, although there appeared to be a less robust placebo effect in the 49 hour group, suggesting that those patients were more impaired at baseline. The clinical efficacy of armodafinil late-in-shift during longer shift durations is consistent with its ! 2014 Informa UK Ltd www.cmrojournal.com
pharmacokinetic and pharmacodynamic profile. When compared on a milligram-to-milligram basis, late-day plasma concentrations of armodafinil are higher than those of modafinil6. In terms of clinical effects, armodafinil 200 mg has been shown to produce longer wake-promoting and attention-sustaining effects compared with modafinil 200 mg starting approximately 6–8 hours after dose administration in a population of healthy adults undergoing a period of acute sleep loss23. Furthermore, the application of a pharmacokinetic/pharmacodynamic model based on pooled data from two clinical studies of armodafinil and modafinil in patients with SWD determined that when administered at the same doses, armodafinil consistently increased wakefulness more than modafinil, including times late in an 8 hour shift24. According to the model, armodafinil 200 mg was estimated to produce a better response than modafinil 200 mg throughout the shift despite both armodafinil (150 and 200 mg) and modafinil 200 mg demonstrating significant improvement in multiple sleep latency test times compared with placebo24. This present analysis is the first to show a clinical benefit of armodafinil treatment specifically in SWD patients working longer shift durations (49 hours). In our study, 27% of patients with SWD worked shifts49 hours. While Armodafinil in patients with shift work disorder Harsh et al.
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the percentage of US workers who work shifts49 hours is not known, US Department of Labor statistics indicate approximately 25% of the US population works 441 hours a week, with approximately 7% working 460 hours a week25, indicating that a significant proportion of US workers may work shifts 49 hours. This is important, given that extended duration work shifts are associated with increased risk for motor vehicle crashes as well as work-related accidents and occupational illnesses13–15. Studies have shown that the risk of work-related accidents increases exponentially after the eighth or ninth hour at work26, with the relative accident risk increasing in an approximately linear fashion for shifts starting later in the day (i.e., 18.3% for the afternoon shift and 30.4% for the night shift, relative to that for the morning shift)27. In our study, patients taking armodafinil and working longer shifts (49 hours) as well as those working shorter shifts (9 hours) demonstrated improvements in sleepiness and overall clinical condition late-in-shift, including the commute home – a time when these patients may be most vulnerable to the symptoms of SWD. Of note, significantly greater overall improvement in functional impairment, including the work-related domain of the SDS-M, was demonstrated among SWD patients working 49 hours. In addition, although patients working49 hours who received armodafinil experienced a higher incidence of adverse events, most adverse events, as noted in the primary analysis, were mild or moderate in severity9. The incidence of headache in the49 hours per shift group was similar to what has been reported in previous trials of armodafinil 150 to 250 mg, suggesting that armodafinil continues to be generally well tolerated among patients with SWD8,9,28,29. The current study results further support the use of armodafinil in a variety of patients with SWD as part of an overall treatment regimen that may include pharmacological, as well as nonpharmacological, treatment options to help address the various symptoms associated with the disorder. The fact that the results were assessed by a post hoc analysis based on prospectively collected data is a limitation to the present analysis, and as a result of the post hoc design, the shift worker populations (9 hours vs 49 hours) were not balanced. Furthermore, with the exception of polysomnography that was used to rule out obstructive sleep apnea, no objective or subjective assessments of patients’ daytime sleep were performed. Patients with SWD often experience insomnia during the daytime sleep period; however, an assessment of patient daytime sleep architecture was not a goal of the primary study9. In addition, subjective rather than objective efficacy measures of excessive sleepiness were used in this study, although both patient- and clinician-rated measures were included, which enhances the generalizability of these results. 950
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Conclusion Overall, these data suggest that the improved clinical condition, functioning, and wakefulness observed with armodafinil can benefit a variety of patients with SWD and that efficacy and safety were maintained regardless of shift duration. These results will need to be confirmed in a prospectively designed randomized trial.
Transparency Declaration of funding This study was sponsored by Cephalon Inc. (now doing business as Teva Pharmaceuticals), a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd (Petah Tikva, Israel). Funding for the preparation of this manuscript was provided by Teva Pharmaceuticals. Declaration of financial/other relationships R.Y. has disclosed that he is an employee of Teva Pharmaceuticals. J.H. and S.G.H. have disclosed that they received sponsorship from Teva for their role in developing this study. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships. Acknowledgments The authors thank Joyce Willets PhD and Sarah Mizne PharmD of MedVal Scientific Information Services LLC for providing medical writing and editorial assistance. This manuscript was prepared according to the International Society for Medical Publication Professionals’ ‘Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP2 Guidelines’. Previous presentations: American Psychiatric Association 165th Annual Meeting, Philadelphia, PA, USA, 5–9 May 2012; Associated Professional Sleep Societies SLEEP 2012 Meeting, Boston, MA, USA, 9–13 June 2012.
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