Ranbaxy Ex. 1012
`IPR Petition - USP 9,050,302
`
`

`
`J CLIN PSYCHIATRY 46:6 — JUNE 1985
`
`SCHARF ET AL.
`
`TABLE 1. Stimulant Usage and Dosage Changes From Baseline to GHB Administration Period
`Baseline
`
`GHB Administration Period
`
`Drug
`Methylphenidate SR
`Methylphenidate
`_
`Pemoline
`Dextroamphetamine
`Methamphetamine
`None
`
`Number
`of Patients
`1
`7
`6
`8
`2
`6
`
`Dosage (mg)
`
`Mean
`20.00
`52.86
`34.38
`21.25
`20.00
`—
`
`SD
`—
`40.30
`7.65
`9.16
`14.14
`—
`
`N
`12
`2
`0
`6
`2
`8
`
`Dosage (mg)
`Mean
`20.00
`11.25
`—
`14.17
`26.67
`—
`
`SD
`0.00
`1.77
`—
`10.57
`20.21
`—
`
`TABLE 2. Tricyclic Usage and Mean Dosage Prior to GHB (Base-
`line)
`
`D°5a9e (mg)
`Number
`Mean
`SD
`of Patients
`Drug“
`51.67
`36.70
`8
`lmipramine
`17.50
`4.18
`6
`Protriptyline
`125.00
`35.36
`2
`Amltriptyline
`50.00
`—
`1
`Chlorimipramine
`—
`—
`14
`None
`“One patient was taking imipramine and amitriptyline concurrently
`prior to entering the study.
`
`TABLE 3. Predrug (Baseline) Means Versus Week 4 on GHB in
`Narcoleptic Patients (N=30) Based on Polysomnographic Fle-
`cordlngs
`
`Baseline
`
`Week 4
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`'
`
`TABLE 4. Predrug (Baseline) Means Versus 6 Months on GHB in
`Narcoleptic Patients (N = 12) Based on Polysomnographic Fle-
`cordings
`
`Baseline
`
`6 Month
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`387.78
`
`35.11
`
`407.78
`
`28.48
`
`90.00
`
`37.83
`
`74.02“
`
`28.71
`
`81.00
`17.08
`
`15.38
`
`51.54
`
`2.25
`
`12.63
`
`7.79
`5.05
`
`5.33
`
`6.00
`
`4.05
`
`5.51
`
`84.58“
`9.27“
`
`14.00
`
`56.38
`
`4.42
`
`12.00
`
`6.06
`3.95
`
`5.07
`
`8.81
`
`6.36
`
`3.39
`
`32.36“
`
`39.37
`
`
`
`-—«~._.;__«'4mg._...-.1gm_:..(j.4-—..r.j; .:..._..T.j.V,
`
`Sleep Variable
`Total sleep time
`(in minutes)
`Total wake time
`(in minutes)
`Sleep efficiency
`(in percents)
`Number of awakenings
`Percent of
`Stage 1
`Percent of
`Stage 2
`Percent of
`Stages 3 and 4
`Percent of
`Stage REM
`Latency to REM
`(in minutes)
`MSLT
`Sleep latency
`(in minutes)
`Latency to REM
`(in minutes)
`“p < .05.
`"p < .005.
`‘p < .025.
`
`.
`
`86.63
`
`37.85
`
`4.55
`
`8.37
`
`3.71
`
`4.99
`
`5.79
`
`13.36‘
`
`5.14
`
`5.55
`
`RESULTS
`
`Sleep Architecture
`Table 3 shows polysomnographic data of 30 patients for
`selected sleep parameters at baseline and at the end of 4
`consecutive weeks on GHB. GHB administration resulted
`in a moderate increase in total sleep time and a moderate
`decrease in total wake time, which was significant at
`p < .025 and p < .05, respectively.
`The number of awakenings decreased from 14.57 t0
`9.48 (p< .005), and the percent of Stages 3 and 4 sleep
`increased from 1.48 at baseline to 4.53 at Week 4
`(p< .005). The percent of REM sleep increased slighfll’
`(N.S.), and REM latency decreased from 102.88 minutes at
`baseline to 48.0 after 4 weeks of GHB (p < .005). During
`the MSLT, however, REM latency increased significantllh
`from 9.2 to 14.4 minutes (p < .005), while sleep latenc)’
`increased from 3.7 to 5.2 minutes (N.S.).
`Table 4 shows polysomnographic data for 12 patients
`who had been on GHB for at least 6 months. The results 2116
`
`Sleep Variable
`Total sleep time
`(in minutes)
`Total wake time
`(in minutes)
`Sleep efficiency
`(in percents)
`Number of awakenings
`Percent of
`Stage 1
`Percent of
`Stage 2
`Percent of
`Stages 3-4
`Percent of
`Stage REM
`Latency to REM
`(in minutes)
`MSLT _
`Sleep latency
`(in minutes)
`Latency to REM
`(in minutes)
`“p< .025.
`"p < .05.
`‘p < .005.
`
`377.06
`
`70.18
`
`406.23“
`
`30.87
`
`94.35
`
`46.40
`
`74.77”
`
`31.59
`
`81.18
`14.57
`
`16.50
`
`51.38
`
`1.48
`
`11.92
`
`8.17
`4.66
`
`5.60
`
`8.33
`
`2.88
`
`5.17
`
`84.42”
`9.48”
`
`14.50
`
`54.30
`
`4.53‘
`
`12.77
`
`6.54
`3.48
`—
`6.61
`
`8.57
`
`4.95
`
`5.00
`
`102.88
`
`80.88
`
`48.04‘
`
`68.76
`
`'
`
`3.70
`
`9.22
`
`2.91
`
`4.42
`'
`
`5.22
`
`14.43”
`
`4.24
`
`5.58
`
`made for means ofWeeks 1,3, 6, 9, 12, 15, 18, 21, 27, and
`30 for those patients reaching the respective treatment
`weeks. Thus, comparisons to baseline were made for 29
`patients for treatment Weeks 1 and 3, but only for 3 patients
`for Week 30. One patient did not complete any subjective :
`reports throughout the study. Statistical significance was
`tested with the Wilcoxon signed-ranks test; data from each '
`treatment time. point were compared to each patient’s own
`baseline.
`
`223
`
`

`
`E J GLIN PSYCHIATRY 46:6 — JUNE 1935
`
`-y-HYDROXYBUTYHATE IN NARCOLEPSY
`
`TABLE 5. Long-Term Effects of GHB on the Narcoleptic Teirad Changes From Baseline Daily Means
`Daytime
`Hypnogogic
`Sleep Attacks‘
`Hallucinations‘
`Mean
`SD
`Mean
`SD
`N
`week
`3.22
`2.59
`0.61
`0.76
`29
`Base“,-19
`1.15
`0.96
`0.12
`0.29
`29
`week 1
`1.10
`0.95
`0.10
`0.27
`29
`week 3
`0.96
`0.54
`0.08
`0.18
`23
`Week 5
`1.01
`0.78
`0.10
`0.27
`21
`Week 9
`0.80
`0.74
`0.04
`0.11
`19
`Week 12
`0.79
`0.76
`0.07
`0.25
`15
`week 15
`0.86
`0.66
`0.02
`0.08
`14
`week 13
`0.81
`0.64
`0.00
`—
`13
`week 21
`0.74
`0.75
`0.00
`-—
`11
`week 24
`‘All differences from baseline significant at p< .005.
`
`Cataplei-iy'
`Mean
`3.91
`1.66
`1.29
`0.58
`0.59
`0.37
`0.43
`0.16
`0.21
`0.12
`
`SD
`8.75
`2.50
`1.80
`0.87
`0.79
`0.74
`1.01
`0.24
`0.34
`0.19
`
`Sleep
`Paralysis‘
`Mean
`0.47
`0.09
`0.04
`0.04
`0.10
`0.04
`0.00
`0.00
`0.00
`0.00
`
`SD
`0.76
`0.22
`0.12
`0.13
`0.25
`0.11
`—
`—
`—
`-
`
`|=|GURE 1. Effects of GHB on the Auxiliary Symptoms of Narco-
`lepsy‘
`
`(p < .005). There was an 80% decrease in the number of
`
`hypnogogic hallucinations during the first week of the study
`(p< .005); 84% by Week 3 (p<.005); 83% by Week 12
`(p < .005); and 97% by Week 18 (p < .005).
`Side effects noted during the course of the study in-
`cluded a single episode of protracted sleep paralysis which
`occurred in 3 patients. These were experienced by the pa-
`tients as extremely frightening. Each episode took place
`shortly after the initial nightly dose of GHB. All 3 episodes
`occurred within the first 2 weeks of the study. Two of the
`episodes occurred within the laboratory and were witnessed
`by the staff. In these cases, the patients experienced inter-
`mittent cataplexy, i.c., sleep paralysis, which lasted almost
`1 hour.
`
`Other side effects included one instance of drug-related
`enuresis and one complaint of increased transient sexual
`drive. Some patients had difficulty staying asleep after the
`second nightly dose of GHB. This problem was resolved by
`splitting the dosage for these patients into thirds and admin-
`istering it three times instead of twice. There were no sub-
`sequent difficulties with these patients’ ability to sleep.
`
`DISCUSSION
`
`The usual treatment for narcolepsy includes sympto-
`matic treatment of daytime drowsiness and sleep attacks
`with stimulants such as dextroamphetarnines, methy1pheni—
`date, or pemoline, while the auxiliary symptoms (cataplexy,
`sleep paralysis, and hypnogogic hallucinations) are treated
`with tricyclic antidepressants such as imipramine or pro-
`triptyline. These treatment modalities are often unsatisfac-
`tory for a number of reasons. Amphetamines and other
`stimulants can cause undesirable side effects, including in-
`somnia, hypertension, palpitations, and, at higher doses,
`may mimic symptoms of schizophrenia. Since tolerance
`frequently develops, the dosages must be increased. This,
`in turn, often leads to an increase in frequency and severity
`of side effects. Tricyclic antidepressants also can cause un-
`desirable side effects, including dry mouth, impotence, loss
`of libido, tachycardia, and others. In addition, they are
`somewhat cardiotoxic and can exacerbate or cause conduc-
`tion disturbance, heart block, or bundle branch block. Fi-
`
`224
`
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`*Shown as percent improvement from baseline.
`
`similar to those at the 4-week time point for the whole
`group.
`
`Narcoleptic Symptoms
`The data show a statistically significant reduction in all
`symptoms, both NREM (sleep attacks and naps) and REM-
`related symptoms (cataplexy, sleep paralysis, and hypno-
`gogic hallucinations). The number of daytime naps
`decreased an average of 48% by Week 3 from 1.89i 1.68
`per day to 0.98i0.68 (p < .005). This was despite the fact
`that we requested patients to take at least one nap every day.
`The number of sleep attacks decreased by 64 % (p < .005) in
`the first week of treatment (Figure 1 and Table 5). The av-
`erage for sleep attacks remained relatively constant and by
`Week 9 was still 69% below the baseline (p < .005).
`As can be seen in Figure 1, cataplectic events decreased
`an average of 58 % in the first week (p < .005). By Week 9
`the total average improvement from baseline was 85 %
`(p < .005). Cataplexy decreased steadily from week to
`week regardless of whether the patients had or had not been
`on tricyclic medication previously.
`The symptoms of sleep paralysis and hypnogogic hallu-
`Cinations also showed marked improvement (see Figure 1).
`Sleep paralysis decreased an average of 81% from baseline
`by the first week (p < .005); 91 % by Week 3 (p < .005); and
`Was completely absent in all subjects by Week 15
`
`

`
`J CLIN PSYCHIATRY 46:6 — JUNE 1985
`
`nally, their concurrent use with stimulants may increase risk
`excessively in patients with hypertension.
`Our results confirm those of previous clinical studies”
`of GHB, namely, that it is a safe, nontoxic substance that is
`effective in tlie treatment of narcolepsy. GHB adrninistra-
`tion results in an increase in slow-wave sleep and does not
`suppress REM sleep. In addition, there was no evidence of
`drug tolerance after 24 weeks of treatment. The improve-
`ments wc found in sleep attacks, daytime drowsiness, cata-
`plexy, hypnogogic hallucinations, and sleep paralysis are
`consistent with findings of Broughton and Mamelakd in
`their 12-month study of 16 narcoleptic patients.
`Although GHB is not purported to be a primary treat-
`ment for daytime sleepiness, our data showed a reduction in
`both the number of naps taken and the number of sleep
`attacks. These changes occurred despite the fact that pa-
`tients were taking less stimulant medication than before and
`were encouraged to take at least one nap every day. Narco-
`leptics often have frequent disruptions in nocturnal sleep.
`The improvement in nocturnal sleep consolidation as seen
`in the decreased number of awakenings may have contrib-
`uted to decreased daytime sleepiness. Despite the decreases
`in naps and sleep attacks, daytime drowsiness persisted. It
`was, however, milder than pretreatment levels. None of the
`patients were able to withdraw completely from stimulant
`medication during the drug period. Twenty—two patients re-
`quired stimulants daily, but at lowered dosages. The re-
`maining 8 patients were able to function well without stimu-
`lants part of the time, but needed mild doses at other times.
`The side effects experienced by our patients were pre-
`dictable and self-limiting. They were consistent with the
`hypothesized explanation of the drug’s action7 and had been
`previously reported by Broughton and Marnelakf In the
`few cases where side effects occurred, they were rated by
`the patients as less bothersome than the side effects of pre-
`vious narcolepsy medications. No patient expressed a de-
`sire to discontinue treatment with GHB.
`
`Broughton and Mamelaks performed continuous 48-
`hour polysomnographic recordings of sleep/waking pat-
`terns on 14 narcoleptic patients before and after 7- 10 days
`of GHB administration. They found that GHB improved the
`quality of night sleep by increasing the amount of Stages 3
`and 4 sleep, reducing Stage 1 sleep, increasing sleep effi-
`ciency, and reducing the number of short sleep periods (less
`than 15 minutes). They also found that nighttime REM
`sleep was reduced in latency and became less fragmented.
`All of these changes were statistically significant. Our re-
`sults were consistent with those of Broughton and Mamelak.
`Polysomnographic data have also been reported by Ma-
`melak et al.8 for a study of GHB in the treatment of insom-
`niac patients. Again, it was found that Stages 3 and 4 sleep
`were significantly increased and REM latency significantly
`decreased.
`
`The patients in this stpdy had serious cases of narco-
`lepsy and were experiencing several attacks of cataplexy
`per day prior to the study despite the use of a TCA in 17
`225
`
`we
`
`SCHAFIF ET AL.
`
`cases. Thus, the effects of GHB in this study are contrasted
`to a “treated” baseline condition. When REM suppressing
`agents are taken for protracted periods,
`the withdrawal
`REM rebound is usually prolonged, lasting several weeks.’
`This can be debilitating in narcoleptic patients because it is
`often accompanied by increased cataplexy, hypnogogic hal-
`lucinations, and sleep paralysis. Broughton and Mamela ,4’
`in their studies of 16 narcoleptics, withdrew patients from
`all previous drug treatment for at least 14 days before initi-
`ating GHB administration. The treatment strategy for this
`study was to overlap GHB administration with TCA with-
`drawal to minimize the marked REM rebound that typically
`occurs. As a result of the TCA withdrawal, the nature of
`
`cataplectic attacks changed somewhat. During baseline ob-
`servations attacks were predictable, usually occurring in
`conjunction with emotional stimuli such as anger or laugh-
`ter. While the TCA patients were in the rebound phase,
`some cataplectic attacks appeared spontaneously without a
`precipitating emotional arousal. The number of attacks
`gradually diminished, presumably as the REM rebound ef-
`fects dissipated.
`Behavioral changes were noted in several patients dur-
`ing the course of the study. During the baseline period they
`carefully avoided situations that might induce cataplexy.
`This seemed to be a well developed self—protective mechan-
`‘ism. During treatment with GHB, however, patients began
`testing the drug’s limits by exercising less emotional re-
`straint and in.some cases seeking out situations that nor-
`mally induced cataplexy. This behavioral change did not
`lead to an increase in cataplexy. In fact, some patients found
`they could not purposely “induce” cataplexy unless they
`were fatigued.
`Our results to date clearly support the efficacy and su-
`periority of GHB compared to previous treatments for the
`treatment of narcolepsy. Unequivocal efficacy, however,
`can only be established by double—blind placebo studies,
`which are currently underway in our laboratory and will be
`reported at a later date.
`
`REFERENCES
`
`1. Dement WC, Carslcadon M, Ley R: The prevalence of narcolepsy. H-
`Slecp Res 2:147, 1973
`Ferriss GS: Narcolepsy. Continuing Education. May 1982, pp 4143
`ms
`. Broughton R, Mamelak M: Gamma-hydroxybutyrate in the treatment
`of compound narcolepsy: A preliminary report. In Guillemjnault C.
`Dement WC, Passouant P (eds): Narcolepsy. New York, Spectrum,
`1976
`
`4. Broughton R, Mamelak M: The treatment of narcolepsy-cataplexy With
`nocturnal gamma-hydroxybutyrate. Can J Neurol Sci 6: 1-6, 1979
`5. Broughton R, Mamelak M: Effects of nocturnal gamma-hydroxylJ“'
`tyrate on sleep/waking patterns in narcolcpsy—cataplexy. Can J Neurol
`Sci 7:23-30, 1980
`6. Mamelak M: The treatment of narcolepsy with gamma—hydr0xyb“'
`tyrate. Sleep Res (in press)
`7.,Vi'ckers MD: Gamma-hydroxybutyric acid. Int Anesthesiol Clin 7:75‘
`89,’ 1969
`8. Mamelak M, Escriu JM, Stokan O: The effects of gammahydroxyb\1'
`tyrate on sleep. Biol Psychiatry 12:273-288, 1977
`_
`9. Dunleavy DLF, Brezinova V, Oswald 1, ct al: Changes during weeks 10
`effects of tricyclic drugs on the human sleeping brain. Br J Psychiaifl’
`120:663-672, 1972