Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 65 of 135
`6/15/01
`
`Frequency of vital sign testing
`
`Study #
`
`
`
`
`OMC-GHB-3
`OMC-SXB-B
`
`OMC-SXB-7
`
`Scrima
`
`
`Baseline, 2 weeks and Months 1,2, 4, 5,6, 8, 10, 12, 14, 16, 18, 21 and 24
`
`Screenino, Week 2 and Months 2 and 6
`Baseline and Months 6, 12, 18 and 24
`No orovision torcheckin- vital sins
`
`
`
`
`
`
`
`
`8. 7.1.2 Lammers Trial
`
`There was no provision for recording vital signs during this trial
`
`8.7.1.3 Integrated Pharmacokinetic Trials
`
`Vital signs recorded and analyzed, when specified, included sitting and standing
`blood pressure, heart rate, respiration, body temperature and body weight.
`
`Vital signs were to be checked in each of the single-dose pharmacokinetic trials
`as follows.
`
`
`
`8. 7.1.4 Scharf Trial
`
`APPEARS THIS W
`0” .
`AY
`QRIGINAL
`
`There was no provision for checking vital signs in the protocol or Case Report
`Form.
`
`8.7.2 Selection of Studies (for Overall Drug-Control Comgarisons And
`
`W 3
`
`.
`.
`
`study groupings have been selected
`0 Controlled Clinical trial: OMC-GHB-2 (this was the only controlled clinical trial
`in which vital signs were checked after administration of study drug)
`Integrated Clinical Trials
`integrated Pharmacokinetic Trials
`
`.
`
`.
`
`8. 7.3 Standard Analvses and Explorations of Vital Si gn Data
`
`8. 7.3.1 Controlled Clinical Trial OMC-GHB-Z
`
`The sponsor has provided a table that displays descriptive statistics for changes
`in vital signs across dose groups from baseline to Visit 6 (end of period of
`double~blind treatment). The mean changes seen were not clinically significant.
`The data suggested a dose-related decrease in weight and sitting diastolic blood
`pressure. An abbreviated form of the sponsor’s main table, including only mean
`changes is reproduced below
`
`

`

`Fianjit 8. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 6b of 135
`6/15/01
`
`Changes from baseline to Visit 6 in vital signs
`
`
`GHB dose (9)
`
`/"s.
`
` signs Placebo 3 6 9
`
`
`
`Changes in vital
`
`
`
`
`
`
`Weight (kg) - mean
`
`Sitting systolic blood
`pressure (mm Hg) -
`mean
`
`Sitting diastolic blood
`pressure (mm Hg) -
`mean
`
`.
`Standing systolic blood
`pressure (mm Hg) -
`mean
`
`Standing diastolic
`blood pressure (mm
`Hg) - mean
`
`Pulse rate (bpm) -
`mean
`
`Respiration (breaths
`per minute) — mean
`
`0.69
`
`1.41
`
`-0.09
`
`-O.34
`
`-0.8
`
`3.56
`
`-1.10
`
`-0.31
`
`2.09
`
`0.53
`
`0.77
`
`-1.83
`
`4.26
`
`5.47
`
`-1.55
`
`0.00
`
`0.
`
`1.74
`
`0.63
`
`-0.55
`
`~2.79
`
`-o.94
`
`1.0
`
`3.16
`
`-1.76
`
`~0.24
`
`-0.87
`
`-0.2
`
`-0.19
`
`4A)
`’36
`0/ 44>
`V0 ,3")
`I533, ’52,,
`’1’? ¢
`‘7! 4»
`
`_
`
`
`
`The sponsor’s main table also indicates that there were no clinically significant
`differences between the placebo group and the individual GHB dose groups in
`minimum and maximum changes for the above adverse events.
`
`8.7.3.2 Integrated Clinical Trials
`
`The sponsor has presented a table containing descriptive statistics for the
`change from baseline to last observation in vital signs. The tables indicate that
`mean changes for all parameters were very small and similar across all treatment
`groups. l have not reproduced these vital signs.
`
`8. 7.3.3 Integrated Pharmacokinetic Trials
`
`individual data listings have been made available for all pharmacokinetic trials
`except OMC-GHB-4; for the latter trial descriptive statistics have been made
`available for vital signs.
`
`These data do not reveal any changes that could be considered clinically
`significant.
`
`

`

`Page 67 of 135
`Ranjit B. Mani, MD, HFD-120 Medical Review
`
`NBA 21196, Xyrem, Orphan Medical, Inc. 6/15/01
`
`8.8 ECG
`
`8.8.1 Extent 0 Electrocardio ram Testin Durin Develo ment
`
`The data below refer only to post-treatment electrocardiograms
`
`8.8.1.] Integrated Clinical Trials
`
`Standard 12-lead resting electrocardiograms were performed.
`
`The frequency at which electrocardiogram testing were intended to be che:ked
`5
`
`a er orotocol
`in these studies is indicated in the followin table
`Frequency of electrocardiogram testing
`
`
`
`
`
`
`
`
`
`8.8.1.2 Lammers Trial
`
`There was no provision for checking electrocardiograms during this trial
`
`8.8.1.3 Integrated Pharmacokinetic Trials
`
`No post-treatment electrocardiograms were checked during these trials
`
`8.8.1.4 Scharf Trial
`A standard 12-lead electrocardiogram was to be checked at or prior to study
`entry, and annually thereafter
`
`8.8.2 Selection of Studies for Overall Drug-Control Comparisons And
`
`W 3
`
`study groupings have been selected
`. Controlled clinical trial: OMC-GHB-Z
`
`Integrated Clinical Trials
`0
`. Scharf trial
`
`8.8.3 Standard Analyses and Explorations of Electrocardiogram Data
`
`8.8.3.1 Controlled Clinical Trial: OMC-GHB-Z
`
`The number and percentage of patients in each treatment group whose values
`went from normal to abnormal in each treatment group between the baseline and
`Week 6 (end of double-blind oeriod visits is summarized in the following table
`
`
`_.IEME-—
`
`
`
`
`
`
`
`
`
`
`
`Details of all 8 patients are summarized in the following table
`
`
`
`
`
`
`
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Abnormal ECGs at Visit 6
`
`Page 68 of 135
`6/15/01
`
`Follow~up (for ECGs
`Patient
`Visit 1
`Visit 6
`not labeled NCS at
`
`number
`Interpretation
`Comments on abnormality
`V6)
`
`105
`
`Within normal limits
`
`Sinus bradycardia — not clinically
`significant
`
`206
`
`Within normal limits
`
`Consider left atrial enlargement
`
`217
`
`Within normal limits
`
`Sinus arrythmia, vertical axis
`
`407
`
`Within normal limits
`
`Normal sinus rhythm, nonspecific T
`wave abnormality
`
`Not clinically signifi-
`cant as determined
`
`by site
`
`Not clinically signifi-
`cant as determined
`
`by site
`
`Not clinically signifi-
`cant as determined
`by site
`No Change from
`baseline, CRF incor-
`rectly reported '
`
`512
`
`Within normal limits
`
`QRS axis range 0 to 14 horizontal
`axis- not clinically significant
`
`818
`
`Within normal limits
`
`Sinus tachycardia - not clinically
`significant
`
`1309
`
`Within normal limits
`
`OCL uniiocal ventricular extra beat
`(VPC), RR complex V1 -V2 indicate
`primary right bundle branch block
`with QFiS 0.10-0.11 seconds
`
`ECG was repeated
`on 12/30/97 and read
`by
`it was
`interpreted as Bor-
`derline ECG Within
`normal limits
`
`1610
`
`Within normal limits
`
`Nonspecific T-wave abnormality in
`anterior-lateral leads when com-
`
`pared with ECG 08/08/97 per -‘
`~\_ - change possibly due to
`hypokalemia - not clinically signifi-
`cant
`
`
`None of the above electrocardiogram abnormalities was felt to be clinically
`significant.
`
`8.8.3.2 Integrated Clinical Trials
`The sponsor has presented shift tables for the categorical change trim baseline
`to last observation in vital signs. The shift categories were:
`Abnormal to abnormal
`Within normal limits to abnormal
`Abnormal to within normal limits
`Within normal limits to within normal limits
`Abnormal to not done '
`Within normal limits to not done
`
`The tables indicate that no shifts of > 10% were seen for the entire population or
`for the “normal to abnormal” category in any single electrocardiogram parameter.
`
`

`

`
`
`
`
`MOO318l$$0d1338
`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 69 'of 135
`6/15/01
`
`
`For the within normal limits to abnormal cate-o the distribution was as follows
`mm.-
`
`_—___—I-_l=-
`
`
`
`Note that all patients in each dose group did not have electrocardiograms done
`both at baseline and subsequently, the last row cannot therefore be used as a
`denominator to calculate percentages for the second row
`
`8.8.3.3 ScharfTrial
`
`All electrocardiograms in the study were categorized as being normal or
`abnormal and a shift table generated which demonstrates categorical change by
`dose group from baseline. This table is reproduced below.
`
`ECG
`
`Shift
`
`6H3 dose (9)
`n (h)
`an
`Patients
`
`3
`
`4 . 5
`
`.
`
`6
`
`7 . S
`
`9
`
`Harm :c. Norm
`home. to Aim"
`Firm :0 Mom?
`Abra :0 Am:
`
`S {5.3}
`36 {25.2}
`5 {3.5:
`35 {27.3)
`
`1
`
`0 (6.03
`(20.0.5
`o (0.0;
`{E
`(0.0}
`
`(6.2)
`3
`11 {22.4t
`3
`(5.33
`13 {26.5}
`
`16.5‘.l
`d
`[25.8]
`If:
`2 [3.2)
`19 (30.6)
`
`(12.3}
`2,
`(22.2}
`4
`o {9.3:
`5 (27.3}
`
`0 (QJJ)
`‘1
`{44.11%
`o {0.0;
`2 122.2%
`
`‘Pazienzs included if they 315:5 E. name}.
`baselLJe ECG and had an 313::ch ECG anytime
`$31129 :e:eivir:g 81-25.
`‘=atien:s included if they had an abnormal
`r. u .
`u.
`'
`ine ECG and had a normal ECG anytime while
`Hr"
`veCuiving GEE.
`
`Source: Section 15~.able 8.
`"
`
`Note that of those patients who had baseline electrocardiograms, some had a
`single repeat recording whether others had multiple recordings done. The interval
`between recordings was highly variable.
`
`Of the 36 patients who had electrocardiograms that were normal at baseline but
`abnormal later
`
`.
`
`0
`
`28 patients had abnormalities that were considered “non-specific, benign and highly
`unlikely to be clinically significant"
`In the remaining 8 patients the abnormalities were considered to possibly be
`clinically significant, but probably not related to study medication. The sponsor has
`provided short descriptions of the conclusions(diagnoses) drawn for the
`electrocardiograms for these 8 patients. The diagnoses reached in these 8 patients
`were distributed in the following 4 categories: except for 1 patient each who were
`considered to have acute pericarditis and ischemic heart disease, the remainder had
`multiple electrocardiograms. No additional information is available for these patients
`and there is no evidence that an attempt was made to correlate electrocardiogram
`abnormalities with symptoms, physical signs or other cardiac tests in these patients.
`Left ventricular hypertrophy
`1 patient
`7
`lschemic heart disease
`3 patient
`Conduction system disease
`3 patient
`Acute pericarditis
`1 patient
`
`

`

`Fianjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, lnc.
`
`Page 70 of 135
`6/15/01
`
`8.9 Withdrawal Phenomenon and Abuse Potential
`
`An separate review of this subject is being performed by the Controlled
`Substances Staff of this Agency
`
`8. 9.] Back round
`
`As indicated earlier in this review, for many years GHB was distributed in this
`country as a health food product under a variety of trade names; in 1990 it was
`removed from the market by this Agency after a number of reports of adverse
`reactions.
`‘
`
`Public Law 106-172 (passed by the United State Congress on February 18,
`2000) has allowed for the designation of GHB as a Schedule I agent, with
`exemption from the security requirements of that schedule for the GHB drug
`product studied under an FDA-approved IND. Upon marketing approval from the
`FDA being received, the GHB drug product would become a Schedule III agent
`with Schedule I penalties for illicit use. All other forms and uses of GHB-
`containing products would remain under Schedule 1, except that use under an
`FDA-approved IND would be exempted (as noted above).
`
`There have been many reports in the media, over the last few years, of instances
`of overdose with illegally-manufactured GHB. A number of anecdotal single case
`reports/case series of a similar nature have also been published in the medical
`literature. There have also been similar reports linked to the use of related
`compounds such as gammabutyrolactone (GBL) and 1,4-butanediol (1 ,4-BD),
`both of which are converted to GHB in the body.
`‘
`
`ffus
`
`According to the sponsor, illicit GHB users in this country obtain the drug from
`the following sources
`. Purchase from illegal vendors, including those selling the drug over the
`Internet
`
`. By home manufacture: both recipes and starting materials are easily
`available
`'
`
`8.9.2 Pumoses For Which GHB Is Misused 0r Abused
`
`These are listed by the sponsor as follows:
`As a steroid replacement in the body building community
`As a sleep aid
`As an intoxicant
`
`As an aphrodisiac
`As a means of enhancing the effects of alcohol and stimulants
`As a “date-rape” drug (related to its sedative and alcohol-enhancing properties)
`
`8.9.3 Clinical Psychological And Physical Degendence In Humans
`
`The sponsor states the following.
`
`. Sodium oxybate does not appear to produce strong psychological or physical
`dependence
`'
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 71 of 135
`6/15/01
`
`0 No formal studies have been conducted to assess dependence with GHB
`. A few case reports have suggested that chronic high-dose GHB use outside a
`clinical setting can, when the drug is withdrawn, lead to an abstinence
`syndrome comprising insomnia, anxiety, tremors and hallucinations. in the
`same setting dose-escalation to maintain a clinical effect has also been
`described. Several case reports also suggest that users outside a clinical
`setting may sometimes increase their dose to maintain a clinical effect.
`0 However
`
`. When GHB was discontinued after 3- and 6-month clinical trials for the treatment
`
`of alcohol withdrawal, no abstinence syndrome was seen. However during the 6-
`month trial an escalation of GHB consumption and craving for that drug was
`reportedin about 10% of patients
`In a clinical study of GHBin 48 narcoleptic patients, lasting 9 years, no tolerance
`to the effects of GHB was observed.
`
`.
`
`0 Anecdotal reports and controlled trials suggest a potential cross-tolerance or
`dependence with alcohol. in alcoholics GHB may not only reduce the
`symptoms of alcohol withdrawal but may also decrease the consumption of
`and craving for alcohol
`. GHB also relieves the abstinence syndrome that follows spontaneous opiate
`withdrawal; a similar effect on precipitated opiate withdrawalis blocked by
`naloxone.
`
`8.9.4 Rebound Symptoms With GHB Withdrawal
`
`In the randomized, double-blind, placebo-controlled, parallel-arm trial OMC—GHB-
`2, the incidence of adverse events suggestive of REM rebound (sleep
`disturbance, hallucinations, abnormal dreaming), and the incidence of cataplexy
`was compared between the following 2 periods
`-
`The period of up to 5 days prior to the completion of double- blind treatment
`.
`A period of up to 5 days between the cessation of double- blind treatment and the post-
`treatment follow--up visit
`
`The difference in the incidence of adverse events was reported by the sponsor
`not to be statistically significant. Comparative data are not provided by the
`sponson
`
`The sponsor has however supplied listings of adverse events which might be
`suggestive of REM rebound during the withdrawal period. 6 patients experienced
`such adverse events (each patient experienced one adverse event). These are
`listed in the followin table
`
`GHB dose durin double-blind nhase
`3 g/day
`
`Adverse events durin- withdrawal chase
`Abnormal dreaming (1 patient)
`Sleeo disorder 1 atlent)
`
`9 g/day
`
`Slee- disorder 1 oatient
`Hallucinations (1 patient)
`Slee disorder (1 natient
`
`
`
`
`
`
`All adverse events were mild and, except for the instance of “sleep disorder”
`seen in a patient who received 3 g/day previously (in whom the adverse event
`
`l"\
`
`r\
`
`
`
`
`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 72'of 135
`6/15/01
`
`lasted 7 days), lasted 1-2 days only. It is unclear exactly what the term “sleep
`disordeI” refers to.
`
`The sponsor also states that there was no tendency to rebound cataplexy during
`the short period of withdrawal.
`
`8.9.5 Extent 0[ GHB Abuse In The United States
`
`According to the sponsor
`. Sodium oxybate abuse is mentioned relatively infrequently in Drug Abuse
`Warning Network reports compared with other sedative/hypnotics that are
`abused such as benzodiazepines
`. Currently sodium oxybate abuse is too rare to be listed in any database
`.
`In the Drug Enforcement Administration June 1998 Drug/Chemical Review it was
`stated that 1000 encounters with GHB had been documented Over an
`
`unspecified period of time
`. Only 82 cases of GHB misuse or abuse had been reported over an 18-month
`period ending December 1997 in a report presented at a February 1998
`American Academy of Pediatric Sciences meeting
`. The Mid-Year 1999 Preliminary Emergency Department Data from the Drug
`Abuse Warning Network had no mention of GHB
`. Only one GHB- related death was reported to the Drug Abuse Warning .
`Network by participating medical examiners between 1992 and 1995; in this
`instance the death occurred in an individual who had concurrently used
`alcohol and GHB.
`
`8.9.6 Pre-Clinical Studies Of Drug Abuse Potential
`
`The sponsor has outlined the results of a battery of animal studies that have
`been done with GHB. These consist of studies of drug discrimination, reinforcing
`effects, and tolerance and dependence.
`8
`
`A full review of these studies is beyond the competence of this reviewer.
`
`Based on these studies the sponsor has made the following conclusions: I
`. Drug discrimination studies consistently fail to show cross-substitution with
`abused depressant drugs such as the benzodiazepines and barbiturates,
`although there is evidence for some cross-substitution with ethanol over‘a
`narrow dose range
`Self—administration studies fail to show evidence for strong reinforcing effects
`.
`. Repeated administration of sodium oxybate may resultIn the development of
`tolerance.
`
`. Overall, “based on preclinical studies alone, there is no compelling evidence
`that sodium oxybate represents a significant drug abuse hazard.”
`
`8.10 Human Reproduction Data
`
`A single patient is reported to have become pregnant while taking GHB. She is
`described briefly in Section 8.3.1.5
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, lnc.
`
`Page 73 of 135
`6/15/01
`
`8.11 Overdose
`
`8.11.1 Background
`
`Descriptions of the clinical effects of GHB overdose are derived almost entirely
`from anecdotal reports related to illegal use of the drug
`
`Section 8.9.2 describes the circumstances under which GHB is used or abused.
`
`.
`
`When the above anecdotal reports are reviewed, the identification of the dose of
`GHB used and determining the causal relationship of the clinical syndrome
`described to GHB are both problematic for the following reasons.
`0 The sources of the drug are clandestine and varied, as are the starting
`materials used to manufacture the drug, and the dose ingested therefore
`unknown in most instances; in addition an evaluation of illegally
`manufactured sodium oxybate liquid samples has shown a high level of
`inconsistency of content.
`In a number anecdotal reports, precursor chemicals, i.e.,
`gammabutyrolactone (GBL) and 1,4-butanediol have been ingested, rather
`than GHB to which the adverse events have been attributed. Although these
`precursor chemicals are converted to GHB in the body, their
`pharmacokinetics are different from GHB: for example, GBL is more lipid
`soluble and more rapidly absorbed
`. Other drugs of abuse are frequently used concurrently including alcohol,
`methamphetamine, and MDMA. In such instances the adverse event has
`been attributed to GHB based, in most instances, on the clinical history
`alone; blood and tissue levels of GHB have been measured only rarely.
`Thus in those instances it has been difficult to know to what extent GHB
`
`contributed to the patient’s clinical syndrome.
`
`Of the 5 deaths reported in the medical literature and attributed to GHB
`consumption, only one was clearly linked to GHB use alone.
`
`8. I 1.2 Clinical Presentation
`
`According to the sponsor the clinical presentation of GHB overdose is influenced
`by the dose and frequency of ingestion, and most importantly, concurrent use of
`other drugs.
`
`Patients presenting in a conscious state may be agitated, combative, anxiohs
`and confused, and may exhibit hallucinations. Varying degrees of obtundation
`may also be seen extending to deep coma that is unresponsive even to pain;
`deep coma has been associated with doses ranging from 2.5 g to 30 9. With an
`increased depths of unconsciousness the following may also be observed;
`bradycardia, hypotension, depressed respiration/Cheyne-Stokes breathing and
`hypothermia. Obtundation may be potentiated by the concurrent use of alcohol.
`
`

`

`Page 74 of 135
`Ranjit B. Mani, MD, HFD-120 Medical Review
`
`NBA 21196, Xyrem, Orphan Medical, Inc. 6/15/01
`
`Other symptoms and signs may include dizziness, nausea, vomiting, myoclonus,
`blurred vision, visual field abnormalities, sluggish pupillary reactions, amnesia
`and hypotonia.
`
`Symptoms may appear as early as 15 minutes after ingestion and may persist for
`2 to 96 hours
`
`Note that in the NDA safety database, 2 patients took, or are presumed to have
`taken overdoses. These patients are further described in Sections 8.3.1.1 and
`8.3.2.2.
`
`A further instance of Xyrem® overdose has been reported in the 120-Day Safety
`Update (see Section 13.104)
`
`8.1 1.3 Treatment
`
`According to the sponsor the treatment of GHB overdose is primarily
`symptomatic and supportive. The measures to be instituted include
`0
`care of the airway, with intubation and artificial ventilation as needed
`.
`consideration of gastric aspiration and lavage with activated charcoal
`- measurement of blood levels of GHB.
`
`While flumazenil and naloxone are ineffective for the treatment of GHB
`intoxication, intravenous physostigmine has been reported anecdotally to
`produce rapid reversal of obtundation.
`
`9. Study OMC-SXB-20
`
`This was an open-label study that was intended to evaluate the effects of 4
`doses of Xyrem® on sleep architecture. The study report was submitted on-
`12/16/00, i.e., after the original NDA submission. The sponsor desires that the
`results of this study be included in labeling.
`
`A brief outline of the study protocol and safety data from this study are presented
`below.
`
`9.1 Objectives
`
`9.1.1 Primafl
`
`The primary objective of this study was to characterize the polysomnographic
`sleep architecture in narcoleptic patients at 4 GHB doses: 4.5 g, 6.0 g, 7.5 g and
`dimw
`.
`
`9.1.2 Secondafl
`
`The secondary objectives of the study were to
`. Assess the effect of Xyrem® on sleep as measured by the Epworth
`Sleepiness Scale
`- Assess the effects of Xyrem® on common symptoms of narcolepsy as
`measured by the Narcolepsy Symptoms Assessment
`
`

`

`Page 75 of 135
`Ranjit B. Mani, MD, HFD-12O Medical Review
`
`NDA 21196, Xyrem, Orphan Medical, Inc. 6/15/01
`
`. Assess EEG measures of wakefulness under soporific conditions using the
`Maintenance of Wakefulness Test
`
`. Assess the safety of Xyrem®
`
`9.2 Design/Summary of Investigational Plan
`
`This was an open-label uncontrolled study divided into 2 phases. Stimulant
`medication was maintained at a constant level during the trial
`
`9.2.] Phase I
`
`This phase lasted 4 weeks
`0
`in the initial 2 weeks of this phase patients were withdrawn from tricyclic
`antidepressants, selective serotonin re—uptake inhibitors and hypnotics
`In the last 2 weeks of this phase patients remained free of tricyclics
`
`.
`
`An overnight polysomnogram was performed at the beginning and end of this
`phase. The Epworth Sleepiness Scale questionnaire was administered at about
`the time of each polysomnogram
`
`9.2.2 Phase II
`
`This phase began with the patient receiving 4.5 g of GHB nightly for the initial 4
`weeks. At the end of this period the dose was increased to 6.0 g nightly and
`further to 7.5 g nightly and 9 g nightly at 2 week intervals. Each total nightly dose
`of GHB was administered in 2 equal divided doses 2.5 to 4 hours apart.
`
`Overnight polysomnograms on the night of the first dose of Xyrem® and on the
`last night of each dose. The Epworth Sleepiness Scale was administered‘at the
`end of each dosing period
`
`)/-.
`
`9.3 Duration
`
`10 weeks
`
`9.4 Sample Size
`
`20-30 planned
`
`9.5 Key Inclusion Criteria
`
`Informed consent
`
`Age 2 18 years
`American Sleep Disorders Association criteria for narcolepsy
`Use of stable doses of tricyclic antidepressants or selective serotonin re-
`uptake inhibitors for narcolepsy for at least 3 weeks. if taking stimulants must
`have been on a stable dose for at least 3 weeks
`lf female must be
`
`.
`
`.
`.
`.
`
`Surgically sterile OR
`2 years post-menopausal OR
`ll of child-bearing potential must be using effective contraception and must continue this treatment
`during the study
`
`0 Adequate support for duration of trial
`
`.‘
`
`

`

`Page 76 of 135
`Ranjit B. Mani, MD, HFDv120 Medical Review
`
`NBA 21196, Xyrem, Orphan Medical, Inc. 6/15/01
`
`9.6 Key Exclusion Criteria
`
`Unstable diseases in any body system, other than narcolepsy, which would
`place the patient at risk or compromise the trial objectives
`Use of tricyclic antidepressants or selective serotonin re-uptake inhibitors for
`depression or for any indication other than narcolepsy
`History of substance abuse, as defined by DSM-IV, currently or within the
`past year
`History of psychiatric disorders that would preclude study participation
`Serum creatinine > 2 mg/dl; AST or ALT > 2 x upper limit of normal; serum
`bilirubin > 1,5 x upper limit of normal; pre-trial electrocardio ram results
`demonstrating a clinically significant arrhythmia or 2nd or 8' degree A-V block;
`history of myocardial infarction within the past 6 months
`Any untreated disorder other than narcolepsy that could be considered a
`primary cause of excessive daytime sleepiness, including sleep apnea
`syndrome (criteria specified)
`Occupation requiring variable shift or routine night shift work
`
`Use of sodium oxybate within the preceding 30 days
`
`Use of any investigational drug within the preceding 30 days
`
`No clinically significant history of head trauma, seizure disorder or previous
`intracranial surgery
`Willing to not operate a car or heavy machinery if the clinical investigator feels
`such a restriction is warranted
`Use of medication for narcolepsy during baseline period, other than a stable
`dose of stimulant medication (“stable dose” defined as one without any-
`significant change in dose for the 5 - day period just prior to the baseline
`period)
`
`Use of hypnotics, tranquilizers, antihistamines (except for the non-sedating
`variety of such drugs) and clonidine at the start of the baseline period.
`
`9.7 Dosage
`
`See Section 9.2
`
`9.8 Outcome Measures
`
`9. 8. I Primagy Efficacy Measures
`
`The following objective overnight polysomnogram parameters
`Wake After Sleep Onset (WASO) in minutes following the first and second dose of
`Xyrem and the summation
`Total Sleep Time (TST) in minutes following the first and second dose of Xyrem and
`the summation
`
`Stage 1 sleep time in minutes following the first and second dose of Xyrem and the
`summation
`
`Stage 2 sleep time in minutes following the first and second dose of Xyrem and the
`summation
`
`Stage 3 & 4 sleep time in minutes following the first and second dose of Xyrem and
`the summation
`'
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 77 of 135
`6/15/01
`
`0 Rapid Eye Movement (REM) sleep time in minutes following the first and second
`dose of Xyrem and the summation
`Sleep latency in minutes following the first and second dose of Xyrem
`REM sleep latency in minutes following the first and second dose of Xyrem ,
`Stage shifts per hour following the first and second dose of Xyrem and an average
`Total awakenings following the first and second dose of Xyrem® and the summation
`Delta power in microvoltsz/Hz following the first and second dose of Xyrem and an
`average
`
`OCOOO
`
`9.8.2 Secondag Efficacy Measures
`
`. Epworth Sleepiness Scale
`. Narcolepsy Symptoms Assessment
`. Maintenance of Wakefulness Test
`
`9.8.3 Saiegy Measures
`
`Adverse events, safety laboratory tests, vital signs, electrocardiograms and
`physical examinations
`
`9.9 Analysis Plan
`
`. Demographic variables at baseline were summarized as follows
`0 Gender and race were summarized by the number of patients in each category
`. Age, height and weight were summarized by descriptive statistics
`o Efficacy variables were analyzed as follows
`.
`Inferential statistics were performed for descriptive purposes only as per the
`sponsor
`
`.
`
`. Quantitative polysomnogram variables and the Epworth Sleepiness Scale were
`analyzed using 2--way ANOVA with patient and dosage as the main effects
`If a statistically significant difference was found among dose groups using
`ANOVA, pain/vise comparisons using the least significant difference test were
`performed. It the assumptions for the above ANOVA were not satisfied the rank
`changes from baseline were analyzed using the ANOVA model. The significance
`of the mean change from baseline (end of Phase I) in each dose group was
`determined using a paired t-test or a Wilcoxon signed rank test
`For the above analysis the level of statistical significance was 0.05 (two-sided)
`.
`. Variables for the narcolepsy symptom questionnaire measured as a change from
`the beginning of Phase I were presented by number and percentage of patients
`. Safety analyses were performed as follows
`. Adverse events were summarized by body system using COSTART term and by
`relationship to treatment, dose and severity
`- Changes from the beginning of Phase 1 to the end of the study in laboratory
`parameters were summarized using descriptive statistics
`0 Changes from the end of Phase I to the end of the study in vital signs were'
`summarized using descriptive statistics
`. Changes from the beginning of Phase I to the end of the study in
`electrocardiogram parameters were summarized
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 78 of 135
`6/15/01
`
`9.10 Results
`
`9.10.] Patient Disgosition
`
`.
`0
`.
`
`27 patients were enrolled in the study
`25 patients were treated with GHB
`21 patients completed the study
`
`9.10.2 Baseline And Demograghic Characteristics
`
`Baseline and demographic characteristics for all 25 treated patients are
`summarized below
`"um
`
`
`
`
`
`
`
`
`Gender: Males 28%; Females 72%
`Race: Caucasian 92%; Black 8%
`
`9.10.3 Tricvclic Antidegressants, Selective Serotonin Re-UQtake Inhibitors
`And Hygnotics At Baseline
`.
`
`These are summarized in the next table, copied from the submission.
`
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`
`9.10.4 Protocol Deviations
`
`These are summarized in the next table copied from the submission. The table
`applies to all 25 treated patients
`
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`
`

`

`Page 79 of 135
`Ranjit B. Mani. MD, HFD-120 Medical Review
`
`NDA 21196, Xyrem, Orphan Medical, lnc. 6/15/01
`
`9.10.5 Treatment Compliance
`
`Treatment compliance at each dose level is summarized in the following table
`copied from the submission. Mean compliance at each dose level was high.
`
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`
`9.10.6 Extent Of Exposure
`The mean duration of treatment was 63.3 nights (standard deviation: 21.29)
`9.10.7 Efizcacy Results
`
`See summary in NDA Efficacy Review
`
`9.10.8 Safety Results
`
`9.10.8.1 All Adverse Events
`18 out of 25 (72% of) patients participating in the study reported at least 1'
`adverse event.
`
`A summary of adverse events in several broad categories, by dose at onset, is
`provided in the next table, copied from the submission.
`
`(gnaw)
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`
`Note that the patient listedIn the table as having a SERIOUS adverse event did notIn fact have one, according to
`the sponsor. 4 days prior to beginning study drug the patient was diagnosed to have a yeast infection and was
`treated with miconazole nitrate suppositories 5 mg daily. Her white blood cell count was elevated at 11.43
`K/microliter at screening. After a single dose of Xyrem® 4.5 g she withdrew her consent to participate in the
`study and was not available tor turther visits or telephone contacts. I have reviewed the Case Report Form tor
`this patient
`
`The next 2 tables list treatment-emergent adverse events, by dose at onset, that
`occurred in 2 5% of patients in any dose group
`
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`
`

`

`Ranjit e. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 80 of 135
`6/15/01
`
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`anorexia, nausea and dizziness
`
`9.10.8.2 Deaths And Serious Adverse Events
`
`There were no deaths or serious adverse events. As noted earlier, the sole
`serious adverse event listed in the table in Section 9.10.8.1 was not a serious
`
`adverse event at all.
`
`9.10.8.3 Adverse Event Discontinuations
`2 patients discontinued treatment on account of adverse events. They are ’
`described further below:
`’
`
`9.10.8.3.1 PATIENT # 17304
`
`This 67 year old woman had a past history of a tonsillectomy and of lumpectomy and
`radiation therapy for right-sided breast cancer.
`
`In Study OMC-SXB-20 she received Xyrem® in the following consecutive dosing
`regimes: 4.5 g/day for 35 days; 6 g/day