Excessive sleepiness is a cardinal symptom of many sleep disorders,

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1 SCIENTIFIC INVESTIGATIONS Evlution of the Sfety of Modfinil for Tretment of Excessive Sleepiness Thoms Roth, Ph.D. 1 ; Jonthn R.L. Schwrtz, M.D. 2 ; Mx Hirshkowitz, Ph.D. 3 ; Milton K. Ermn, M.D. 4 ; Jeffrey M. Dyno, M.D. 5 ; Snjy Aror, Ph.D. 5 1 Henry Ford Sleep Disorders Center, Detroit, MI; 2 Integris Sleep Disorders Center nd University of Oklhom Helth Science Centers, Oklhom City, OK; 3 Michel E. DeBkey VAMC Sleep Center nd Bylor College of Medicine, Houston, TX; 4 University of Cliforni, Sn Diego, CA; 5 Cephlon, Inc., Frzer, PA Study Objectives: Modfinil is wke-promoting gent shown to improve wkefulness in ptients with excessive sleepiness (hypersomnolence) ssocited with shift work sleep disorder, obstructive sleep pne, or nrcolepsy. Sfety nd tolerbility dt from 6 rndomized, doubleblind, plcebo-controlled studies were combined to evlute modfinil cross these different ptient popultions. Methods: One thousnd five hundred twenty-nine outptients received modfinil 200, 300, or 400 mg or plcebo once dily for up to 12 weeks. Assessments included recording of dverse events nd effects of modfinil on blood pressure/hert rte, electrocrdiogrm intervls, polysomnogrphy, nd clinicl lbortory prmeters. Results: Two hundred seventy-three ptients with shift work sleep disorder, 292 with obstructive sleep pne, nd 369 with nrcolepsy received modfinil; 567 received plcebo. Modfinil ws well tolerted versus plcebo, with hedche (34% vs 23%, respectively), nuse (11% vs 3%), nd infection (10% vs 12%) the most common dverse events. Adverse events were similr cross ll ptient groups. Twenty-seven serious dverse events were reported (modfinil, n = 18; plcebo, n = 9). In modfinil-treted ptients, cliniclly significnt increses in distolic or systolic blood pressure were infrequent (n = 9 nd n = 1, respectively, < 1% of ptients). In the studies, 1 ptient in the modfinil group nd 1 in the plcebo group hd cliniclly significnt increse in hert rte. New cliniclly meningful electrocrdiogrm bnormlities were rre with modfinil (n = 2) nd plcebo (n = 4). Cliniclly significnt bnormlities in men lbortory prmeters were observed in fewer thn 1% of modfinil-treted ptients t finl visit. Modfinil did not ffect sleep rchitecture in ny ptient popultion ccording to polysomnogrphy. Conclusions: Modfinil is well tolerted in the tretment of excessive sleepiness ssocited with disorders of sleep nd wkefulness nd does not ffect crdiovsculr or sleep prmeters. Keywords: Excessive sleepiness, hypersomnolence, modfinil, nrcolepsy, obstructive sleep pne, shift work sleep disorder, wke-promoting gent Cittion: Roth T; Schwrtz JRL; Hirshkowitz M et l. Evlution of the sfety of modfinil for tretment of excessive sleepiness. J Clin Sleep Med 2007;3(6): Disclosure Sttement The study ws supported by Cephlon, Inc., Frzer, PA. Dr. Roth hs received reserch support from Aventis, Cephlon, Glxo-SmithKline, Neurocrine, Pfizer, Snofi, SchoeringPlough, Seprcor, Somxon, Syrex, Tked, TrnsOrl, Wyeth, nd Xenoport; is consultnt for Abbott, Accdi, Acoglix, Actelion, Alchemers, Alz, Ancil, Aren, AstrZenec, Aventis, BMS, Cephlon, Cypress, Dove, Eln, Eli Lilly, Evotec, Forest, GlxoSmithKline, Hypnion, Jzz, Johnson & Johnson, King, Ludbeck, Mc-Neil, MedicNov, Merck, Neurim, Neurocrine, Neurogen, Novrtis, Orexo, Orgnon, Orginer, Prestwick, Proctor nd Gmble, Pfizer, Purdue, Restiv, Roche, Snofi, ShoeringPlough, Seprcor, Servier, Shire, Somxon, Syrex, Tked, TrnsOrl, Vnd, Vivometrics, Wyeth, Ymnuchi, nd Xenoport; nd hs prticipted in speking enggements supported by Snofi nd Tked. Dr. Schwrtz hs received reserch support from AstrZenec, Cephlon, Glxo-Smith-Kline, Neurogen, nd ShoeringPlough; hs consulted for AstrZenec, Boehringer Ingelheim, Cephlon, Glxo-Smith-Kline, Pfizer, ShoeringPlough, Tked, nd Jzz Phrmceuticls; nd is on the speker s bureu for AstrZenec, Boehringer Ingelheim, Cephlon, Seprcor, Glxo-Smith-Kline, Pfizer, ShoeringPlough, nd Tked. Dr. Hirshkowitz s sleep disorders nd reserch center hs been pid for work underwritten by Snofi, Tked, Merck, Glxo- Smith-Kline, Cephlon, Seprcor, Respironics, ResMed, nd NBI; nd is consultnt for nd on the speker s bureu of Snofi, Tked, nd Cephlon. Dr. Ermn hs received reserch support from Snofi, Mllinckrodt, Cephlon, Tked, Aventis, Pfizer, Phrmci, ResMed, Merck, Schwrz, Orgnon, Glxo-Smith-Kline, Eli Lilly, nd Aren; hs consulted for Snofi, JCSM Journl of Clinicl Sleep Medicine, Vol. 3, No. 6, Cephlon, Tked, nd Neurocrine; is in the spekers bureu for Snofi, Forest, nd Tked; nd hs finncil interests in Cephlon, Forest, Neurocrine, Pfizer, Seprcor, Merck, nd Snofi. Drs. Dyno nd Aror re employees of Cephlon, Inc. Submitted for publiction September, 2006 Accepted for publiction Mrch, 2007 Address correspondence to: Thoms Roth, PhD, Henry Ford Sleep Disorders Center, 277 West Grnd Blvd, Detroit, MI, 48202; Tel: (313) ; Fx: (313) ; E-mil: TRoth1@hfhs.org Excessive sleepiness is crdinl symptom of mny sleep disorders, including shift work sleep disorder (SWSD), obstructive sleep pne (OSA), nd nrcolepsy. 1,2 SWSD is clssified s circdin rhythm sleep disorder resulting from sleep-wke pttern tht is out of synchrony with the individul s internl biologic rhythm. 1 Excessive sleepiness during wking hours is more common in workers on the night shift thn in those who regulrly work during the dy. 2 Approximtely 45% of night-shift workers hve excessive sleepiness, nd it often interferes with their ctivities of dily life. 2 SWSD hs been estimted to occur in 14% to 32% of night-shift workers. 2 Excessive sleepiness lso occurs in up to 90% of ptients with OSA, 3 sleep disorder cused by frequent rousls from sleep ssocited with obstruction of ir-

2 T Roth, JRL Schwrtz, M Hirshkowitz, et l flow through the upper irwys. 1 Nsl continuous positive irwy pressure is the preferred tretment for OSA, 4 nd it reduces excessive sleepiness 5 ; however, residul excessive sleepiness cn persist even with dequte use of nsl continuous positive irwy pressure. 6 Finlly, nrcolepsy is sleep disorder inherently ssocited with excessive sleepiness. The presence of excessive sleepiness on n lmost dily bsis is required dignostic criterion in ptients with nrcolepsy, sleep-wke dysregultion disorder. 1 The excessive sleepiness my be ccompnied by ctplexy, which is sudden loss of muscle tone tht is typiclly triggered by strong emotions. 1 Excessive sleepiness is ssocited with impired cognitive nd psychomotor function nd diminished qulity of life, 7 including impired physicl nd socil functioning, emotionl stte, nd mentl helth. Typiclly, individuls with excessive sleepiness hve diminished sense of well-being, 8 often with ftigue nd reduced energy levels. 9,10 There re lso significnt socioeconomic costs ssocited with excessive sleepiness. Serious injury nd deth, costing billions of dollrs nnully, result from ccidents cused by sleepiness. 11,12 Excessive sleepiness is lso fctor in occuptionl ccidents, nd ptients with SWSD re more likely to hve ccidents thn dytime workers. 2 Job productivity is lso lower for shift workers with SWSD thn for shift workers without SWSD. 2 These dverse economic nd public helth relted consequences of excessive sleepiness in the generl popultion underscore the need for timely nd pproprite dignosis nd tretment. Modfinil, wke-promoting gent, significntly improves wkefulness in ptients with excessive sleepiness ssocited with SWSD, 13,14 OSA, 15,16 or nrcolepsy. 17,18 Objectively nd subjectively mesured sleepiness decreses in response to modfinil dministrtion. Modfinil differs chemiclly nd phrmcologiclly from centrl nervous system stimulnts. 19,20 Furthermore, modfinil crries lower potentil for buse nd dverse crdiovsculr events thn centrl nervous system stimulnts. 21,22 The purpose of this rticle is to ggregte sfety results cross studies in disorders of sleep nd wkefulness reported previously These findings re summrized in the context of the sfety nd tolerbility of modfinil in ptients with excessive sleepiness ssocited with SWSD, OSA, nd nrcolepsy. METHODS Six rndomized, double-blind, plcebo-controlled, prllelgroup studies support the efficcy of modfinil for the tretment of dults with excessive sleepiness ssocited with chronic SWSD, 13,14 OSA, 15,16 or nrcolepsy. 17,18 These studies were nlyzed to evlute the overll sfety profile of modfinil. In ech of these studies, ptients met stndrd dignostic criteri 1 for the respective disorder being investigted nd hd no other cuse of excessive sleepiness. Study protocols were pproved by locl ethics committees nd bided by the guidelines of the Declrtion of Helsinki nd its mendments. Ptients meeting eligibility criteri provided written informed consent before study entry. The 6 studies were conducted t 139 sites in the United Sttes nd United Kingdom. The studies were designed by the sponsor nd expert specilists in the field of sleep in conjunction with helth uthorities in ech respective country. As per these study designs, the sponsor ws responsible for monitoring the nlysis of dt collected by investigtors t ech site s well s for dt storge nd verifiction. Dt were fully ccessible to ll uthors, with the studies sponsor plcing no limits JCSM Journl of Clinicl Sleep Medicine, Vol. 3, No. 6, on interprettion or publiction. All uthors were involved with the preprtion of the mnuscript. PATIENTS Ptients t lest 18 yers of ge with complint of excessive sleepiness were eligible to prticipte in ech study if they were within the upper ge limit for the individul studies (60 yers for SWSD, 65 or 70 for OSA, nd 65 for nrcolepsy). Ptients in the 2 SWSD studies were eligible if they hd complint of excessive sleepiness ssocited with chronic SWSD. Ptients lso hd to hve worked t lest 5 night shifts per month (ech shift 12 hours, with 6 hours of ech shift worked between 2200 nd 0800), with t lest 3 shifts occurring on consecutive nights. 13,14 For 1 of the SWSD studies, 13 dditionl criteri included men sleep ltency of 6 minutes or less on screening Multiple Sleep Ltency Test nd sleep efficiency of 87.5% or less on dytime polysomnogrphy. Ptients in the 2 OSA studies must hve hd residul excessive sleepiness bsed on the Epworth Sleepiness Scle (ie, score 10). 15,16 In 1 of the OSA studies, ptients hd to hve residul excessive sleepiness defined s reduction in the pne-hypopne index to less thn 10 nd greter thn 50% decrese from the historicl mesurement obtined prior to nsl continuous positive irwy pressure use. 16 Ptients in the 2 nrcolepsy studies were eligible if they hd dignosis of nrcolepsy ccording to The Interntionl Clssifiction of Sleep Disorders criteri. 23 In ddition, objective documenttion of sleepiness with the Multiple Sleep Ltency Test ws required (ie, men sleep ltency 8 minutes). 17,18 Alternte inclusion criteri included complint of excessive sleepiness or sudden muscle wekness with ssocited fetures (eg, sleep prlysis or hypnogogic hllucintions) nd men sleep ltency of 5 minutes or less. Ptients were excluded if they hd dignosis or documented primry sleep disorder other thn the one for which they were enrolled. Ptients with history of therpeutic filure for excessive sleepiness or ny uncontrolled medicl disorder were excluded from prticiption. Additionl exclusion criteri included drug sensitivity or drug llergy to stimulnt medictions nd ny prior experience with modfinil. Self-reported cffeine consumption ws limited to 500 to 900 mg/dy or less, depending on the study. Further exclusions included use of ny mediction with stimulting (eg, methylphenidte, mphetmines) or sedting (eg, sedting ntihistmines) properties. Antictplectic therpy for nrcolepsy ptients ws prohibited. A urine drug toxicology test ws performed before dministering ny study mediction. Some concomitnt medictions, such s nlgesics, vitmins, nd nti-infectives, were mintined t stble regimens. Study Design Studies of SWSD evluted modfinil tken only when the ptient ws working night shift; 1 study 13 evluted modfinil 200 mg, nd the other 14 evluted modfinil 200 nd 300 mg. In both SWSD studies, dosing occurred 30 to 60 minutes before ech regulrly scheduled night shift nd continued for 12 weeks. Ptients were not titrted to the trget dose in the SWSD studies nd did not tke modfinil on dys when they were not working. One OSA study 15 evluted modfinil 200 nd 400 mg tken once dily in the morning for 12 weeks; the other 16 evluted modfinil 400 mg tken once dily in the morning for 4 weeks. Both nrcolepsy stud-

3 Sfety of Modfinil for Tretment of ES Tble 1 Ptient Disposition by Tretment Group nd Dose SWSD OSA Nrcolepsy Modfinil PL Modfinil PL Modfinil PL Rndomized, no Sfety nlysis 273 (96.1) 194 (95.6) 292 (99.0) 188 (99.5) 369 (99.5) 185 (98.9) Completed 201 (70.8) 141 (69.5) 241 (81.7) 174 (92.1) 335 (90.3) 169 (90.4) Discontinued study 83 (29.2) 62 (30.5) 54 (18.3) 15 (7.9) 36 (9.7) 18 (9.6) Deth 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Adverse event 27 (9.5) 9 (4.4) 32 (10.8) 4 (2.1) 19 (5.1) 3 (1.6) Lck of efficcy 1 (0.4) 0 (0) 1 (0.3) 1 (0.5) 3 (0.8) 5 (2.7) Consent withdrwn 12 (4.2) 14 (6.9) 8 (2.7) 2 (1.1) 9 (2.4) 3 (1.6) Protocol violtion 8 (2.8) 4 (2.0) 1 (0.3) 4 (2.1) 4 (1.1) 2 (1.1) Noncomplince 2 (0.7) 8 (3.9) 5 (1.7) 2 (1.1) 1 (0.3) 2 (1.1) Lost to follow-up 16 (5.6) 15 (7.4) 3 (1.0) 0 (0) 0 (0) 1 (0.5) Other 17 (6.0) 12 (5.9) 4 (1.4) 2 (1.1) 0 (0) 2 (1.1) Combined Modfinil 200 mg 300 mg 400 mg All PL Rndomized, no Sfety nlysis 477 (97.9) 90 (96.8) 367 (99.2) 934 (98.3) 567 (97.9) Completed 400 (82.1) 61 (65.6) 316 (85.4) 777 (81.8) 484 (83.6) Discontinued study 87 (17.9) 32 (34.4) 54 (14.6) 173 (18.2) 95 (16.4) Deth 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Adverse event 26 (5.3) 18 (19.4) 34 (9.2) 78 (8.2) 16 (2.8) Lck of efficcy 4 (0.8) 1 (1.1) 0 (0) 5 (0.5) 6 (1.0) Consent withdrwn 13 (2.7) 3 (3.2) 13 (3.5) 29 (3.1) 19 (3.3) Protocol violtion 9 (1.8) 2 (2.2) 2 (0.5) 13 (1.4) 10 (1.7) Noncomplince 4 (0.8) 2 (2.2) 2 (0.5) 8 (0.8) 12 (2.1) Lost to follow-up 16 (3.3) 3 (3.2) 0 (0) 19 (2.0) 16 (2.8) Other 15 (3.1) 3 (3.2) 3 (0.8) 21 (2.2) 16 (2.8) All vlues re number (%) except where indicted otherwise. OSA refers to obstructive sleep pne; PL, plcebo; SWSD, shift work sleep disorder. ies evluted modfinil 200 nd 400 mg tken once dily in the morning for 9 weeks. Ptients in the OSA nd nrcolepsy studies were titrted to the trget dose over 2- to 9-dy period. Sfety Assessments Assessments included dverse events, vitl signs (ie, resting systolic nd resting distolic blood pressures, hert rte, nd body weight), electrocrdiogrm (ECG) intervls, clinicl lbortory prmeters, nd polysomnogrphy during the dy (SWSD) or during the night (OSA nd nrcolepsy studies). All observed nd spontneously reported dverse events were recorded by type nd dy of onset. Vitl signs were monitored t ech lbortory visit. Cliniclly meningful dverse events specificlly ssocited with blood pressure nd hert rte were tbulted on the bsis of the frequency of increses in blood pressure or hert rte defined by the Food nd Drug Administrtion. Clinicl thresholds for concern were 120 or more bets per minute nd n increse of 15 or more bets per minute for hert rte, 180 mm Hg or higher nd n increse of 20 mm Hg or more for systolic blood pressure, nd 105 mm Hg or higher nd n increse of 15 mm Hg or more for distolic blood pressure. A ptient ws considered to hve newly dignosed bnorml ECG finding when ECG ws norml t bseline but bnorml t ny time fter tretment begn. ECG dt were recorded t bseline prior to modfinil dministrtion nd t the finl visit using 12-led ECG. Physicl exmintions were conducted t the screening visit nd t the lst observtion of ech JCSM Journl of Clinicl Sleep Medicine, Vol. 3, No. 6, study. Blood nd urine smples were collected t the screening visit, bseline visit, nd lst observtion. Lbortory-ttended, comprehensive polysomnogrphy ws performed using electroencephlogrphy (centrl nd occipitl leds), electrooculogrphy, electromyogrphy (submentl nd tibilis), ECG, rteril hemoglobin oxygen sturtion (oximetry), nd mesures of respirtory flow (nsl nd orl) nd effort (thorcic nd bdominl). Sttisticl Anlysis All ptients who received t lest 1 dose of modfinil or plcebo were included in the current nlyses. Dt were summrized in severl wys: (1) by disorder of sleep nd wkefulness (ie, SWSD, OSA, or nrcolepsy); (2) by tretment group (ie, the dosge ptient ws rndomly ssigned to receive, including once-dily modfinil 200, 300, nd 400 mg; ll modfinil dosges combined; nd plcebo); nd (3) ll studies combined. All nlyses were originlly specified priori in the sttisticl nlysis plns. Ptient disposition, including investigtors documenttion of resons for discontinution, ws summrized s ctegoricl dt for rndomized ptients. Demogrphic dt (ie, ge, sex, rce, nd body mss index) were noted mong tretment groups t bseline. All reported dverse events were clssified by body system nd preferred term ccording to the Coding Symbols for Thesurus of Adverse Rection Terms nd summrized s ctegoricl dt. Sttisticl significnce between the combined modfinil group nd the plcebo

4 T Roth, JRL Schwrtz, M Hirshkowitz, et l Tble 2 Bseline Chrcteristics of the Study Popultion SWSD OSA Nrcolepsy Modfinil PL Modfinil PL Modfinil PL Age, y 39.2 (9.4) 39.3 (9.0) 48.7 (9.2) 50.6 (9.6) 42.0 (13.4) 41.3 (13.2) Men b 145 (53) 105 (54) 229 (78) 139 (74) 168 (46) 85 (46) Rce b White 196 (72) 132 (68) 257 (88) 166 (88) 301 (82) 154 (83) Other 77 (28) 62 (32) 35 (12) 22 (12) 68 (18) 31 (17) BMI, kg/m (6.7) 30.8 (6.3) 36.1 (7.6) 36.2 (8.0) 28.9 (6.4) 28.3 (6.1) Combined Modfinil 200 mg 300 mg 400 mg All PL Age, y 41.7 (11.7) 40.2 (9.7) 46.1 (11.8) 43.3 (11.8) 43.7 (11.8) Men b 277 (58) 43 (48) 222 (60) 542 (58) 329 (58) Rce b White 374 (78) 67 (74) 313 (85) 754 (81) 452 (80) Other 103 (22) 23 (26) 54 (15) 180 (19) 115 (20) BMI, kg/m (7.6) 29.8 (6.6) 32.7 (7.9) 31.7 (7.7) 32.0 (7.9) Dt re presented s men (SD). b Dt re presented s number (%). BMI refers to body mss index; OSA, obstructive sleep pne; PL, plcebo; SWSD, shift work sleep disorder. Tble 3 Adverse Events Reported by 5% or More of Ptients Adverse Event SWSD OSA Nrcolepsy Totl Modfinil PL Modfinil PL Modfinil PL Modfinil PL n = 273 n = 194 n = 292 n = 188 n = 369 n = 185 n = 934 n = 567 Hedche 63 (23) 37 (19) 73 (25) b 22 (12) 183 (50) b 74 (40) 319 (34) b 133 (23) Nuse 31 (11) b 7 (4) 29 (10) b 5 (3) 47 (13) b 7 (4) 107 (11) b 19 (3) Infection 12 (4) 14 (7) 34 (12) 25 (13) 51 (14) 29 (16) 97 (10) 68 (12) Nervousness 18 (7) b 3 (2) 21 (7) b 4 (2) 30 (8) 12 (6) 69 (7) b 19 (3) Rhinitis 9 (3) 9 (5) 18 (6) 10 (5) 42 (11) 14 (8) 69 (7) 33 (6) Bck pin 8 (3) 3 (2) 9 (3) 7 (4) 35 (9) 16 (9) 52 (6) 26 (5) Dirrhe 12 (4) 8 (4) 16 (5) 10 (5) 30 (8) 8 (4) 58 (6) 26 (5) Anxiety 8 (3) 1 (<1) 23 (8) b 3 (2) 13 (4) b 1 (<1) 44 (5) b 5 (<1) Dizziness 8 (3) 7 (4) 18 (6) 6 (3) 17 (5) 7 (4) 43 (5) 20 (4) Dyspepsi 10 (4) 3 (2) 8 (3) 4 (2) 26 (7) 14 (8) 44 (5) 21 (4) Insomni 18 (7) b 2 (1) 16 (5) b 2 (1) 11 (3) 2 (1) 45 (5) b 6 (1) Anorexi 10 (4) b 1 (<1) 8 (3) 3 (2) 17 (5) b 2 (1) 35 (4) b 6 (1) Dry mouth 9 (3) 5 (3) 9 (3) 3 (2) 19 (5) b 1 (<1) 37 (4) b 9 (2) Influenz syndrome 14 (5) 5 (3) 10 (3) 5 (3) 13 (4) 7 (4) 37 (4) 17 (3) Phryngitis 11 (4) 7 (4) 5 (2) 2 (1) 23 (6) 5 (3) 39 (4) 14 (2) Accidentl injury 12 (4) 9 (5) 15 (5) 9 (5) 3 (<1) b 12 (6) 30 (3) 30 (5) Hypertension 10 (4) b 0 (0) 14 (5) 3 (2) 6 (2) 0 (0) 30 (3) b 3 (<1) OSA refers to obstructive sleep pne; PL, plcebo; SWSD, shift work sleep disorder. Vlues re presented s number (SD). b p <.05 vs plcebo. group for dverse events ws determined by Fisher Exct Test. The bseline, finl visit, nd corresponding chnge from bseline to finl-visit vlues for vitl signs (ie, resting systolic blood pressure, resting distolic blood pressure, hert rte, nd body weight) were summrized s continuous dt within study popultions (SWSD, OSA, or nrcolepsy) nd tretment groups. Sttisticl significnce between the combined modfinil group nd the plcebo group for vitl signs ws determined by the Wilcoxon Test. The incidences of cliniclly significnt blood-pressure nd hert-rte vlues t ny time during tretment were summrized by study popultion nd by tretment group using criteri defined by the Food nd Drug Administrtion nd summrized s ctegoricl dt. JCSM Journl of Clinicl Sleep Medicine, Vol. 3, No. 6, Ptients RESULTS In the 6 studies, 1529 ptients were rndomly ssigned to receive either modfinil or plcebo (Tble 1), with 1501 ptients (98%) receiving t lest 1 dose of study drug. A totl of 1261 ptients completed these studies; the percentges of ptients completing were similr for ll studies (pproximtely 80%). The overll discontinution rtes were comprble for individuls receiving modfinil (18%) nd those receiving plcebo (16%). Discontinution rtes were 34% for ptients receiving modfinil 300

5 Tble 4 Men Hert Rte, Systolic Blood Pressure, Distolic Blood Pressure, nd Body Weight t Bseline nd Finl Visit for Ech Disorder SWSD OSA Nrcolepsy Modfinil PL Modfinil PL Modfinil PL Prmeter Time Point n = 273 n = 194 n = 292 n = 188 n = 369 n = 185 Hert rte, bpm Bseline 71.1 (9.9) 69.9 (8.8) 72.4 (10.2) 71.1 (9.9) 75.3 (11.4) 74.1 (11.0) Finl visit 71.5 (10.3) 70.3 (9.9) 72.2 (10.0) 71.3 (10.8) 75.4 (10.4) b 73.3 (10.4) Blood pressure, mm Hg Systolic Bseline (13.1) (12.3) (12.7) (12.3) (16.4) (15.4) Finl visit (13.3) (13.8) (12.7) (12.3) (15.5) b (15.4) Distolic Bseline 77.9 (9.6) 79.0 (9.1) 80.0 (8.0) 80.4 (8.3) 76.0 (10.6) 75.5 (9.9) Finl visit 77.9 (9.8) 78.4 (8.9) 79.3 (8.5) 78.8 (8.4) 75.4 (10.7) 74.6 (10.2) Body weight, kg Bseline 89.6 (20.9) 87.3 (16.8) (22.8) (24.2) 84.2 (19.6) 83.2 (19.2) Finl visit 88.6 (21.0) 87.3 (16.9) (23.4) (24.2) 83.9 (19.6) 84.2 (19.3) bpm refers to bets per minute; OSA, obstructive sleep pne; PL, plcebo; SWSD, shift work sleep disorder. All vlues re number (SD). b p <.05 vs plcebo. Sfety of Modfinil for Tretment of ES mg per dy, 18% for those receiving 200 mg per dy, nd 15% for those receiving 400 mg per dy. Seventy-eight (8.2%) ptients receiving modfinil nd 16 (2.8%) ptients receiving plcebo discontinued becuse of dverse events. The most frequent dverse event cited s the reson for discontinution ws hedche (2%). Nuse, nxiety, dizziness, insomni, chest pin, nd nervousness (ech < 1%) were the next most frequent dverse events. Few ( 1%) ptients discontinued becuse of lck of efficcy in either group. A totl of 934 ptients received modfinil tretment (200 mg, n = 477; 300 mg, n = 90; 400 mg, n = 367), nd 567 ptients received plcebo. Approximtely 60% of ptients were men, nd pproximtely 80% were white (Tble 2). In the OSA studies, with 76% mle enrollment, ptients hd men bseline body mss index of greter thn 36 kg/m 2. The verge durtion of modfinil tretment ws 42.3 dys in ptients with SWSD, 65.0 dys in ptients with OSA, nd 60.0 dys in ptients with nrcolepsy. Adverse Events Hedche ws the most frequently reported dverse event in these studies (Tble 3). Most (nerly 90%) dverse events occurred during the first 4 weeks of tretment nd were grded s mild to moderte. The overll incidence of dverse events ws similr mong the 3 modfinil dosge groups. The most common dverse event reported by ptients receiving modfinil ws hedche (modfinil, n = 319 [34%]; plcebo, n = 133 [23%]). A dose-relted trend ws seen only for hedche (200 mg, 32%; 300 mg, 26%; 400 mg, 40%; p <.05 vs plcebo). Other leding events included nuse (modfinil, n = 107 [11%]; plcebo, n = 19 [3%]) nd infection (modfinil, n = 97 [10%]; plcebo, n = 68 [12%]). Adverse events occurring more frequently in the modfinil group thn in controls included hedche, nuse, dry mouth, norexi, nervousness, insomni, nxiety, hypertension, nd phryngitis. The cumultive incidence of hedche for modfinil ws 20% t 1 week, 29% t 1 month, nd 34% t 3 months. For plcebo, the cumultive incidence of hedche ws 9% t 1 week, 18% t 1 month, nd 23% t 3 months. The cumultive incidence of nuse for modfinil ws 7% t 1 week, 10% t 1 month, nd 11% t 3 months. For plcebo, the cumultive incidence of nuse ws 2% t 1 week nd 3% t 1 month nd t 3 months. JCSM Journl of Clinicl Sleep Medicine, Vol. 3, No. 6, In ptients tking modfinil, 18 serious dverse events occurred. In the plcebo group, there were 9 serious dverse events. Seven dverse events were considered tretment relted; these included chest pin, leukopeni, bnorml liver enzymes, extrsystoles, plpittions, dyspne, nd hypoventiltion. Blood Pressure, Hert Rte, nd Body Weight There were no significnt chnges from bseline to finl visit in men hert rte, systolic blood pressure, or distolic blood pressure between the modfinil nd plcebo groups for the SWSD or OSA studies. In the nrcolepsy studies, the men chnge from bseline to finl visit in hert rte nd systolic blood pressure ws sttisticlly significnt between the modfinil nd the plcebo groups (p <.05; Tble 4). These differences were due to greter chnge from bseline in the plcebo group (men ± SD: hert rte, -0.8 ± 9.8 bets/min; systolic blood pressure, -3.1 ± 13.0 mm Hg) thn in the modfinil group (men ± SD: hert rte, 0.1 ± 11.7 bets/min; systolic blood pressure, -1.3 ± 13.5 mm Hg). Overll, cliniclly significnt bnormlities in blood pressure nd hert rte were rre in both groups regrdless of the clinicl popultion ( 1% of ptients in most cses; Tble 5). Cliniclly significnt elevtions in distolic blood pressure ( 105 mm Hg nd n increse from bseline 15 mm Hg) were observed in 9 (< 1%) ptients who received modfinil nd in none of the ptients who received plcebo; 5 of these 9 ptients hd dignosis of OSA. The initition or increse in dose of ntihypertensive mediction ws 2.4% in modfinil-treted ptients nd 0.7% in those receiving plcebo. When only OSA studies were included, ltertions in use of ntihypertensive medictions were required for 3.4% of modfinil-treted ptients nd for 1.1% of ptients receiving plcebo. Regrdless of ptient group, there were no significnt chnges from bseline in men body weight (Tble 4). Nonetheless, cliniclly significnt decreses in body weight (defined s 7% decrese from bseline) were reported for 28 (3%) ptients receiving modfinil (Tble 5). Weight loss ws more common in the OSA studies, with cliniclly significnt decreses reported for 20 (7%) ptients in the modfinil group. Cliniclly significnt weight loss ws seen in 7 (1%) plcebo ptients cross ll studies nd in 2 (1%) plcebo ptients in the OSA studies.

6 T Roth, JRL Schwrtz, M Hirshkowitz, et l Tble 5 Cliniclly Significnt Abnorml Vlues in Vitl Signs Bsed on Prespecified Criteri SWSD OSA Nrcolepsy Modfinil PL Modfinil PL Modfinil PL Vrible Criteri n = 273 n = 194 n = 292 n = 188 n = 369 n = 185 Hert rte, bpm SBP, mm Hg DBP, mm Hg 120 nd increse 15 0 (0) 0 (0) 0 (0) 1 (<1) 1 (<1) 0 (0) 50 nd decrese 15 2 (<1) 2 (1) 0 (0) 0 (0) 2 (<1) 4 (2) 180 nd increse 20 0 (0) 0 (0) 1 (<1) 0 (0) 0 (0) 0 (0) 90 nd decrese 20 1 (<1) 0 (0) 4 (1) 1 (<1) 4 (1) 2 (1) 105 nd increse 15 1 (<1) 0 (0) 5 (2) 0 (0) 3 (<1) 0 (0) 50 nd decrese 15 0 (0) 0 (0) 1 (<1) 1 (<1) 6 (2) 2 (1) Body weight (kg) Increse 7% 1 (<1) 0 (0) 5 (2) 0 (0) 4 (1) 5 (3) Decrese 7% 2 (<1) 3 (2) 20 (7) 2 (1) 6 (2) 2 (1) bpm refers to bets per minute; DBP, distolic blood pressure; OSA, obstructive sleep pne; PL, plcebo; SBP, systolic blood pressure; SWSD, shift work sleep disorder. All vlues re number (%). Electrocrdiogrm Modfinil ws similr to plcebo in terms of cliniclly significnt ECG chnges, nd there ws no tretment-emergent pttern of ECG bnormlities. Newly dignosed bnorml ECG findings were reported in 162 (17%) of 934 ptients receiving modfinil nd 102 (18%) of 567 ptients receiving plcebo. Of these, only 2 (< 1%) ptients receiving modfinil nd 4 (< 1%) ptients receiving plcebo hd ECG results tht met priori criteri for clinicl significnce. All 6 of these ptients were enrolled in the OSA studies. Clinicl Lbortory Prmeters In ptients with nrcolepsy, men ± SD gmm-glutmyl trnsferse (GGT) nd lkline phosphtse plsm levels were 36.6 ± nd 78.4 ± U/L, respectively, following dministrtion of modfinil nd 25.9 ± nd 77.3 ± U/L, respectively, for plcebo; however, fewer thn 1% of ll elevtions were higher thn 3 times the upper limit of norml. In ptients with SWSD, men GGT nd lkline phosphtse levels incresed following dministrtion of either modfinil or plcebo. GGT levels were not mesured in ptients with OSA; however, lkline phosphtse levels incresed following modfinil dministrtion nd decresed with plcebo. Cliniclly significnt bnormlities in lnine minotrnsferse nd sprtte minotrnsferse (> 3 times the upper limit of norml 24,25 ), blood ure nitrogen ( mmol/l), cretinine ( 177 µmol/l), uric cid (men, 625 µmol/ L; women, 506 µmol/l), nd totl bilirubin ( 34.2 µmol/l) were infrequent (observed in < 1% of ptients for ll prmeters), without tretment-emergent bis towrd ctive drug. Effects on Desired Sleep Polysomnogrphy indicted tht modfinil hd no dverse effect on ptients sleep rchitecture (Figure 1). No cliniclly significnt difference for sleep efficiency emerged between modfinil nd plcebo for ll 3 ptient popultions (SWSD, p =.85; OSA, p =.11; nrcolepsy, p =.11). DISCUSSION Figure Men ± SEM in sleep efficiency (time sleep s percentge of the totl time in bed) t bseline nd finl visit s determined by polysomnogrphy. Differences between the modfinil nd plcebo groups were not sttisticlly significnt for ny indiction (shift work sleep disorder [SWSD], p =.85; obstructive sleep pne [OSA], p =.11; nrcolepsy, p =.11). Dt from these 6 studies (2 SWSD, 2 OSA, nd 2 nrcolepsy) show tht modfinil 200, 300, or 400 mg once dily is well tolerted in ptients with excessive sleepiness ssocited with disorders of sleep nd wkefulness. Hedche nd nuse were the most common dverse events observed in ptients receiving modfinil. The mjority of dverse events were mild to moderte in nture, nd only hedche ws ssocited with dose-relted effect. Moreover, modfinil ws not ssocited with cliniclly significnt chnges in men vitl signs, ECGs, or sleep when sleep ws desired. At finl visit, elevtions in men GGT nd/or lkline phosphtse were observed in ptients receiving modfinil but not in those receiving plcebo. Cliniclly significnt bnor- JCSM Journl of Clinicl Sleep Medicine, Vol. 3, No. 6,

7 Sfety of Modfinil for Tretment of ES mlities in lbortory prmeters were rre nd reported in fewer thn 1% of ptients receiving modfinil or plcebo. Excessive sleepiness is common symptom of ptients seen by both primry cre nd specilty medicine physicins. 9 A survey conducted by the Ntionl Sleep Foundtion indicted tht 37% of dults (18-54 yers old) report tht excessive sleepiness interferes with their dily ctivities t lest some of the time, nd 16% report tht it interferes few dys or more per week. 26 Excessive sleepiness my hve potentilly serious physiologicl consequences, especilly in ptients with OSA who hve n incresed risk for crdiovsculr disese. 27 Results from prospective popultion-bsed study show greter thn 2-fold increse in ll-cuse nd crdiovsculr mortlity in OSA ptients with excessive sleepiness, even fter controlling for hypertension nd crdiovsculr disese. 28 There is lso evidence tht shift workers with repeted disturbnces in circdin rhythms experience negtive impct on performnce, qulity of life, nd helth, with n incresed risk for peptic ulcers nd crdiovsculr disese. 2,29,30 Importntly, in the current nlysis, modfinil did not elevte men blood pressure or hert rte more thn did plcebo in popultion of ptients t risk for crdiovsculr events (eg, ptients with OSA). Reduced sleep efficiency in ptients with SWSD likely results from insomni nd disturbed sleep nd is presumbly relted to work-dictted sleep schedules plced in opposition to ptients internl circdin sleep-wke cycles. Excessive sleepiness in ptients with SWSD hs been ssocited with impired performnce nd lower job productivity, incresed bsenteeism, nd more ccidents thn in dytime workers. 2 Modfinil hs been shown to improve lertness in ptients dignosed with SWSD with fvorble sfety profile. One of the min limittions of these results reltes to the short durtion (4-12 weeks) of the 6 studies. However, modfinil hs been well tolerted during long-term open-lbel studies of ptients with nrcolepsy. 31,32 Adverse events in these open-lbel studies were consistent with those observed in the double-blind clinicl studies nd were mild to moderte in nture. Additionlly, no cliniclly meningful chnges in vitl signs or ECGs were found. 31,33,34 Modfinil tken in the morning or t the beginning of night shift does not dversely ffect subsequent sleep occurring 8 to 16 hours lter ,35 The fvorble sfety profile of modfinil my, in prt, be due to its selective ction in the sleep-wke brin centers, 19 rther thn widespred centrl nervous system stimultion vi dopminergic pthwys. In contrst to trditionl nervous system stimulnts, the buse potentil for modfinil is considered low, nd clinicl evidence for the development of dependence or tolernce hs not been found. 21,36,37 In conclusion, modfinil is well tolerted. Furthermore, it ppers from these 6 prospective reserch studies tht dily modfinil dministrtion confers low risk of dverse events or severe dverse events. These results mke for positive risk-benefit rtio for using modfinil to tret excessive sleepiness in ptients with SWSD, OSA, nd nrcolepsy. 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