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`HEALTH SCIENCFS LIBRARY
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`University of Wisconsin
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`j A PUBLICATION OF THE SOCIETY OF BIOLOGICAL PSYCHIATRY
`VOLUME 26, NUMBER 4
`AMN1032
`
`AUGUST 1989
`
`IPR ofU.S. Patent No. 7,765,106
`
`BIPCBF 26(4)1989 I
`ISSN 0006-3223
`
`AMN1032
`IPR of U.S. Patent No. 7,765,106
`
`

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`Biological Psychiatry is cited in Beck Medical Information, Biological Abstracts, Chemical Abstracts, Curre/nt Contents, Excerpta Medica,
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`AMN1032
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`IPR of U.S. Patent No. 7,765,106
`
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`AMN1032
`IPR of U.S. Patent No. 7,765,106
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`BIOL PSYCHIATRY
`1989;26i331—343
`
`331
`
`4 E
`
`fficacy of Gamma-Hydroxybutyrate versus
`Placebo1n Treating Narcolepsy—Cataplexy:
`Double-Blind Subjective Measures
`
`L.LaWrence Scrima, Paul G. Hartman, Frank» H. Johnson, Jr., and
`
`-.F Charles Hiller
`
`‘
`
`The efficacy of gamma-hydroxybutyrate' (GHB) versus/ placebo for treating narcolepsy
`' was evaluated in 20 patients with narcolepsy, 10 men and 10 women, using a double—
`blind counterbalanced crossover design. Each patient completed a daily sleep—wake log
`and questionnaire during a 14-day baseline, a 29-day placebo period, a 29-day GHB
`period ,(50 mg GHB/kg/night. given-25 mg/kg h.s. and 25 mg/kg 3 hrxlater), and a 6-day
`washout period after each treatment. Cataplexy frequency was significantly lower during
`GHB treatment than during placebo treatment (p = 0.022). Compared to baseline values,
`the number ofcataplex'y attacks per day declined by 52%. and 69% during GHB treatment
`weeks I and 4, respectively. The number of subjective arousals from sleep was less with
`GHB than with placebo (p = 0.035) and the number ofsleep attacks was not significantly
`dtflerent during GHB versus placebo treatment. GHB did not have a significant efl'ect
`on subjective estimates of sleep onset latency, total sleep time, Stanford Sleepiness Scale
`ratings at morning wake-up, methylphenidate usage, or the number of naps per day. The
`results indicate that'GHB is efficacious for reducing the frequency of cjataplexy attacks
`and subjective nocturnal arousals in patients with narcolepsy within the first 4 weeks of
`treatment.
`'
`V
`
`' Introduction
`
`Narcolepsy isa chronic, incurable disorder characterized by intermittent excessive daytime
`sleepiness and abnormal rapid _eye movement(REM) sleep manifestations, such as sleep-
`' onset REM periods, cataplexy, sleep paralysis, and/0r hypnagdgic hallucinations (Associ-
`ation or Sleep Disorders Centers 1979) Cataplexy1s a sudden loss of musc1e tone that occurs
`primarily during emotional arousal; sleep paralysis is an inability to move upon first lying
`.down or upon Waking; and hypnagogic hallucinations are dream—like hallucinations that
`occur at sleep onset. Most patients with narcolepsy also have disrupted nocturnal sleep
`(Montplaisir 1976). Narcolepsy is generally treated with a central nervous system stimulant
`
`
`
`From the Sleep Disorders Center Pulmonary Division, Department of Medicine, University of Arkansas for Medical Sciences,
`Little Rock, AR.
`Supported1n part by Orphan Products Grant FD—R—000115 from the Food and Drug Administration
`Address reprint requests to Dr L. Scrima, Sleep Disorders Cener, Slot 594, University of Arkansas for Medical Sciences,
`4301 West MarkhamStreet, Little Rock, AR72205..
`Received July 29, 1988; revised December 14,1988.
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`IPR ofU.S. Patent No. 7,765,106
`
`
`‘ 0006-3223/89/$03.50
`
`AMN1032
`IPR of U.S. Patent No. 7,765,106
`
`

`

`332
`
`BIOL PSYCHIATRY
`1989;26:331—343 ‘
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`(eg., amphetamine methylphenidate, or pemoline) to reduce excessive daytime sleepiness
`(EDS) (Parkes 1976) and an antidepressant (e g., imipramine or protriptyline) to control
`cataplexy and other REM sleep-related symptoms (Takahashi 1976). Stimulants, howeVer
`do not fully control EDS111 most narcolepsy patients (Parkes 1976) and can have undesirable
`side effects on the cardiovascular, gastrointestinal, and central nervous systems (Gilman et
`al. 1985). Treatment of Cataplexy with antidepressants has been reported to be successfulin
`most cases (Takahashi 1976; Billiard et al. 1983), but these drugs have adverse effects,
`including (1) prolonged cardiac conduction times that may promote dangerous ventricular
`arrhythmias; (2) postural hypotension; (3) anticholinergic effects, such as blurred vision
`dry mouth, and1mpotence (Gilman etal; 1985); (4) suppression of REM sleep (Zung 1969;
`Cadilhac 1976); and (5) increased nocturnal myoclonus (Guilleminault et a1. 1976). The
`anticholinergic side effects oftrén result in patient self-withdrawal from antidepressants, which
`- is usually followed by an increase in the frequency and severity of cataplexy events (Scrima
`1981, Scharf and Fletcher 1988). Both stimulants and anticataplexy drugs may become less
`effective as tolerance1ncrea3es (Parkes 1976; Broughton and Mamelak 1979)
`Gamma—hydroxybutyrate (GHB)1s a four-carbon fatty acid that occurs naturally1n the
`mammalian central nervous system (Muyard and Laborit 1977) and has been termed a
`“putative neurotransmitter” (Mandel et al. 1987). GHB was reported to induce anesthesia
`at 60—70 mg/kg (Vickers 1969), but the report does not make it clear Whether the doses
`were given orally or intravenously. Lower oral doses of GHB were reported to induce
`sleep in psychiatric patients (Mamelak etal. 1977), but the minimum GHB dose that
`will induce sleep has\not been systematically determined; Unlike other hypnotics, GHB
`given orally, induces and maintains sleep without'suppressing REM or delta stages of
`sleep (Mamelak et a1. 1977). It was first reported in 1976 (Broughton and Mamelak) that
`GHB , given orally h. s. and two to three additional times during the sleep period, improved
`nighttime sleep and reduced cataplexy and sleep attacks in patients with narcolepsy.
`Subsequent studies confirmed that most narcolepsy patients had moderate to large re—
`ductions in cataplexy frequency and daytime sleepiness, as well as reduced sleep dis—
`ruption, hypnagogic hallucinations, and sleep paralysis after taking GHB in divided dose,
`i.e. , a dose h.s. and one to two additional times during the night (Broughton and Mamelak
`1979, 1980; Scharf et al. 1985). Polysomnographic recordings indicated that narcolepsy
`patients taking a divided dose of GHB had increased sleep continuity, decreased REM
`fragmentation, and increased amounts of delta sleep (Broughton and Mamelak 1980;
`Scharf et a1; 1985). However, 1 month of oral administration of a single h.s. dose of
`GHB improved daytime sleepiness in only 39% of patients with narcolepsy, though
`cataplexy frequency was reduced1n 83% of the patients (Montplaisir and Godbout 1986)
`Tolerance to GHB has not been found to develop, even after daily use by patients with
`narcolepsy for as long as 9 years (Mamelak et al. 19.86) Adverse side effects havebeen"
`infrequent, mild, and have occurred mainly during the first few days of treatment (Brough'
`ton and Mamelak 1979; Scharf et al. 1985; Mamelak et a1. 1986).
`This report describes the results of the first double—blind study of the effects ofiGHEZ
`. on subjective symptoms of narcolepsy as compared to those of a placebo.
`
`Methods
`
`Subjects
`
`Ten women and 10 men with narcolepsy, diagnosed at the accredited Sleep Dis(.)1'ders
`Center (SDC) of the University of Arkansas for Medical Sciences (UAMS), partiCIPated
`
`AMN1032
`IPR of US. Patent No. 7,765,106
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`; T"
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`Efficacy of Gamma Hydroxybutyrate .
`
`BIOL PSYCHIATRY
`1989;26:331—343
`4
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`333
`
`in the study; All patients were interviewed by an accredited clinical polysomnographer, I
`were given a physical examination by a physician, and had sleep disdrders diagnostic
`tests (Guilleminault 1982). The diagnostic tests included an overnight polysomnogram
`(PSG) and an evaluation of their daytime sleepiness with the multiple sleep latency test
`' (MSLT). The criteria for inclusion in this study were: (1) a history of excessive daytime
`sleepiness and cataplexy, (2) >2 REM onsets on the MSLT, (3) a sleepiness index of
`275 on the MSLT, (4) at least 10 cataplexy attacks subjectively reported on a daily log
`during a 2-week baseline period, and (5) age between 16 and 65 years. Patients were
`excluded if they had other major health prOblemS; were fertile Women Who were not
`practicing birth control; were nursing mothers; or had previously taken GHB or had other
`sleep disorders, with the exception of those commonly associated with narcolepsy, such
`as sleep paralysis, mild to moderate sleep apnea (arterial oxygen saturation 280%), and
`nocturnal myoclonus.
`’
`_
`, The age mean i standard error was 45.9 it 4.6 years (range 16—64) for the women
`and 49.1 i 4.0 (21—64) for the men. Weight (kg) mean 1 SE was 851: 5.2 (range
`57—113) for women and 80.4 i 3.6 (54~90) for men. Body mass index was 31.8 ' i
`I 2.5 (17.6—45.4) for women and 26.2 i 0.9 (20.3~29.1) for men. Prior to the study, 7
`patients were on stimulants alone (methylphenidate, ‘pernoline, or dextroamphetamine),
`11 were on a combination of stimulants and anticataplexy medications (imiprarnine or
`protriptyline),and 2 patients were not taking stimulants or anticataplexy medications.
`Patients who we're taking stimulants other than methylphenidate switched to methyl-
`phenidate (S30 mg/day) for the duration of the study. Seven patients were withdrawn
`from anticataplexy medications at least 2 ”Weeks before the baseline period, and the
`remaining 4 patients on anticataplexy medications were withdrawn from imipramine 6,
`6, 5, and 3 days ”prior to baseline, respectively. Only the patient who stopped imipramine
`5 days prior to baseline appeared to have elevated amounts of cataplexy events during
`the first 2 days of the baseline (18 and 12>events, respectively; mean and SD for the rest
`of the baseline period: 5.7 i 3.5 events); these 2'days were excluded from the analysis.
`One patient continued taking propranolol to control hypertension throughout the Study at
`a dose (40 mg/day) that was half the lowest dose of propranolol (80—480'h1g/day) reported
`to reduce narcolepsy symptoms for some patients (Kales et a1. 1979; Meier-Ewert et a1.
`1985). This patient was included in the analysis of results, but analySis of the data with
`this patient excluded yielded the same pattern of statistically significant results.
`
`'
`
`'
`
`Procedures
`
`A double—blind, crossover design, ‘with order of treatment counterbalanced and randomly
`assigned, was utilized. Thus, each subject provided data for all phases of the Study:
`baseline (14 days), first treatment (29 days), first’washout (6 days), second treatment (29
`.days), and second washout~(6 days). Order of treatment was randomly assigned by the
`VUAMS pharmacy, so that half of the men and half of the women received GHB in the
`first treatment period and placebo in the second, whereas the remaining subjects received
`placebo first and‘GHB second. All SDC staff were blind to the order of treatment for
`subjects. During GHB treatment, subjects received 58 bottles prepared by the pharmacy,
`each containing 25 mg GHB/kg body weight, mixed with distilled water and syrup of
`orange. During the placebo treatment, subjects received 58 identical bottles with an
`equivalent amount of fluid, consisting of syrup of orange in distilled water. During each
`treatment period, subjects were instructed orally and in writing to (1) refrigerate, but not
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`-
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`334
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`BIOL PSYCHIATRY
`-
`1989;26:331—343
`‘
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`L. Scrim
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`freeze, the bottles, (2) put two bottles by their bedside when they went to bed, (3)Ingest
`one entire bottle immediately before going to bed, and (4) ingest the second entire bottle
`3 hr later. Subjects were told to set an alarm to insure that they woke up 3 hr after bedtime
`to take their second placebo or GHB dose. Subjects were also instructed not to use
`alcohol, sleeping pills or other central nervous system depressants during the experiment
`and to avoid drinking caffeinated beverages late1n the day Subjects were permitted to
`. use methylphenidate (up to 30 mg/day) to counter excessive daytime sleepmess, but Were
`instructed not to take methylphenidate after 6:00 PM.
`Subjects were required to complete a sleep log and questionnaire for each day of the
`experiment. The sleep log consisted ofa grid on which subjects noted the time periods
`when they were awake, lying down, sleeping, and when they took methylphenidate. On'
`the questionnaire, subjects recorded dailysubjective reports of (1) sleep onset latency for
`nighttime sleep, (2) number of arousals from sleep, (3) total sleep time, excluding naps,
`(4) Stanford Sleepiness Scale rating upon morning awakening, (5) number of “sleep
`attacks,” i. e, periods when they experienced an irresistible urge to sleep, (6) number of-
`cataplexy events, (7) number of naps, and (8) amount of methylphenidate taken. Patients
`reported icomplying with instructions for taking GHB and placebo, and most patients
`Completed their daily sleep logs and questionnaires thoroughly.
`Each subject had an 8.07hr PSG performed onthe last night of baseline and the first
`and last nights of both treatment periods, with an MSLT performed the day following
`each PSG (5 PSGs and 5 MSLTs); these results will be reported following statistical
`analysis of the data.
`Patients were encouraged to call the SDC staff to report adverse reactions during the
`experiment. Patients were asked about the possible occurrence of adverse reactions in
`interviews by phone 2 weeks into each treaMent period and by1n-person interviews at
`the end of each treatment.
`
`‘
`
`Data Analysis .
`
`A mixed-design Analysis of Variance (ANOVA) was used with two between-subject
`factors—gender and order of treatment—and two within—subjectfactors—~treatment (GHB
`versus placebo) and week of treatment (first versus fourth week). For each daily dependent
`measure (number of cataplexy events, sleep attacks, etc.), means were computed for the
`baseline and'each week of both treatments. The units of analysis for each subject were
`the change scores, i. e, the differences between the baseline mean and the means for
`weeks 1 and 4 of GHB treatment and weeks 1 and 4 of placebo treatment. Placebo effects
`were evaluated by contrasts of the baseline mean versus the means on placebo weeks 1
`and 4. The data were also analyzed with a modification of the nonparametric Wilcoxon
`test (Koch 1972), as the superiority of parametric versus nonparametric statistics has not
`been demonstrated for this design Results of the nonparametric tests will be reported
`only when they are not in agreement with the parametric statistics.
`7
`‘
`" ‘
`Washout effects, i.e., carryover or rebound effects during 5 days following cessatiofi
`of treatment, were also tested with a mixed--design ANOVA. Separate mixed-design
`ANOVAs were used to contrast each day of the GHB washout with the corresponding
`day of placebo washout, and to contrast each day of both washout periods with the
`baseline period. Each washout period consisted of at least 6 nights and days, but only
`the data from the first 5 days were analyzed, as subjectsspent the sixth day in transit to
`the sleep laboratory and being prepared for their fourth overnight PSG.
`
`AMN1032
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`IPR of U.S. Patent No. 7,765,106
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`BIOL PSYCHIATRY
`1989;26:331—343
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`Figure 1. Cataplexy events per day during baseline, placebo, and GHB treatment. For each patient, " ‘64
`the mean number of cataplexy events per day was calculated for the baseline and for each week
`of both treatments. The 'figure shows the means and standard errors of patients’ baseline and weekly
`means for cataplexy.
`’
`
`Results
`
`Cataplexy Frequency '
`Figure 1 shows the means and standard errors for cataplexy events during baseline,
`placebo, and GHB treatment periods. GHB treatment caused a significantly greater decline
`in cataplexy frequency .than did placebo treatment (F = 6.58; df '=. 1,15; 1) = 0.022).
`Compared to cataplexy eVents per day during baseline (mean 1 standard error 3.1 i
`
`,
`
`0.5), cataplexy events per day declined during GHB weeks 1y(1.5 i 0.2) and 4'(0.9 i
`
`0.2) by 52% and 69%, respectively, and declined during placebo weeks 1 (1.7 i 0.3)
`and 4 (2.0 i 0.3) by 43% and 33%, respectively. Placebo effects versus baseline were
`significant during placebo week 1 (F =0 10.36; df = 1,15; p = 0.006) and were nearly
`significant for placebo week 4 (F = 4.01; df = 1,15; p = 0.064).. Sex of the patients
`did not have a significant interaction with the effect of GHB on cataplexy frequency.
`Of 19 patients with log entries for cataplexy during baseline, placebo, and GHB
`treatments, 16 (84%) had fewer cataplexy events per day during the fourth week of GHB
`versus the fourth week of placebo. Nine (47%) had at least 1 less cataplexy attack per
`day, and 7 (37%) had 0.1—0.99 fewer cataplexy attacks per day with GHB. Four patients
`(21%) had no cataplexy attacks during the fourth week of GHB treatment, whereas 1
`patient (5%) had no cataplexy attacks during the fourth week of placebo treatment. Seven
`patients (37%) continued to have at least 1 cataplexy attack per day during the fourth
`week of GHB treatment. The daily logs of one patient (“p”) were collected but subse-
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`336
`
`BIOL PSYCHIATRY
`1989;26:331—343
`»
`
`A
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`L. Scrim
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`Figure 2. Catapl'exy events per day during baseline and washout periods. Means and standard
`errors of the patients’ baseline means and cataplexy events per day during washout periods are
`shown
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`' participants, patient p was interviewed at the end of the patient’ 8 participation in the
`study, with experimenters and patient still blind to treatment order. The patient indicated
`that cataplexy frequency was 10/day during baseline, 2. 5/day during treatment 1 (GHB),
`and 10/day during treatment 2 (placebo)
`There was a significant interaction between the effects of treatment and the week of
`treatment on cataplexy frequency (F = 7.45; df = ‘1,15;p = 0.016). Therefore, cataplexy
`frequency was analyzed with week held constant and with treatment held constant, re-
`spectively. At week 1 of each treatment, the number of cataplexy attacks per day was
`not significantly different with GHB than with placebo treatment. At week 4, cataplCXY
`g
`frequency was significantly less with GHB than with placebo (F: 10. 50; df = 1 15;
`’
`p = 0.006). Post hoc analysis of the Second and third weeks of treatment indicated that
`cataplexy frequency was significantly less with GHB than placebo during the third treat- _' l:
`ment week (F’ = 10.02; df = 1,15; p = 0.006), but not during the second WeGkvr'
`1
`Analyses with treatment held constant indicated that cataplexy attacks declined signifi—
`i
`cantly from week 1 to week 4 of GHB treatment (F = 15.10; df = 1,15; p = 0.002)-
`g
`Post hoc trend analysis of all 4 weeks of GHB treatment indicated that there W354,
`significant linear component to the decline in cataplexy frequency during GHB treatment W '
`(F—— 18. 81, df—— 1,15; p: 0.0006) There was no significant change in cataplexy
`frequency from week 1 to week 4 of placebo treatment.
`Figure 2 shows the means and standard errors for cataplexy events during each day
`of the washout periods following placebo and GHB treatment, respectively Fewer 03'
`taplexy events tended to occur during GHB washOut than placebo washout (p = 0 091)
`Analysis of each day of the washouts separately indicated that although the number of
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`Efficacy of Gamma-Hydroxybutyrate
`
`BIOL PSYCHIATRY
`1989;26:331—343
`
`337
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`errors shown were derived as in Figure .1.
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`Figure3.Sleepattacksperdayduringbaseline,placebo,andGHBfreatrnept.Meansandstandard
`
`cataplexy events was lower on each day of the GHB washoutversus the corresponding
`.day of the placebo washout, this difference was significant on only the first day of the
`washout periods (p = 0.010). Compared to the baseline period, cataplexy frequency was
`significantly lower during GHB washout days 1—5 (p < 0.05 for‘ each comparison) and .
`during placebo Washout days 1, 2, and 4 (p < 0.05 for each comparison), and tended
`to be lewer during placebo washout days 3 and 5 (0.05 < p < 0.10). Although treatment
`effects extended into the washout week, the main treatment effect of Gl-IB versus placebo
`on cataplexy was not influenced by carryover effects, i.e. , the interaction between treat— .
`ment and order of treatment was not significant (p = “0.679).
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`Daytime Sleepiness
`Figure 3 shows the means and standard errors for sleep attacks during baseline, placebo,
`and GHB treatment periods. Compared to 'sleep attacks per day during baseline (mean
`t SE 3.3 i 0.4), sleep attacks «per day declined during GHB weeks 1 (1.8 i 0.2) and
`4 (2.1 i 0.3) by 47% and 38%, respectively, and declined during placebo weeks 1 (2.1
`i 0.3) and 4 (2.0 i 0.2) by 37% and 41%, respectively. There were no significant
`differences between GHB and placebo effects on sleep attacks. Contrasts between each
`condition and baseline indicated that the number of sleep attacks declined significantly
`during placebo week 1 (F = 23.37; df = 1,13; p = 0.0003), placebo week 4 (F =
`21.37; df = 1,13;p = 0.0005), GHB week 1 (F = 24.93;,df = 1,13;p = 0.0002),
`and GHB week 4 (F = 7.71; df = 1,13; p ,=~0.016). The frequency of sleep attacks
`declined to <1/day in only 1 patient (6%) during placebo week 4 and in 3 patients (16%)
`during GHB week 4.
`,
`There was a statistical tendency for sleep attacks to occur less frequently during placebo
`’ "washout than during GHB washout (p = 0.0996), but differences between GHB and
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`~ BIOL PSYCHIATRY
`1989;26:331—343
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`Figure 4. Subjective arousals per night during the baseline, placebo, and GHB treatment. Means
`and standard errors shown were derived as in Figure l. The Overall GHB versus placebo treatment
`effect was significant (p = - 0.035). The treatment-by—week interaction was not significant, so GHB
`versus placebo comparisons were not made for each week separately.
`
`placebo washout conditions were slight, ranging from 0.0 to 0.4 sleep attacks per washout
`.day. Analysisxof each day separately indicated that no placebo washout day was signif-
`icantly different from the corresponding GHB washout day for sleep attacks; Compared
`to sleep attacks during the baseline period (mean t SE 3.3 i 0.4), the number of sleep
`attacks was significantly lower (p < 0.05) during placebo washout days 3, 4, and 5 (2.0
`i 0.2, 1.8 i 0.3, and 2.0 1- 0.2, respectively) and during GHB washout days -2-5
`(2.3 i 0.4 and 2.5-:03, respectively). The main comparison of GHB versus placebo
`effects on sleep} attacks was not affected by carryovereffects, i.e., the interaction between
`treatment and order of treatment was not significant for sleep attacks (p = 0.599).
`Stanford Sleepiness Scale (SSS) ratings at morning wake—up time, methylphenidate
`usage, and the number of daytime naps were not significantly different during GHB Versus
`placebo treatment or placebo versus baseline. SSS ratings (means t SE) at baselinewere ‘
`3.0 i 0.3; at placebo weeks 1 and 4 were 2.7 i 0.2 and 2.7 i 0.2, respectively; and "”0." ’
`at GHB weeks 1 and 4 were 2.7 i 0.2 and 2.5 i 0.2, respectively. The number 015:7
`mg methylphenidate tablets taken per day-(means i SE) at baseline was 2.7 i 0.6; at
`placebo weeks 1 and 4 was 3.1' 1- 0.5 and 2.9 i 0.5, respectively, and at GHB weeks
`1 and 4 was 3.0 i 0.6 and 2.8 i 0.6, respectively. The number of daytime naps (means . _ .
`i SE) at baseline. was 1.3 i 0.3; at placebo weeks 1 and 4, 1.2 i 0.2 and 1.1 : OLZE’:":*"'
`and at GHB weeks land 4,1.1 'J: 0.2 and 1.1 i' 0.3.
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`Subjective Noetiufnal Sleep
`
`Figure 4 shoWs the means and standard errors for subjective nocturnal arousals during
`baseline, placebo, and GHB treatment periods. Compared to subjective necturnal arousals
`at baseline (3.6 . i 0.8), subjective arousals from sleep declined during GHB weeks 11”,,
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`
`
`Efficacy of Gamma-Hydroxybutyrate
`
`.
`
`BIOL PSYCHIATRY
`1989;26:331—343
`
`339
`
`
`
`(2.5 i 0.4) and 4 (2.4 i 0.3) by 32% and 33%, respectively, and increased during
`both placebo weeks 1 (3.8 :t 0.8) and 4 (3.8 i 1.1) by 4%. The difference between
`GHB versus placebo treatment effects on arousals from sleep was‘significant (F = 5.43;
`df = 1,14; p = 0.035). Neither sex nor order of treatment interacted significantly with
`the effect of treatment on subjective arousals from sleep. Of 18‘ patients with log entries
`for nocturnal arousals during baseline, placebo, and GHB treatments, 11 (61%) had fewer
`subjective arousals on GHB than on placebo. Placebo, effects were not significant for
`subjective arousals.
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`The difference between nocturnal arousals during placebo washout versus GHB wash-
`out was not significant overall or for any single washout day. There were no significant
`differences in nocturnal arousals during any placebo or GHB washout day compared to
`baseline, but there was a trend (p = 0.091) for fewer nocturnal arousals to occur on
`GHB washout day 1 compared to baseline.
`‘
`Subjective sleep onset latency and total sleep time were not significantly different for
`GHB versus placebo treatment ‘or placebo versus baseline. Subjective sleep onset latency
`(means t SE) at baseline was 13.9 i' 4.8 min; at placebo weeks 1 and 4, 14.1 i 4.2
`min and 13.1 i 4.1 min, respectively; and at GHB weeks 1 and 4, 9.1 i 1.5 min and
`7.8 i 1.2 min. Total sleep time (means i- SE) at baseline was 6.7 i 0.4 hr; at, placebo
`weeks '1 and 4, 6.9 i 0.3 hr and 7.1 i 0.3 hr, respectively; and at GHB weeks 1 and
`\
`,4, 7.1‘ i 0.2mm 7.1 i 0.2 hr.
`'
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`Hypnagogic Hallucinations and Sleep Paralysis
`Ten narcolepsy patients (5 women and 5 men) ratedthe severity of hypnagogic hallu—
`cinations and sleep paralysis (1—10 rating scale with 10 being most severe) at the end of
`each‘treatment period. Of seven patients who reported hypnago’gi‘c hallucinations during .
`placebo treatment (median'severity rating 4.5, range 3—8), only one also reported hyp-
`nagogic hallucinations during'GHB treatment. This patient rated hypnagogic hallucina-
`tions to be slightly‘less severe during GHB treatment than during placebo treatment. No
`other patients reported hypnagogic hallucinations during GHB treatment. The effect of _
`GHB versus placebo treatment on hypnagogic hallucinations was significant (sign test,
`' p = 0.008).
`.
`Only 3 of 10 patients reported having sleep paralysis during either treatment. Two
`patients had sleep paralysis during placebo but not GHB treatment, and the third had
`sleep paralysis duringGHB treatment only.
`'
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`Side Efiects
`Physical symptoms and problems reported by patients during GHB treatment, but nOt
`during placebo treatment or baseline, were as follows (number of patients in parentheses):
`upset stomach (3); upset stomach with vomiting during the first week of GHB treatment
`(1); sluggishness and stiffness upon morning awakening (2); dizziness after the second
`GHB dose of the night (1); urinary urgency (1); occurrence of cataplexy during physical
`exertion, which had not occurred prior to GHB treatment (1); general weakness and
`fatigue (1); one episode of dizziness during the day (1). The total number of adverse
`reactions reported during GHB treatment was less than during placebo treatment.
`Two episodes that occurred in the sleep laboratory were noteworthy. One woman
`fainted for a few seconds before taking the GHB doseonthe evening of her final'night
`of GHB treatment; she did not faint at any other time in the study. Secondly, a technician _
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`AMN1032
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`IPR ofU.S. Patent No. 7,