A Double-Blind, Placebo-Controlled Study Demonstrates Sodium Oxybate Is Effective for the Treatment of Excessive Daytime Sleepiness in Narcolepsy

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1 A Double-Blind, Placebo-Controlled Study Demonstrates Sodium Oxybate Is Effective for the Treatment of Excessive Daytime Sleepiness in Narcolepsy International Xyrem Study Group Volume: 1 Issue: 4 Pages

2 A Double-Blind, Placebo-Controlled Study Demonstrates Sodium Oxybate Is Effective for the Treatment of Excessive Daytime Sleepiness in Narcolepsy SCIENTIFIC INVESTIGATIONS The Xyrem International Study Group Orphan Medical, Inc., A Subsidiary of Jazz Pharmaceuticals, Palo Alto, CA Study Objective: Assess the efficacy of sodium oxybate for the treatment of narcolepsy with an emphasis on excessive daytime sleepiness. Design: Eight-week, multicenter, double-blind, placebo-controlled trial. Setting: Forty-two sleep clinics in the United States, Canada, and Europe. Participants: Two hundred twenty-eight adults with narcolepsy with cataplexy. Interventions: Patients were withdrawn from antidepressant treatment and then randomly assigned to receive 4.5 g, 6 g, or 9 g of sodium oxybate nightly or placebo for 8 weeks. Six-gram and 9-g doses were titrated in weekly 1.5-g increments. Patients who were receiving placebo underwent a mock dose-titration schedule. Stimulant use continued unchanged. Excessive daytime sleepiness was measured using the Epworth Sleepiness Scale and Maintenance of Wakefulness Test. The Clinical Global Impression of Change was used to measure changes in disease severity. Changes in narcolepsy symptoms and adverse events were recorded in daily diaries. Results: After 8 weeks, patients treated with 9 g of sodium oxybate nightly displayed a significant median increase of > 1 minutes in the Maintenance of Wakefulness Test (p <.1). Patients displayed doserelated decreases in median Epworth Sleepiness Scale scores and frequency of weekly inadvertent naps, which were significant at the 6-g and 9-g doses (for each, p <.1). The improvements in excessive daytime sleepiness were incremental to those achieved by concomitant stimulants alone. Significant improvements in the Clinical Global Impression of Change were noted for each group treated with sodium oxybate (p.1). Adverse events were consistent with the known safety profile of sodium oxybate. Conclusions: When combined with its previously demonstrated anticataplectic effects, the results of the current study indicate sodium oxybate is the first drug to demonstrate efficacy for the 2 major symptoms of narcolepsy. Keywords: Maintenance of wakefulness test, epworth sleepiness Scale, excessive daytime sleepiness, narcolepsy, sodium oxybate, gamma-hydroxybutyrate Citation: International Xyrem Study Group. A double-blind, placebocontrolled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med 25;1(4): Disclosure Statement This was an industry supported study supported by Orphan Medical Inc. Dr. Ahmed has participated in speaking engagements supported by Sanofi, Cephalon, and Orphan Medical. Dr. Becker has received research support from Sanofi-Aventis, GlaxoSmithKline, Boehringer Ingelheim, Schwartz, Pfizer, and Merck; has participated in speaking engagements supported by Sanofi, Sepracor, and GlaxoSmithKline; and is a consultant for Sanofi, Takeda, GlaxoSmithKline, and Boehringer Ingelheim. Dr. Biber has received research support from Orphan Medical. Dr. Black has received research support from Cephalon, Orphan Medical, and GlaxoSmithKline. Dr. Bogan has received research support from and serves on the speakers bureau for Orphan Medical. Dr. Chesson has received research support from Orphan Medical and Cephalon. Dr. Duntley has received research support from Orphan Medical, Merck, Neurocrine, Boehringer Ingelheim, Swartz, and Cephalon; has participated in speaking engagements supported by Sanofi, Cephalon, and Orphan Medical; and serves as a consultant for Merck. Dr. Emsellem has received research support from Boehringer Ingelheim, Cephalon, Merck, Neurocrine, Orphan Medical, Sanofi-Zolog, Sepracor, and Takeda. Dr. Erman has received support from Elan, King Pharmaceuticals, Sanofi, Mallinckrodt, Cephalon, Takeda, Neurocrine, Aventis, Pfizer, Pharmacia, Orphan Medical, ResMed, Merck, Sepracor, and Somaxon; serves on the advisory board or speakers bureau for Elan, King Pharmaceuticals, Sanofi, Cephalon, Takeda, and Sepracor; is a consultant for Elan, King Pharmaceuticals, Sanofi, Mallinckrodt, Cephalon, Takeda, Somaxon, Janssen, and Cypress; and is a stock shareholder of Cephalon, Forest, Neurocrine, Journal of Clinical Sleep Medicine, Vol. 1, No. 4, Pfizer, Sepracor, Merck, and Sanofi. Dr. Feldman has received research support, honoraria, and consultant fees from Orphan Medical. Dr. Geisler has received research support from Orphan Medical, Cephalon, Pfizer, and Schwartz; and has participated in speaking engagements supported by Cephalon. Dr. Hagaman has received research support from Orphan Medical. Dr. Hayduk is a member of the speakers bureau for Sepracor. Dr. Hornfeldt is a full-time employee of Orphan Medical. Dr. Houghton is an employee and stock shareholder of Orphan Medical. Dr. Husain serves on the speakers bureau for Orphan Medical. Dr. Kaelin has received research support from Boehringer Ingelheim, GlaxoSmithKline, Cephalon, Novartis, Altana, and Omnicare; and has participated in speaking engagements supported by Boehringer Ingelheim and GlaxoSmithKline. Dr. Lammers has received research support from Orphan Medical. Dr. Leech has received research support from Cephalon and Aventis Pharma. Dr. Mamelak has received research support and has participated in a speaking engagement supported by Orphan Medical. Dr. Mayer has received research support from Orphan Medical. Dr. Moldofsky has received research support from Orphan Medical. Dr. Montplaisir has received research support from Orphan Medical; and has received consulting fees and has participated in speaking engagements supported by Shire BioChem. Dr. Nevsimalova has received research support from Cephalon and Orphan Medical. Dr. Orr has received research support from Orphan Medical, AstraZeneca, Pfizer, Janssen, and Novartis; and has received speaking/consulting fees from Wyeth, AstraZeneca, Novartis, and Orphan Medical. Dr. Pascualy has received research support from Orphan Medical. Dr. Pegram has received research support

3 Xyrem Group from Sepracor and Orphan Medical. Dr. Perkins is a partner at Raiety Neurology; and participates in speaking engagements supported by Orphan Medical. Dr. Phadke has received research support from Orphan Medical. Dr. Ristanovic has received research support from and participated in speaking engagements supported by Orphan Medical. Dr. Shneerson has received research support from Orphan Medical. Dr. Stevens has received research support from and participated in speaking engagements supported by Orphan Medical. Dr. Swick has received research support from Orphan Medical, Cephalon, Sanofi-Aventis, Merck, and Takeda Pharmaceuticals; and has participated in speaking engagements supported by Orphan Medical and Cephalon. Dr. Walsleben has received research support from Orphan Medical; and is a consultant or speaker for Cephalon, Orphan Medical, GlaxoSmithKline, and Sepracor. Dr. Walter has received research support from Orphan Medical and Takeda; has participated in speaking engagements supported by Cephalon, GlaxoSmithKline, and Sanofi-Aventis; and is a partner in Columbus Sleep consultants. Dr. Ware has received research support from Orphan Medical. Dr. Winslow has received research support from GlaxoSmithKline, Takeda, Orphan Medical, Merck, Sanofi, Cephalon, Aventis, Altana, Pfizer, Neurocrine, Somaxon; and has participated in speaking engagements supported by Sanofi, Cephalon, and GlaxoSmithKline. Drs. Cook, Fleming, Hill, Lankford, Morehouse, Mosocovitch, and Whitten have indicated no financial conflicts of interest. The data are generated from research studies by Orphan Medical and are reviewed and analyzed by the authors. The paper was written and reviewed jointly by the authors. Submitted for publication March 18, 25 Accepted for publication June 29, 25 Address correspondence to: William C. Houghton, M.D., Jazz Pharmaceuticals, Inc., 318 Porter Drive, Palo Alto, CA 9434; Tel: (65) ; Fax: (65) ; contact@jazzpharma.com Among patients with narcolepsy, excessive daytime sleepiness (EDS) is a ubiquitous and sometimes the most debilitating symptom of the disease. During the 193s, pharmacotherapy for EDS in narcolepsy began with the introduction of ephedrine and benzedrine, and, today, psychomotor stimulants remain the most commonly used medications for the treatment of narcolepsy (for a brief review, see Mitler et al 1 ). In the most recently published standards of practice from the American Academy of Sleep Medicine, modafinil is considered to be the treatment standard, based on its superior safety profile in controlled studies; 2 however, amphetamine, methamphetamine, methylphenidate, and dextroamphetamine are considered to be mainstays of therapy for EDS despite the paucity of published trial data. 2 Although selegiline and pemoline are also considered efficacious for treating EDS, their use is limited by potentially dangerous interactions with dietary tyramine and hepatotoxicity, respectively. In the United States, only dextroamphetamine, methylphenidate, and modafinil are currently approved for the treatment of EDS in narcolepsy. The clinical benefit of these drugs for the treatment of EDS in narcolepsy has been objectively demonstrated by the use of the Maintenance of Wakefulness Test (MWT), producing improvement in sleep latency in most patients. Unfortunately, these improvements do not generally approach a normal degree of alertness. In a review of the available literature, the highest doses of stimulants tested only increased sleep latency to about 7% of normal. 3 Sodium oxybate is approved by the Food and Drug Administration for the treatment of cataplexy in patients with narcolepsy, and, unlike stimulants, sodium oxybate is taken at bedtime. Although the exact mechanism of action remains unknown, the nightly administration of sodium oxybate results in significant improvements in daytime cataplexy attacks. 4,5 In addition, the use of nocturnal sodium oxybate is associated with improvements in sleep architecture. 6 Of special interest are clinically meaningful decreases in EDS that have resulted from the nightly administration of sodium oxybate to patients with narcolepsy in two clinical trials. In a 4-week double-blind, placebo-controlled study, patients with narcolepsy who were randomly assigned to a nightly dose of 9 g of sodium oxybate showed significant improvement in EDS compared with patients receiving placebo. This was demonstrated by a significant decrease in median Epworth Sleepiness Scale (ESS) scores. This improvement in wakefulness occurred even though most patients remained on stable doses of stimulant medications during the trial. 4 During a 12-month open-label extension of the above trial, the median change in ESS scores improved even further, becoming significant across all doses after an additional 8 weeks of treatment and was maintained for the duration of the trial. 7 Because current stimulant therapies appear to be generally less than optimal for the treatment of narcolepsy, the following study was conducted to test the hypothesis that the nightly administration of sodium oxybate will effectively improve both objective and subjective measures of EDS in patients with narcolepsy. The effect of sodium oxybate on cataplexy in this patient population has been presented elsewhere. 8 Subjects METHODS Patients were included in the trial if they were 16 years of age or older and met the following criteria: a prior diagnosis of narcolepsy based on a overnight polysomnogram (PSG) and Multiple Sleep Latency Test (MSLT) performed within the previous 5 years; current symptoms of narcolepsy, including EDS, cataplexy, and recurrent sleep attacks almost daily for at least 3 months; evidence of adequate support for the duration of the trial, including transportation to and from the trial site; willingness to forgo operating a car or heavy machinery if indicated by the investigator; and agreement to complete the entire trial as described in the protocol by signing an informed consent. Women of child-bearing potential were required to use a medically accepted method of birth control unless surgically sterile or 2 years postmenopausal. The following criteria were used to exclude patients from the trial: use of sodium oxybate or any investigational therapy during the 3 days prior to trial entry; a diagnosis of sleep apnea or any other cause of daytime sleepiness; use of hypnotics, anxiolytics, sedating antihistamines, anticonvulsants, or clonidine at the start of the baseline period; the presence of any unstable disease that placed the patient at risk during the trial or compromised the study objectives; a current or recent history of a substance use disorder; a serum creatinine greater than 2. mg/dl, liver function tests more than twice the upper limit of normal, or serum bilirubin more than 1.5 times the upper limit of normal, or an abnormal electrocardiogram demonstrating clinically significant dysrhythmias; a history of myocardial infarction within the last 6 months; an occupation that requires variable shift work or routine night shifts; or a history of seizure disorder, head trauma, or past invasive intracranial surgery. In addition, patients were excluded from the study if the initial (Visit 2) PSG study indicated the presence of sleep apnea syndrome, defined as an apnea index of > 1 per hour, or and apnea-hypopnea index > 15 per hour. Journal of Clinical Sleep Medicine, Vol. 1, No. 4,

4 Dosing and Administration of Study Drug Trial medication was provided as a liquid oral solution containing sodium oxybate at a concentration of 5 mg/ml, while placebo consisted of a sodium citrate solution that was equimolar to the study drug with respect to sodium. Previous taste tests have indicated that the placebo solution is indistinguishable from the sodium oxybate solution (Orphan Medical, Inc., unpublished data on file). Study drug or placebo was administered in 2 equally divided doses each night. The first dose was consumed immediately before going to sleep, and the second dose was taken 2.5 to 4 hours later. To ensure that they awoke for their second dose, patients were encouraged to use an alarm clock. Patients were cautioned against the use of alcoholic beverages at any time during the trial. Similarly, patients were cautioned about the use of potentially sedating medications, such as opiate analgesics or skeletal muscle relaxants. All study subjects were encouraged to discuss the use of over-the-counter and prescription medicines for treatment of colds, flu, allergies, or headaches with the investigator. Although 78% of patients were taking central nervous system stimulants for the treatment of EDS, the dose of these medications was held constant throughout the trial. The most commonly used stimulates were modafinil (41.1%), methylphenidate (23.6%), and dextroamphetamine (18.7%). In addition, 14% of patients were using a dextroamphetamine/amphetamine combination product for the treatment of obesity. Subsequent analysis revealed that the use of stimulant medications was uniformly distributed across placebo and active-drug groups (range, 74.6%-83.6%). Study Design Following the initial clinic visit, patients recorded narcolepsy symptoms and adverse events associated with drug therapy for the treatment of narcolepsy symptoms in daily diaries during a 14-day lead-in period (see Figure 1). Following Visit 2, patients were gradually tapered from antidepressant medications or any other medication used for the treatment of cataplexy during a 21- day withdrawal period. This was followed by a washout period beginning at Visit 3, lasting 5 days or 5 times the half-life of the discontinued drug, whichever was longer, but not exceeding 18 days; however, if the patient was using fluoxetine, withdrawal was initiated at Visit 1 due to the very long elimination half-life of this medication and its active metabolite. Following the washout period, patients who continued to meet the inclusion criteria entered a 14-day baseline period (Visit 4), during which all patients received placebo in single-blind fashion, and a baseline assessment of narcolepsy symptoms was made. If the investigator believed the frequency of cataplexy attacks had not stabilized, the baseline period was extended to 21 days. To qualify for the double-blind phase of the study, each patient must have recorded an average of 8 or more cataplexy attacks per week during the baseline period. The dose-titration phase (Visit 5) was conducted as follows in randomized and double-blind fashion: Week 1: One fourth of the study patients received placebo, while three fourths received 4.5 g of sodium oxybate nightly. Week 2: One third of patients taking sodium oxybate remained at the 4.5-g dose, while two thirds increased their dose to 6 g nightly; two thirds of placebo patients increased the volume of their dose by an equivalent volume to match the 6-g dose. Journal of Clinical Sleep Medicine, Vol. 1, No. 4, Week 3: One half of patients taking 6 g of sodium oxybate remained at this dose, while the remaining half increased their dose to 7.5 g nightly; half of the patients taking the mock 6-g dose of placebo continued taking the same volume, while the remaining half increased the volume of their dose to match the 7.5-g dose. Week 4: All patients taking the 7.5-g sodium oxybate dose increased their dose to 9 g nightly, while the patients taking the mock 7.5-g dose increased the volume of their dose by an equivalent amount. Each subject returned to the clinic at Visit 6, at which time all study measures for efficacy were conducted and safety assessments were made. Patients then continued at their assigned dose for the remaining 28 days of the study before returning for the final efficacy and safety assessments at Visit 7. Efficacy Measures The ESS was administered at Visit 2 and repeated following the baseline period (Visit 5), after the 4-week titration period (Visit 6), and at the conclusion of the trial (Visit 7). A 4-minute MWT was conducted following nocturnal PSGs performed at Visits 2, 5, 6, and 7, according to validated standards. 9 Briefly, the MWT began at approximately 1: AM and consisted of four 4-minute tests, 2 hours apart. Patients were required to recline in a quiet, dimly lit, bedroom and instructed to remain awake for as long as possible. The trial was concluded after the onset of sleep or after 4 minutes if sleep did not occur. The onset of sleep was recorded using a standard PSG montage and defined as 3 consecutive 3- second epochs of stage 1 sleep or 3 seconds of sleep stage 2, 3, 4, or rapid eye movement sleep. Safety Measures Safety assessments were made at the beginning and end of the trial and included a physical examination and measurement of vital signs. A central laboratory was used for all clinical laboratory tests, which included hematology, clinical chemistry, and a serum pregnancy test, if applicable. Clinically significant laboratory parameters that were outside the reference range of the central laboratory were repeated. Finally, a 12-lead electrocardiogram was performed at Visit 1 and repeated at Visit 7 if clinically indicated. The trial investigators reported all adverse events that occurred during the trial until resolution of the event. In each case, the nature of the signs or symptoms, duration, severity, relationship to treatment or other therapy, any action taken, and the outcome of each event was reported. All patients who received trial medication during the double-blind phase but chose to discontinue the trial prior to completion were asked to provide a final measurement of vital signs and clinical laboratory tests before discontinuation. If the early termination was due to an adverse event, the patient was followed until satisfactory resolution and determination of outcome of the event was obtained. Statistics Sodium Oxybate Is Effective For Treating EDS Although adequate statistical power would be rendered by enrolling 16 patients in 4 groups, the study design planned for enrolling 2 patients. Statistical efficacy computations were performed on an intent-to-treat basis using patients who received trial drug and completed a posttreatment evaluation visit using

5 Xyrem Group the Statistical Analysis System (SAS Institute, Inc., Cary, NC). The test for a normality of data was performed using the Wilks- Shapiro test, and the homogeneity of the variability was examined graphically. The primary efficacy variables were the change in EDS from baseline to endpoint, as measured by the ESS and were analyzed using analysis of variance, and the significance of the mean change from baseline for each treatment group was determined using a paired t test. The Clinical Global Impression change (CGI-c) was analyzed using a logistic regression model. For all comparisons between the effect of sodium oxybate and placebo, statistical significance was established if a 2-sided p value was <.5. Safety analysis included all patients who receive at least 1 dose of double-blind medication. Ethics This trial was conducted in the United States, Canada, United Kingdom, Germany, France, Switzerland, the Netherlands, and the Czech Republic and was approved by the Institutional Review Board/Ethics Board of each participating trial center. Written informed consent was obtained from each patient prior to initiation of the study. This study was conducted in accordance with the ethical principles delineated in the Helsinki Declaration of 1975, as revised in RESULTS Of 41 patients enrolled in the trial, 228 entered the doubleblind phase of the trial: 149 (65.4%) were female and 79 (34.6%) were male. The average age was 4.5 years (range 16-75), average height was cm (range ), and average weight was 87.5 kg (range ); 196 patients were Caucasian, 25 were of African descent, 2 were Asian, 2 were Hispanic, and 2 were of other ethnic origins. An analysis among the 3 dose groups and placebo group indicated that the patients were evenly distributed with respect to the above demographic parameters. The study was completed by 29 of the 228 patients who entered the doubleblind treatment phase of the trial. Excessive Daytime Sleepiness EPWORTH SLEEPINESS SCALE Prior to being withdrawn from other medications used for the treatment of cataplexy (Visit 2), the patients reported a considerable degree of EDS. While remaining on stimulants medications, ESS scores ranged from 17 to 19 (normal < 1) across the 4 treatment groups and were essentially unchanged at the end of the baseline phase (Visit 5). At the end of the study (Visit 7), patients receiving sodium oxybate reported dosed-related decreases in median ESS scores, which were significant at all doses compared with baseline values (for each, p <.1; Table 1). When compared with placebo, the median decrease in ESS scores was significant in the 6-g and 9-g dose groups (for each, p <.1) at the end of the 8-week study period (Table 1 and Figure 2). Actual median ESS scores decreased from 19 to 15 in the 6-g dose group and from 19 to 12 in the 9-g dose group. FORTY-MINUTE MWT At Visit 2, patients displayed median MWT scores ranging from 8.63 to 9.56 minutes in patients assigned to receive sodium Table 1 Changes in measures of excessive daytime sleepiness following 8 weeks of sodium oxybate treatment Measurement Placebo Sodium Oxybate 4.5g 6g 9 g Epworth Sleepiness Scale Visit (59) 19. (63) 18. (58) 19. (45) Visit (58) 18. (61) 19. (58) 19. (47) Visit (57) 17. (63) 16. (54) 13. (41) Visit (57) 16. (63) 15. (51) 12. (38) Visit (58) -1. (61) -2. (55) -5. (43) (change from baseline) Within-group p =.137 p <.1 p <.1 p <.1 significance Significance, compared with placebo p =.93 p <.1 p <.1 Maintenance of Wakefulness Test Visit (59) 9.26 (64) 9.56 (58) 8.63 (47) Visit (59) 8.53 (62) 9. (57) 7.63 (47) Visit (56) 11.3 (64) 6.75 (54) 17.5 (41) Visit (55) (63) 6. (51) (36) Visit 7. (57) 1.75 (62) 1. (53) 1.13 (41) (change from baseline) Within-group p =.888 p =.1 p =.335 p <.1 significance Significance, compared with placebo p =.11 p =.52 p <.1 Weekly Inadvertent Naps Visit (58) (64) 17.5 (58) (46) Visit (58) (64) 18. (58) 14. (46) Visit (56) (61) 12.5 (54) 1.17 (4) Visit (55) (61) 14. (53) 8.5 (43) Visit (58) (62) -6.5 (57) -6. (45) (change from baseline) Within-group p =.215 p <.1 p <.1 p <.1 significance Significance, compared with placebo p =.99 p <.1 p =.2 Data are presented as median (number). Visit 2 took place prior to patients being tapered from any existing anticataplectic medications; Visit 5, at the end of the 2-week baseline period; and Visit 7, following 8 weeks of treatment. oxybate, while the median MWT score in patients assigned to receive placebo was minutes (Table 1); however, MWT results became more uniform at the end of the baseline period (Visit 5). At the end of the trial, patients receiving 4.5 g of sodium oxybate displayed an increase of 1.75 minutes in the MWT, which was significant compared with baseline (p =.1); patients receiving the 9-g dose displayed a robust median increase of more than 1 minutes in the MWT, which was significant when compared with baseline as well as with placebo (for each, p <.1; Table 1), whereas there was no statistical change in the median MWT score in patients receiving the 6-g sodium oxybate dose. WEEKLY INADVERTENT NAPS (SLEEP ATTACKS) The median frequency of weekly sleep attacks decreased in a dose-related fashion. At the end of the trial, this improvement was Journal of Clinical Sleep Medicine, Vol. 1, No. 4,

6 Sodium Oxybate Is Effective For Treating EDS significant across all doses compared with the median frequency of events occurring at baseline. Compared with placebo, these changes were significant in the 6-g (p <.1) and 9-g (p =.2) dose groups (Table 1). CLINICAL GLOBAL IMPRESSION OF SEVERITY AND CGI-C At the end of the baseline period (Visit 5), the Clinical Global Impression of Severity (CGI-s) indicated that most patients (82%) were described by the investigators as moderately or markedly ill. Following 8 weeks of nightly sodium oxybate administration, a prehoc responder analysis indicated that 5% (p =.1), 51.7% (p <.1), and 63.8% (p <.1) of patients were reported to be either Much Improved or Very Much Improved by the trial investigators at the 4.5-g, 6-g, and 9-g doses, respectively, compared with 22% in placebo-treated patients (Table 2). Lead in Visit 1 2 Withdrawal from anticataplectic therapy Washout Baseline Dose titration Stable dosing SODIUM OXYBATE g R A N D O 6. g 14d 21d 5-18d M I 14-21d 7d 7d 7d 7d 28d 4.5 g Z A mock 4.5g T I mock 6.g O N mock 9. g PLACEBO Figure 1 The study was performed as follows: baseline cataplexy frequency was recorded during the 2-week lead-in phase. Subsequently, anticataplectic medications were withdrawn over a 21-day period following Visit 2 with the exception of fluoxetine, which was withdrawn following Visit 1. The washout period was 5 days or 5 times the half-life of the withdrawn medication, whichever was longer but did not exceed 18 days. Following randomization, patients were started on placebo in single-blind fashion and recorded baseline cataplexy occurrences over a 14-day period which was extended to 21 days if the investigator believed cataplexy had not yet stabilized. Patients initiated treatment with study medication or placebo and were titrated to their final dose, as shown. ESS, MWT and narcolepsy symptom assessments were performed at Visits 2, 5, 6 and Safety Twenty-one patients discontinued the trial due to an adverse event in the placebo (n=1), 4.5-g (n=1), 6-g (n=4), and 9-g (n=15) dose groups, and only 14 unique events occurred with a frequency significantly greater than placebo; however, some patients assigned to the 6-g and 9-g dose groups discontinued during the titration phase and did not actually reach their assigned dose. Adverse events with greater than 5% incidence included nausea, dizziness, and enuresis, which appeared to be dose related. Events occurring with a less than 5% incidence included feeling drunk (n=2), contusion (n=3), back pain (n=5), muscle cramp (n=4), somnolence (n=8), disturbance in attention (n=6), dysarthria (n=2), tremor (n=2), disorientation (n=5), sleep walking (n=3), dyspnea (n=5), and snoring (n=4). Six serious adverse events were reported during the study; however, 3 occurred in patients receiving placebo medication. Of the remaining 3, 1 event involved a patient with pneumonitis and was considered unrelated to sodium oxybate. Another patient suffered a fractured ankle following an accidental fall. In this case, the relationship to study medication was reported to be unknown. The third patient was found to have abnormal amino alanine Figure 2 Compared to baseline, the nightly administration of sodium oxybate was associated with dose-related improvements in Epworth Sleepiness Scale scores at the end of the 8-week trial. * denotes p <.1 compared to placebo. Table 2 Clinical Global Impression of Severity and Change Following 8 Weeks of Sodium Oxybate Treatment CGI-s: Baseline Severity Normal no signs of illness Borderline Ill Slightly Ill Moderately Ill Markedly Ill Among the Most Extremely Ill CGI-c Change at Week 8 Normal Very Much Improved Much Improved Minimally Improved No Change Minimally Worse Much Worse Very Much Worse Placebo Sodium Oxybate (n=59) 4.5 g (n=64) 6 g (n=58) 9 g (n=47) Total (n=228) 1 (1.7) 3 (5.1) 25 (42.4) 25 (42.4) 5 (8.5) 5 ( 8.5) 8 (13.6) 12 (2.3) 26 (44.1) 4 (6.8) 3 (5.1) Data are presented as numbers of patients (%). CGI refers to Clinical Global Impression. 5 (7.8) 24 (37.5) 28 (43.8) 7 (1.9) 1 (15.6) 22 (34.4) 21 (32.8) 9 (14.1) 1 (1.6) 2 (3.4) 4 (6.9) 24 (41.4) 25 (43.1) 3 (5.2) 1 (1.7) 14 (24.1) 16 (27.6) 13 (22.4) 8 (13.8) 2 (3.4) 1 (1.7) 5 (1.6) 12 (25.5) 24 (51.1) 5 (1.6) 18 (38.3) 12 (25.5) 4 (8.5) 3 (6.4) 1 (2.1) 3 (1.3) 17 (7.5) 85 (37.3) 12 (44.7) 2 (8.8) 1 (.4) 47 (2.6) 58 (25.4) 5 (21.9) 46 (2.2) 6 (2.6) 6 (2.6) Journal of Clinical Sleep Medicine, Vol. 1, No. 4,

7 Xyrem Group Figure 3 Patients who were judged to be Much Improved and Very Much Improved comprised 5.%, 51.7% and 63.8% of patients receiving 4.5, 6. and 9.g sodium oxybate, respectively. These improvements were significantly greater than placebo-treated patients reporting 22.% improvement. * denotes p =.1 and ** denotes p <.1 compared to placebo. transferase and aspartate amino transferase levels at the conclusion of the trial, becoming normal approximately 8 months later. This event was believed to be possibly due to sodium oxybate. These events are described in greater detail elsewhere. 8 DISCUSSION Journal of Clinical Sleep Medicine, Vol. 1, No. 4, The use of sodium oxybate for the treatment of narcolepsy has previously been associated with diminished EDS. The earliest studies conducted with sodium oxybate for the treatment of narcolepsy included subjective patient reports of increased ability to stay awake during the day and a lessened severity of sleep attacks. 1 Small uncontrolled studies on the effects of sodium oxybate for EDS demonstrated significant reductions in daytime naps and sleep attacks compared with baseline. 11 Placebo-controlled pilot studies also showed that sodium oxybate significantly decreased daytime sleep attacks and the severity of EDS 12 although objective measures of EDS as measured using the MSLT in small patient populations had not been clearly demonstrated in the currently used dosing range. 12,13 More recently, the use of the ESS, a validated self-administered questionnaire, 14 has become widely accepted as a subjective measure of patient EDS. In 1 double-blind, placebo-controlled study, nightly doses of 3 g, 6 g, or 9 g of sodium oxybate or placebo were randomly assigned to 136 narcolepsy patients, and changes in EDS were assessed using ESS at the beginning and end of the 4-week trial. Compared with placebo, ESS scores improved in a dose-related manner in patients receiving sodium oxybate, becoming significant at the 9-g dose. A decrease in the median score from 17. to 12. at the 9-g dose demonstrates that the subjective degree of sleepiness improved to normal for some patients. This improvement occurred even though 113 of 136 patients enrolled in the study (83%) remained on stable doses of stimulant medications throughout the trial; that is, sodium oxybate provided incremental improvement in EDS beyond that achieved with stimulant medications. 4 In a 12-month open-label extension of the above study, the median change in ESS scores was significant across all doses after 8 weeks of treatment with sodium oxybate, and the improvement in EDS was maintained for the duration of the trial. 7 In an open-label pilot study comprising 21 narcolepsy patients, treatment with 4.5 g of sodium oxybate nightly also resulted in a significant increase in a mean sleep latency of 3.7 minutes in the 2-minute MWT compared with the mean baseline value of 4.5 minutes; subsequent titration to 9 g of sodium oxybate nightly resulted in a mean increase of 6.1 minutes. Significant dose-related improvements in ESS scores were documented during the same period. Similar to previous trials, the decrease in EDS produced by the administration of sodium oxybate was incremental to that produced by concurrent stimulant medications. 6 The present study examined the effect of sodium oxybate on both subjective and objective measures of EDS and represents the largest sodium oxybate study for the treatment of narcolepsy to date. These results confirm earlier reports that nightly treatment with sodium oxybate results in patient reports of significantly diminished daytime sleepiness, as measured by decreased ESS scores 4,6,7 and significant reductions in inadvertent naps or sleep attacks. 11,12 As previously reported in sodium oxybate trials, this incremental improvement in EDS occurred despite the fact that the majority of patients were already taking stimulant medications. Current stimulant therapy for EDS is therefore less than optimal, and the combined use of sodium oxybate with traditional stimulants provides the prospect of greater efficacy for the treatment of EDS. The MWT, which measures the inability of patients to remain awake under sleep-inducing conditions, is often used to measure the efficacy of medications for the treatment of EDS, including patients with narcolepsy. 3 In an open-label pilot study, the nightly administration of sodium oxybate at doses of 4.5 g and 9 g in 21 patients resulted in significant improvements in MWT scores after 4 and 1 weeks of treatment, compared with baseline. 6 Similarly, 4.5-g and 9-g doses produced significant improvements in MWT scores compared with baseline in the current study. The improvements in MWT, which occurred in patients receiving 9 g of sodium oxybate nightly, were extremely robust compared with placebo and compare favorably with the improvements reported in narcolepsy patients taking 4 mg to 6 mg modafinil daily. 15 In the largest sodium oxybate study to date, these data support previous results indicating that the nightly administration of sodium oxybate is associated with significant improvements in EDS. Because sodium oxybate already has proven efficacy for the treatment of cataplexy, we propose that sodium oxybate provides added benefit for the treatment of EDS for many patients with narcolepsy. The clinical evaluation of sodium oxybate for the treatment of EDS is ongoing. ACKNOWLEDGEMENTS The members of the Xyrem International Study Group are: Mansoor Ahmed, MD, Cleveland Sleep Center, Middlebrook Heights, OH; Philip Becker, MD, Sleep Medicine Association of Texas, Plano, TX; Michael Biber, MD, Center for Sleep Diagnostics, Newton, MA; Jed Black, MD, Stanford Sleep Disorders Clinic, Stanford, CA; Richard Bogan, MD, Palmetto Baptist Medical Center, Columbia, SC; Andrew Chesson, Jr, MD, Louisianan State University Sleep Disorders Center, Shreveport, LA; James Cook, MD, The Center for Sleep & Wake Disorders, Danville, IN; Stephen Duntley, MD, Washington University Medical Center, St. Louis, MO; Helene Emsellem, MD, Center for Sleep & Wake Disorders, Chevy Chase, MD; Milton Erman, MD and Roza Hayduk, MD, Pacific Sleep Medicine Services, La Jolla, CA; Neil Feldman, MD, St. Petersburg Sleep Disorders Center, St. Petersburg, FL; John Fleming, MD, Vancouver Hospital, Vancouver, British Columbia, Canada; Peter Geisler, MD, Psy-

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