Download A Randomized, Double Blind, Placebo

NARCOLEPSY
A Randomized, Double Blind, Placebo-Controlled Multicenter Trial Comparing the
Effects of Three Doses of Orally Administered Sodium Oxybate with Placebo for
the Treatment of Narcolepsy
The U.S. Xyrem Multicenter Study Group
Study Objectives: To evaluate and compare the efficacy and safety of
three doses of sodium oxybate and placebo for the treatment of narcolepsy symptoms.
Design: A multicenter, double blind, placebo-controlled trial.
Setting: N/A
Participants: Study subjects were 136 narcolepsy patients with 3 to 249
(median 21) cataplexy attacks weekly.
Interventions: Prior to baseline measures, subjects discontinued anticataplectic medications. Stable doses of stimulants were permitted.
Subjects were randomized in blinded fashion to receive 3, 6, or 9 g doses
of sodium oxybate or placebo taken in equally divided doses upon retiring
to bed and 2.5-4 hours later for 4 weeks.
Measurements and Results: Disease symptoms and adverse events
were recorded in daily diaries. The primary measure of efficacy was the
change from baseline in weekly cataplexy attacks. Secondary measures
included daytime sleepiness using the Epworth Sleepiness Scale (ESS),
inadvertent daytime naps/sleep attacks and nighttime awakenings.
Investigators assessed changes in disease severity using Clinical Global
Impression of Change (CGI-c). Compared to placebo, weekly cataplexy
attacks were decreased by sodium oxybate at the 6 g dose (p=0.0529)
and significantly at the 9 g dose (p=0.0008). The ESS was reduced at all
doses, becoming significant at the 9 g dose (p=0.0001). The CGI-c
demonstrated a dose-related improvement, significant at the 9 g dose
(p=0.0002). The frequency of inadvertent naps/sleep attacks and the
nighttime awakenings showed similar dose-response trends, becoming
significant at the 9 g dose (p=0.0122 and p=0.0035, respectively).
Sodium oxybate was generally well-tolerated at all three doses. Nausea,
headache, dizziness and enuresis were the most commonly reported
adverse events.
Conclusions: Sodium oxybate significantly improved symptoms in
patients with narcolepsy and was well tolerated.
Key words: Sodium oxybate; gamma hydroxybutyrate; narcolepsy; cataplexy
cult to identify, considerably fewer patients are actually diagnosed and treated. The primary cause remains unknown; however, recent human and animal data has provided strong evidence
that the pathophysiology of narcolepsy involves the neuropeptide
hypocretin (orexin).4 Hypocretin-containing neurons are found
in the lateral hypothalamus where they project to various parts of
the brain including nuclei believed to regulate sleep. Disrupting
hypocretin neurotransmission, either at the level of the neurotransmitter5 or the receptor,6 results in animals exhibiting many
of the classic symptoms of narcolepsy. This is supported by the
fact that hypocretin is undetectable in cerebrospinal fluid in a
large percentage of patients with narcolepsy.7 In addition, postmortem examination of brains from narcoleptics revealed a 85%95% decrease in hypocretin-containing cells.8
The excessive sleepiness associated with narcolepsy is commonly treated with stimulants, such as methylphenidate or dextroamphetamine,9 or with the wakefulness-promoting agent
modafinil.10 While they improve daytime sleepiness and diminish cataplexy to a limited extent, they are not considered a principal treatment for cataplexy. The REM-related symptoms of
cataplexy, sleep paralysis and hypnagogic hallucinations are typically treated with antidepressants of the tricyclic (TCA) or selective serotonin reuptake inhibiting (SSRI) classes.9 Hypnotics are
sometimes prescribed to help maintain sleep at night.
Unfortunately, there are disadvantages to these therapies as
well. Tolerance to continuous stimulant therapy has been well
established and their benefits may wane over time.9 The abrupt
withdrawal of TCAs or SSRIs may result in a marked rebound of
the REM-related symptoms.9,11 Most importantly, these conventional treatments do nothing to restore the integrity of sleep in
INTRODUCTION
NARCOLEPSY IS A DEBILITATING, LIFE-LONG CENTRAL
NERVOUS SYSTEM DISORDER WHICH MAY FOLLOW A
VARIABLE CLINICAL COURSE AND INCLUDE AN
ARRAY OF SEEMINGLY UNRELATED SYMPTOMS.
Narcolepsy usually begins with excessive daytime sleepiness and
sleep attacks during the second and third decades of life. Other
symptoms of the disease, including cataplexy, sleep paralysis and
hypnagogic hallucinations may follow later. These added symptoms reflect the intrusion of REM sleep and its atonic motor
component into normally wakeful periods. In time, sleep fragments and variable periods of non-REM and REM sleep may
drift around the clock, alternating with periods of wakefulness.1,2
Although there are no universally accepted figures, the most
commonly used estimate for the prevalence of narcolepsy in the
general population is about 0.05%.3 As narcolepsy may be diffi-
Disclosure Statement
None of the U.S. Xyrem Multicenter Study Group Members have any significant
financial involvement in any organization with a direct commercial interest in
the subject discussed in the submitted manuscript. The research involved in
this manuscript involves the use of an Investigational New Drug. This study
was sponsored by Orphan Medical, Inc., Minnetonka, MN.
Submitted for publication: August 2001
Accepted for publication November 2001
Address correspondence to: H. Cook, Orphan Medical, Inc., 13911 Ridgedale
Drive, Suite 250, Minnetonka, MN 55305; Tel: 888-867-7426;
Fax: 952-541-9209; E-mail: [email protected]
SLEEP, Vol. 25, No. 1, 2002
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Placebo-Controlled Multicenter Trial—U.S. Xyrem Multicenter Study Group
narcoleptic patients.12
The administration of sodium oxybate, a unique endogenous
neurotransmitter/neuromodulator,13 has been shown to improve
the symptoms of narcolepsy and be well tolerated by patients. Its
nocturnal administration appears to consolidate both REM and
NREM sleep and diminish fragmented nighttime sleep14,15,16,17
resulting in improved daytime performance.14,15,16 To date, many
narcolepsy patients have participated in numerous clinical trials
with this agent.16,17,18,19 Two of these were small double blind,
placebo-controlled crossover studies in which narcolepsy
patients received nightly divided doses of 50-60 mg/kg for
approximately one month. In both trials, sodium oxybate showed
promise as a treatment of narcolepsy. GHB improved sleep quality and continuity,17,19 improved daytime sleepiness and
decreased REM-related symptoms.19
Long-term experiences with open trials of sodium oxybate
lasting as long as 20 months have also been described.15,20,21
These long-term studies demonstrated that sodium oxybate therapy alleviated the signs and symptoms of narcolepsy with no evidence of tolerance in doses ranging from 2.5 g-7 g nightly.
The objectives of the present study were to evaluate and compare the safety and efficacy of three doses of sodium oxybate and
placebo for the treatment of symptoms associated with narcolepsy.
This washout period was used to train and habituate patients to
the use of daily diaries. Patients were permitted to remain on
stimulant medications provided stable doses were used beginning
five days prior to baseline and continuing until the end of the
trial. Of the 136 patients entering the trial, 113 (83.1%) remained
on a stable dose of stimulant. Those patients not taking previous
medications entered baseline following the five-day washout
period. During a subsequent 14-21 day baseline period, patients
recorded the frequency of cataplexy and other specified symptoms of narcolepsy in daily diaries.
The daily patient diaries were developed with input from the
FDA and included detailed descriptions of the symptoms to be
recorded by each patient should they occur. Patients were
instructed on the use of diaries by study coordinators and investigators and captured information on the primary outcome measures. These included the frequency of cataplexy events, number
and duration of nocturnal awakenings, total amount of sleep each
night, the number of hypnagogic hallucinations, and the incidence of sleep paralysis. In addition, they were used to document
the occurrence of all adverse events. Patients were encouraged to
utilize the daily diary every morning and evening. The use of
daily diaries has previously been shown to be a satisfactory
means for collecting patient response information in sleep
medicine studies.22
Most patients exhibited moderate to severe cataplexy; however, a minimum of three cataplexy attacks per week during the last
two weeks of the baseline period was required to enter the double-blind treatment phase of this study.
At the beginning of the four-week treatment period, each
patient randomly received 3, 6, or 9 g sodium oxybate or placebo nightly without titration. Sodium oxybate or placebo was
administered in equally divided doses immediately upon retiring
to bed and 2.5-4 hours later. When necessary, patients were
encouraged to use an alarm clock to insure waking for the second
nightly dose of sodium oxybate. Each patient received a telephone call from a trial center study coordinator after their first
night on medication and three times weekly thereafter during the
trial. All patients returned to their trial center after two and four
weeks of treatment. Compliance with study protocol was assured
by comparing the amount of medication remaining at each visit
with the amount predicted to remain if the patient were compliant. Clinical assessments were conducted at the end of the fourweek trial period and three to five days after the study medication
was discontinued. Patients who successfully completed this double-blind study were given the opportunity to enter a long-term
open-label sodium oxybate trial.
Daytime somnolence was assessed using the Epworth
Sleepiness Scale (ESS) at study baseline and endpoint. The overall severity of disease was measured at baseline using the Clinical
Global Impression of Severity (CGI-s) measure. The change in
disease severity was assessed at endpoint with the Clinical
Global Impression of Change (CGI-c) measure. During the
study, patients used personal diaries to record the number of cataplexy attacks, number and duration of nocturnal awakenings,
the total amount of sleep each night, the number of hypnagogic
hallucinations, the incidence of sleep paralysis and adverse
events.
Safety assessment was conducted by reviewing daily diary
entries, interviewing patients regarding possible adverse events,
clinical laboratory studies, electrocardiogram and changes in
METHODS
Subjects
This study included previously diagnosed narcolepsy patients
who were 18 years of age or older and expressed a willingness to
complete the entire study. Diagnostic criteria included a valid
polysomnogram (PSG) within the previous five years and a current diagnosis of narcolepsy for at least six months based on criteria established by the American Sleep Disorders Association.
This study excluded patients who were: diagnosed with sleep
apnea or had coexisting causes of daytime sleepiness; taking hypnotics, anxiolytics, antidepressants (for depression), antihistamines, clonidine, or anticonvulsants; at risk of pregnancy;
experiencing unstable disease states which placed them at risk
during the study or any history of seizure disorder; history of psychiatric disorders which would preclude them from completing
the study; at risk of substance abuse because of current or recent
history of chemical dependency; shown to have serum creatinine
greater than 2.0 mg/dL, aminotransferase values more than twice
normal or a serum bilirubin more than 1.5 times normal; shown
to have an abnormal electrocardiogram or history of recent
myocardial infarction; taking medication for their narcolepsy
other than a stable dose of stimulant for treating excessive daytime sleepiness; working in an occupation requiring variable
shifts or routine night shifts.
Treatments
Following an initial screening visit, patients discontinued hypnotic medications and, over a four-week period, gradually withdrew from medications previously used to treat cataplexy symptoms to avoid rebound phenomena. This was followed by a fiveday washout period or five times the half-life of the discontinued
anticataplectic medication up to 28 days, whichever was longer.
SLEEP, Vol. 25, No. 1, 2002
43
Placebo-Controlled Multicenter Trial—U.S. Xyrem Multicenter Study Group
Median change in cataplexy attacks per
week from baseline to endpoint
5
0
-5
-10
-15
-20
-25
-30
-35
-40
Placebo
3g
6g
9g
Figure 1—Median change in weekly cataplexy attacks at the end of the 4-week trial period (* denotes p=0.0008). For placebo, 3, 6 and 9 g groups, the median
changes in the frequency of cataplexy attacks were –4.3, -7.0, -9.9 and –16.1, respectively. This change was significant across doses (p=0.0021), indicating a doserelated effect.
Median percent change in cataplexy
0
-10
-20
Placebo (-28)
-30
-40
3g (-49)
-50
-60
6g (-49)
-70
9g (-69)
*
-80
0
2
Time (weeks)
4
Figure 2—Median percent change from baseline for cataplexy attacks per week, by sodium oxybate dose. This change was significantly different across doses
(p=0.021) and was significant at the 9 g dose (* denotes p=0.0008). These data also demonstrate the greatest improvement occurred during the first two weeks of
therapy.
placebo was performed using least-squares means with Dunnet’s
adjustment. The significance of the median change from baseline
for each treatment group was assessed using a paired t-test.
Those measures that did display a normal distribution without log
transformation included Epworth Sleepiness Scale, total amount
of nighttime sleep, and number of inadvertent naps/sleep attacks
per day. For these measures, the analysis was conducted on
untransformed values. The CGI-c was assessed using CochranMantel-Haenszel Tests for Nonzero Correlation between the
CGI-c score and treatment. For all measures, a level of significance was established at p<0.05.
physical condition.
Statistical Analysis
The planned analysis called for ANOVA on the change from
baseline to endpoint done on the intent-to-treat population. In
addition, ANCOVA was planned for the primary efficacy variable
(change in frequency of cataplexy attacks) using the baseline
value as the covariate. In the event that the assumptions for
ANCOVA were not satisfied, the planned analysis included logtransformation to provide a more normal distribution of the data.
At the time of analysis, the Wilk-Shapiro test for normality
indicated several measures required log transformation. These
included the total number of cataplexy attacks, daily episodes of
sleep paralysis and hypnagogic hallucinations, and number of
nighttime awakenings. Comparison of sodium oxybate dose to
SLEEP, Vol. 25, No. 1, 2002
Ethics Statement
The Institutional Review Board for each of the 18 trial centers
approved the protocol. Written informed consent was obtained
44
Placebo-Controlled Multicenter Trial—U.S. Xyrem Multicenter Study Group
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 1997.
significance at the 6 g dose (p=0.0529) becoming highly significant at the 9 g dose (p=0.0008) when compared to placebo.
RESULTS
Daytime Sleepiness
There were 136 patients enrolled in the study: 57 (41.9%)
were male and 79 (58.1%) were female. The mean age was 43.1
years, mean height 170.9 cm and mean weight 82.9 kg.
Caucasians comprised 124 (91.2%) of the patients, AfricanAmericans 9 (6.6%), Asians 1 (0.7%) and Other 2 (1.5%). At
baseline, the frequency of weekly cataplexy attacks ranged from
3-249 (median 21). The study was completed by 120 (88%)
patients.
The demographics of each dose group were well balanced and
there were no significant between-group differences except the 6
g group, which had a higher percentage of male (63.6%), and correspondingly taller, patients. There were no significant differences in the frequency of cataplexy, hypnagogic hallucinations,
sleep paralysis, or inadvertent naps/sleep attacks between the different treatment groups during the three-month screening period
or during baseline measures. At that time, cataplexy, excessive
daytime sleepiness, and inadvertent sleep attacks occurred in virtually all patients.
The ESS improved in all of the sodium oxybate treatment
groups in a dose-related manner, becoming significant at the 9 g
dose (p=0.0001) when compared to placebo. This improvement
in wakefulness occurred even though the majority of patients
remained on stable doses of stimulant medications. The median
score at the 9 g dose dropped from 17.0 to 12.0, indicating that,
for some patients at this dose, the subjective measure of sleepiness fell into the normal range (Epworth Scale <10).23 The data
from all groups are graphically presented in Figure 3.
Clinical Global Impressions of Change (CGI-c)
The Clinical Global Impression of Change from baseline
assessment of severity exhibited a significant difference across
doses (p=0.0014), suggesting a dose-related response that
became significant at 9 g (p=0.0002). These data are presented
graphically in Figure 4. At the 9 g dose, 24 of 30 patients (80%)
were either Much Improved or Very Much Improved after four
weeks of nightly sodium oxybate therapy compared to 11 of 34
(32.4%) in the placebo group.
Efficacy
Cataplexy
Other Parameters
The baseline and endpoint cataplexy values for placebo and
the three doses of sodium oxybate are shown in Figure 1. The
administration of nightly sodium oxybate produced a decrease in
the reported frequency of cataplexy attacks. Figure 2 also illustrates that this change was significant across doses (p=0.0021),
representing a dose-related effect. This improvement approached
There was a significant reduction in the number of inadvertent
naps/sleep attacks seen at both 6 g and 9 g doses of sodium oxybate (p=0.0497 and p=0.0122, respectively). The 9 g dose also
produced a significant decrease in nocturnal awakenings
(p=0.0035). For each of these symptoms there was evidence of a
dose-response relationship.
The incidence of sleep paralysis
Placebo
24
B
22
E
3.0g
B
E
6.0g
B
E
9.0g
B
E
Epworth Sleepiness Score
20
18
Narcolepsy
Range
16
14
12
10
8
Normal
Range
6
Figure 3—Median change from baseline to endpoint in daytime subjective sleepiness represented by Epworth Sleepiness Scale (ESS), by sodium oxybate dose. The
ESS improved in all of the sodium oxybate treatment groups, becoming significant at the 9 g dose (* denotes p=0.0001). The whiskers represent the first and third
quartiles. Thus, 25% of patients fall into in the normal range (Epworth Scale <10) for the 6 and 9 g groups.
SLEEP, Vol. 25, No. 1, 2002
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Placebo-Controlled Multicenter Trial—U.S. Xyrem Multicenter Study Group
Clinical global impression of change (%)
100
90
80
70
60
50
40
30
20
10
0
Placebo
3g
6g
9g
Figure 4—Percent change from baseline to endpoint in Clinical Global Impression of Change (CGI-c). The CGIC-c exhibited a significant difference across doses (p
= 0.0014). At the 9 g dose, 24 of 30 patients (80%) were either Much Improved or Very Much Improved after 4 weeks of nightly sodium oxybate therapy (* denotes
p = 0.0002).
Table 1—Adversie events by costart term
Body System
Costart Term
Body as a whole
Headache
Infection
Pain
Digestive
Vomit
Nausea
Nausea vomit
Diarrhea
Nervous
Anxiety
Confusion
Dizziness
Dream abnormality
Sleep Disorder
Thinking Abnormal
Skin and appendages
Sweat
Urogenital
Incontinence, urine
Dysmenorrhea
Placebo (N = 34)
3 gm (N=34)
6 gm (N= 33)
9 gm (N=35)
p-value
7 (20.6%)
1 (2.9%)
2 (5.9%)
3 (8.8%)
3 (8.8%)
3 (8.8%)
5 (15.2%)
5 (15.2%)
4 (12.1%)
11 (31.4%)
0
7 (20.0%)
0.1141
0.0338
0.3382
0
2 (5.9%)
0
0
0
2 (5.9%)
0
0
2
5
2
2
(6.1%)
(15.2%)
(6.1%)
(6.1%)
4 (11.4%)
12 (34.3%)
2 (5.7%)
2 (5.7%)
0.0475
0.0045
0.2594
0.2595
1
1
2
0
1
0
1
3
8
0
2
1
0
1 (3.0%)
10 (30.3%)
3 (9.1%)
4 (12.1%)
0
2 (5.7%)
5 (14.3%)
12 (34.3%)
1 (2.9%)
5 (14.3%)
2 (5.7%)
0.9021
0.2779
0.0178
0.0549
0.3195
0.6167
(2.9%)
(2.9%)
(5.9%)
(2.9%)
(2.9%)
(8.8%)
(23.5%)
(5.9%)
(2.9%)
0
1 (2.9%)
1 (3.0%)
4 (11.4%)
0.1567
0
1 (2.9%)
0
3 (8.8%)
2 (6.1%)
5 (15.2%)
5 (14.3%)
0
0.0143
0.0338
Selected adverse events by Coding Symbols for the Thesaurus of Adverse Reactions Terms (COSTART) term and sodium oxybate treatment group.
Adverse events occurring with statistical significance (p<0.05) across doses are highlighted; term "incontinence, urine" actually reported as enuresis in
most instances; term "sleep disorder" included prolonged sleep paralysis, sleep walking, poor sleep maintenance/frequent arousal, and microsleep.
and hypnagogic hallucinations ranged from 74%-76% and 74%85%, respectively, across treatment groups. Although there was
significant improvement within each treatment group receiving
sodium oxybate (p=0.05), these improvements were not significant compared to placebo.
SLEEP, Vol. 25, No. 1, 2002
Safety
Adverse Events
Most adverse events occurred within the first few days following the start of treatment and tended to decrease over time.
Of the 16 patients who did not complete the trial, ten patients
withdrew from the study due to the occurrence of an adverse
event. All but one was considered to be mild or moderate in
severity.
46
Placebo-Controlled Multicenter Trial—U.S. Xyrem Multicenter Study Group
Total number of weekly
cataplexy attacks 6g dose group
350
300
250
200
150
100
50
0
0
2
Time (weeks)
4
Figure 5—Mean change in cataplexy attacks per week by individual patients at the 6 g sodium oxybate dose exhibiting the aberrant effect seen in one patient.
The adverse events believed to be related to sodium oxybate
that occurred at a significant level and in a dose-related fashion
included nausea, vomiting, dizziness, and enuresis (for each
p<0.05). Adverse events are summarized in Table 1. Enuresis
was reported as 15 single events in 8 of the 136 patients in the
trial. One patient in the 6 g treatment group experienced a serious adverse event consisting of an acute confusional state. This
occurred less than one week following the initiation of therapy,
occurred in the afternoon following nighttime dosing on the previous evening and despite the extremely short half-life of the
study medication. The patient was treated and recovered. The
patient was discontinued from the study medication.
During the three to five day washout period at the conclusion
of the trial, there was an increase in the mean number of cataplexy attacks occurring in each treatment group, including placebo (actual numbers were extrapolated to seven days). A significant increase was seen in the 6 g group where the median number of cataplexy attacks increased from 8.0 to 16.3 (p=0.0001)
but did not approach the mean baseline value of 23.0. A similar
change was seen in the 9 g dose, increasing from 8.0 to 14.0
(p=0.0017; median at baseline 23.5).
DISCUSSION
Efficacy
The data from this double-blind placebo-controlled study
demonstrate that 3 to 9 g doses of sodium oxybate, taken nightly
in equally divided doses at bedtime and repeated 2.5-4 hours
later, produced clinical improvement in the symptoms of narcolepsy. These improvements occurred even though the dose of
sodium oxybate each patient received was randomly assigned
without consideration of patient size or severity of symptoms.
Most importantly, sodium oxybate decreased the frequency of
cataplexy, the primary outcome measure in this study. This effect
was seen at the 3 g dose but became much more apparent at the
6 g and 9 g doses. This improvement in cataplexy is in agreement
with several other studies, which have also demonstrated significant improvement in cataplexy after nightly administration of
sodium oxybate (GHB).15,16,17,19
A single patient in the 6 g treatment group who reported 249
cataplexy attacks during the week of baseline measures, and 332
and 346 attacks after two and four weeks of therapy, respectively, seriously skewed the results as demonstrated in Figure 5. The
patient may have been experiencing REM-rebound following
discontinuation of prior anticataplectic medication. Re-evaluation of these results after removing this single patient from the
data significantly altered the median number of cataplexy attacks
to 7.75 (p=0.0327) at the 6 g dose. This modification results in
data that are more consistent with previous reports where total
nightly sodium oxybate doses of 50-60 mg/kg, corresponding to
approximately 4.2 g or 4.7 g nightly, produced significant
improvement in daytime cataplexy.17,19
Over the four-week treatment period, sodium oxybate in
nightly 6g and 9g doses significantly improved daytime somnolence as reported by study patients and measured by the ESS.
These doses also significantly reduced the reported number of
inadvertent naps/sleep attacks during the day. It is noteworthy
that these improvements occurred while patients remained on stable doses of stimulant medications.
Laboratory Abnormalities
The administration of sodium oxybate appeared to have no
measurable effect on serum electrolytes, hematological measures, hepatic or renal function or electrocardiogram. A slight
dose-related increase in urine pH (0.67 pH unit at the 9 g dose)
was attributed to the increased sodium consumption associated
with the study medication. Blood pressure remained unchanged.
Abnormal laboratory findings were reported in 10 patients, however these were previously either present at baseline, occurred in
placebo patients or resolved during the study, making a relationship with the study medication unlikely.
SLEEP, Vol. 25, No. 1, 2002
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Placebo-Controlled Multicenter Trial—U.S. Xyrem Multicenter Study Group
Although the ESS does not correlate well with more objective
measures of sleepiness, such as the maintenance of wakefulness
test (MWT) or multiple sleep latency test (MSLT),24 it remains a
valid assessment tool for daytime sleepiness23 and has been useful in measuring drug-induced changes in sleepiness in narcolepsy patients.25,26 Additional studies, which may confirm these
results using MWT, are currently being conducted.
The CGI-c indicate that investigators judged their patients to
be Very Much Improved or Much Improved in more than half the
patients in the 6 g and 9 g doses after four weeks of sodium oxybate therapy. These results compare very favorably with other
recent pharmacological interventions, which improved the overall disease state of narcolepsy patients.25,26
Secondary measures of clinical improvement included
decreased frequency and duration of reported inadvertent
naps/sleep attacks that were significant at 6 g and 9 g doses. The
reported number of nighttime awakenings was also significantly
reduced at the 9 g dose. Together, these results confirm the
observations of other investigators,15,16,17,19 and provide further
evidence for a therapeutic role of sodium oxybate for the treatment of narcolepsy.
and Wake Disorders, Chevy Chase, MD; N. Feldman, St.
Petersburg Sleep Disorders Center, St. Petersburg, FL; M.
Hagaman, Sleep Medicine Associates, Nashville, TN; G. Hertz,
Center for Sleep and Insomnia Disorders, Huntington, NY; V.
Iyer, Sleep Disorders Center University of Louisville Hospital,
Louisville, KY; S. Kathawalla, Pulmonary Department Park
Nicollet Clinic, Minneapolis, MN; D. Lankford, Sleep Disorders
Center of Georgia, Atlanta, GA; M. Mitler and R. Hayduk,
Pacific Sleep Medicine Services, La Jolla, CA; R. Pascualy,
Providence Sleep Disorders Center, Seattle, WA; P. Sahota,
University of Missouri Division of Neurology, Columbia, MO;
T. Roth, Sleep Center Henry Ford Hospital, Detroit, MI; M.
Scharf, Center for Research in Sleep Disorders, Cincinnati, OH;
L. Scrima, Sleep-Alertness Disorders Center, Inc., Aurora, CO;
J. Schwartz, Southwest Medical Center, Oklahoma City, OK; G.
Zammit, Sleep Disorders Institute St. Luke’s—Roosevelt
Hospital Center, New York, NY.
The authors extend their deep appreciation to Dr. Merrill
Mitler for his thoughtful review of this manuscript.
Safety
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ACKNOWLEDGMENTS
The members of the U. S. Xyrem Multi-Center Study Group
were J. Black and C. Guilleminault, Stanford Sleep Disorders
Clinic, Stanford, CA; R. Bogan, Baptist Medical Center Sleep
Disorders Center, Columbia, SC; H. Emsellem, Center for Sleep
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