Does Xyrem Influence Brain Dopamine in Patients With Narcolepsy? A PET Imaging Investigation
Phase: PHASE4
Conditions: Narcolepsy With Cataplexy, Healthy Controls
Sponsor: Centre for Addiction and Mental Health



DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
A PET IMAGING INVESTIGATION 
PROTOCOL: 017/2014, V5.0 
filename: CAMHPET-CTA-A-98-01_StudyProtocol_V6_20170913.docx 
 
PI: KISH  
QI: O’LEARY  
REV:SEPTEMBER 13
TH, 2017 
 
 
 
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Protocol Version  
Date Issued  
Summary of Revisions  
V 1.0 
24-Feb-2014 
- original REB submission 
V 2.0 
08-Apr-2014 
- removal of stimulant using group and all related text (including 
associated consent form) 
- removal of antidepressants as an exclusion 
- revision of negative drug test requirement on scan days 
- expansion of precautions after taking Xyrem
® 
- minor corrections as necessary 
V 3.0 
09-Dec-2014 
- change in title 
 
V 4.0 
22-Jun-2015 
- change to Dr. Shapiro’s clinic location/contact information 
- change to study start/finish dates 
- addition of Data Management and Regulatory Issues sections 
- corrections and reformatting as necessary 
V 5.0 
05-Jun-2017 
- addition of J. Warsh as Co-Investigator, I. Vitcu as monitor 
- addition of healthy control group 
- request for permission to access participants’ GP and/or medical records 
for medical screening (optional) 
- additional blood sample taken at 0.5 hours post Xyrem
® 
- corrections and reformatting as necessary 
V 6.0 
13-Sep-2017 
- removal of Dr. Shapiro and TWH-UHN as a study Co-investigator / site 
with subsequent changes to: Site Number; Recruitment and Screening 
procedures 
- slight modification to inclusion criteria indicating that all narcolepsy 
participants will have a confirmed diagnosis, as determined by a sleep 
specialist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
A PET IMAGING INVESTIGATION 
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Table of Contents 
1. 
LIST OF INVESTIGATORS ................................................................................................................. 5 
2. 
BACKGROUND AND RATIONALE .................................................................................................... 6 
3. 
OBJECTIVE AND HYPOTHESES ...................................................................................................... 8 
4. 
TOTAL NUMBER OF SITES AND NUMBER OF CANADIAN SITES ............................................... 9 
5. 
STUDY PARTICIPANTS ..................................................................................................................... 9 
5.1. 
SAMPLE SIZE ................................................................................................................................. 9 
5.2. 
PATIENT POPULATION .................................................................................................................... 9 
5.3. 
INCLUSION CRITERIA ...................................................................................................................... 9 
5.4. 
EXCLUSION CRITERIA .................................................................................................................... 9 
6. 
STUDY DESIGN AND DURATION ................................................................................................... 10 
6.1. 
SUMMARY OF DESIGN .................................................................................................................. 10 
6.2. 
DURATION ................................................................................................................................... 11 
6.3. 
DETAILS OF STUDY DESIGN .......................................................................................................... 11 
6.3.1. Recruitment ........................................................................................................................... 11 
6.3.2. Schedule of Activities ............................................................................................................ 11 
6.3.3. Pre-Study Screening and Baseline Evaluation (Days 1 and 2) ............................................ 12 
6.3.4. Treatment/Assessment visits ................................................................................................ 13 
6.3.5. Unscheduled Visits ............................................................................................................... 14 
6.4. 
PET AND MRI SCAN PROCEDURE, DATA ACQUISITION, AND IMAGE ANALYSIS ................................... 14 
7. 
EFFICACY VARIABLES AND ANALYSIS ....................................................................................... 15 
8. 
STUDY DRUG ................................................................................................................................... 15 
8.1. 
DRUG FORMULATION ................................................................................................................... 15 
8.2. 
DOSAGE REGIMEN ....................................................................................................................... 15 
8.3. 
WASHOUT PERIOD ....................................................................................................................... 16 
9. 
CONCOMITANT MEDICATION ........................................................................................................ 16 
10. RESCUE MEDICATION AND RISK MANAGEMENT ...................................................................... 16 
10.1. 
RISKS FROM XYREM® ................................................................................................................... 16 
10.2. 
OTHER RISKS THAT MIGHT RESULT FROM STUDY PROCEDURES ...................................................... 17 
11. PREMATURE WITHDRAWAL/DISCONTINUATION CRITERIA ..................................................... 18 
12. SAFETY VARIABLES AND ANALYSIS ........................................................................................... 18 
12.1. 
ADVERSE EVENTS ....................................................................................................................... 18 
12.2. 
SERIOUS ADVERSE EVENTS ......................................................................................................... 18 
13. STATISTICAL ANALYSIS ................................................................................................................ 19 
14. DATA MANAGEMENT AND RETENTION ....................................................................................... 20 
15. REGULATORY ISSUES .................................................................................................................... 20 
15.1. 
ETHICS APPROVAL ....................................................................................................................... 20 
15.2. 
CONSENT .................................................................................................................................... 20 
15.3. 
CONFIDENTIALITY ........................................................................................................................ 20 
15.4. 
SPONSOR .................................................................................................................................... 20 
15.5. 
FUNDING ..................................................................................................................................... 20 
15.6. 
AUDITS ....................................................................................................................................... 20 
16. REFERENCES .................................................................................................................................. 21 

DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
A PET IMAGING INVESTIGATION 
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DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
A PET IMAGING INVESTIGATION 
PROTOCOL: 017/2014, V5.0 
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1. LIST OF INVESTIGATORS 
 
Principal Investigator 
Stephen Kish, Ph.D. 
Research Imaging Centre - Human Brain Lab  
Centre for Addiction and Mental Health 
250 College Street 
Toronto, ON 
M5T 1R8 
Phone:  
416-535-8501 x 36256 
Fax:  
416-979-6871 
Email:  
Stephen.kish@camh.ca 
 
Qualified Investigator 
Gerald O’Leary, MD 
Anesthesiologist-in-Chief 
University Health Network – Toronto General 
Hospital 
200 Elizabeth Street, EN3-460 
Toronto, ON 
M5G 2C4 
Phone:  
416-340-4359 
Email:  
Gerald.O’Leary@uhn.on.ca 
 
Co-Investigator 
Isabelle Boileau, Ph.D. 
Research Imaging Centre - Addiction 
Imaging Section 
Centre for Addiction and Mental Health 
250 College Street 
Toronto, ON 
M5T 1R8 
Phone:  
416-535-8501 x 34918 
Email:  
Isabelle.boileau@camh.ca 
 
 
Co-Investigator 
Jerry Warsh, MD 
Laboratory of Cellular and Molecular 
Pathophysiology 
Centre for Addiction and Mental Health 
250 College Street 
Toronto, ON 
M5T 1R8 
Phone: 
416-535-8501 x 34279 
Email:  
Jerry.warsh@camh.ca 
 
Monitor 
Irina Vitcu 
PET Centre, Research Imaging Centre 
Centre for Addiction and Mental Health 
250 College Street 
Toronto, ON 
M5T 1R8, 
Phone:  
416-535-8501 x 36491 
 
 
Clinical laboratory involved in the trial 
CAMH Clinical Laboratory 
Queen Street Site 
100 Stokes Street - Bell Gateway Building 
Toronto, ON  
M6J 1H4 
Phone:  
416-535-8501 x 32052 
Fax:   
416-583-4605 
 
 
 

DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
A PET IMAGING INVESTIGATION 
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2. BACKGROUND AND RATIONALE   
Animal data suggest that the sedative drug Xyrem® (Sodium Oxybate, Gamma-hydroxybutyrate 
(GHB)), used in treatment of patients with narcolepsy, might act on the brain dopamine system, 
but human findings are lacking. 
GHB is a short chain endogenous fatty acid and GABA metabolite that has sleep-inducing CNS 
depressant effects.  Sodium oxybate, the sodium salt of GHB is approved in Canada (as “Xyrem®”) for 
the (night-time) treatment of cataplexy in patients diagnosed as having narcolepsy with cataplexy 
(hereafter referred to as “narcolepsy”), a sleep disorder characterized in part by excessive daytime 
sleepiness.  GHB has also been proposed for use as a “neuroprotective” agent in brain disorders such 
as Alzheimer’s disease  and major depressive illness, and is also an illicit recreational, abused drug (for 
reviews see [1] and [2]). 
 
Because Xyrem® is presently approved for clinical use in Canada, and is likely to be used in future for 
other conditions (e.g., see ongoing clinical trials in “clinicaltrials.gov”), information on the mechanism of 
action of Xyrem® in subjects having medical conditions which might benefit from its use, might help in 
understanding the actions and unwanted side effects of this clinically used drug.  At present, 
information on the possible mechanism of action of this drug is limited to animal studies of uncertain 
relevance to the human and to our preliminary findings in normal subjects. 
 
As described below, the overall aim of this investigation is to establish whether an action of Xyrem® on 
the brain dopamine system in patients with narcolepsy, and in a comparison control group, might 
explain part of the anti-narcoleptic effect of the drug.   
 
Xyrem®, taken at night, is thought to act by providing continuous “refreshing” sleep to patients with 
narcolepsy resulting in less periods of daytime sleepiness.  The mechanisms of this action are 
unknown; however, the manufacturer suggests that, based on animal literature, a key action might be a 
reduction in brain dopaminergic activity during sedation ([3] ; see also below).  In this regard, some 
animal data suggest that an acute dose of Xyrem® depresses activity of brain dopamine neurones and, 
as a result, dopamine is not released from the nerve ending (see below).  On the other hand, 
investigators leading a study of Xyrem® in Parkinson’s disease patients who have sleep problems 
suggest a different mechanism: that Xyrem®-induced improvement of daytime sleepiness might be 
caused by above-normal release of dopamine (acting as a modest dopamine-delivering stimulant) 
during drug withdrawal (which would occur at daytime), as the dopamine built up in the neurone during 
sleep/sedation is released during the day [4].   
 
Animal data (since 1966 [5]), which could address the above questions are still contradictory and 
sparse on the nature of GHB-dopamine interactions [6-10] (e.g., review “Does GHB inhibit or stimulate 
central DA release?”)[11].  Cruz and colleagues, on the basis of some electrophysiological findings 
speculate that “recreational” doses of GHB could stimulate dopamine neurones, but that at “higher” 
concentrations dopamine release might be inhibited [12].  Missing from experimental animal studies are 
data convincingly showing effects of GHB “withdrawal” on dopamine (i.e., is withdrawal associated with 
a potentially beneficial dopaminergic hyperactivity?).  
 
Animal findings, however, can only suggest what might occur in the human and need to be confirmed in 
the clinically relevant human.  
 
In light of the speculations above, the available animal findings, and our preliminary brain imaging 
findings in normal subjects described below, we wish to determine in a brain imaging study whether 
Xyrem® might produce a concentration and time-dependent biphasic change in dopamine activity in 

DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
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(Xyrem®-naïve) patients with narcolepsy. We will also include a group of control subjects in order to 
determine whether this proposed mechanism of action of Xyrem® might or might not be dependent on 
disease state. 
 
How can brain dopamine be measured in living humans?   
Extracellular dopamine levels cannot be directly measured in living human brain and can only be 
inferred by conducting a brain imaging (e.g., positron emission tomography; PET) study in which 
binding of a short-lived radiolabelled probe to components of the brain that are competitively acted 
upon by dopamine is measured.   
 
The radiolabelled probes that we have selected are 11C-raclopride and 11C-dihydrotetrabenazine (11C-
DTBZ).  11C-raclopride, has low affinity for the D2 dopamine receptor in the dopamine-rich striatum 
(caudate, putamen), and its binding can be influenced by changes in the concentration of extracellular 
dopamine.  Thus, in imaging studies, administration of a stimulant drug (e.g., amphetamine) that 
promotes neuronal release of dopamine, and consequently increased extracellular dopamine levels, will 
reduce the specific binding of 11C-raclopride in striatum (see [13] and references therein). 11C-DTBZ 
binds to the striatal vesicular monoamine transporter (VMAT2) and is sensitive to changes in vesicular 
neuronal stores of dopamine.  This tracer can be used to establish whether vesicular (intraneuronal) 
dopamine levels are altered during Xyrem® exposure (see [14, 15]). 
 
Should Xyrem® initially decrease activity of brain dopamine neurones and dopamine release during the 
sedated state, one would expect increased binding of 11C-raclopride to the D2 dopamine receptor, 
localized outside the dopamine neurone, because of decreased competition from dopamine at the 
dopamine receptor.  We would expect a decrease in 11C-DTBZ binding to VMAT2 due to attenuated 
dopamine release, accelerated dopamine biosynthesis, and resultant increase of dopamine in vesicular 
stores competing with 11C-DTBZ for binding at VMAT2. 
  
In contrast, during withdrawal from Xyrem®, a time at which some animal data suggest that dopamine 
release might be increased (as part of a “rebound” phenomenon) we would expect binding of 11C-
raclopride to be decreased, a result of increased competition from dopamine.  As described below, our 
preliminary data in normal subjects support these predictions. 
 
Preliminary Study supports possibility that Xyrem® induces biphasic dopamine changes in 
normal human brain. 
As part of a Health Canada-approved study (CTA 139361, CTA-A1 154385, CTA-A2 157188) of the 
influence of Xyrem® on brain dopamine measures we have obtained pilot PET data suggesting that 
Xyrem® changes both intra- and extra-neuronal dopamine levels in brain, initially depressing 
dopaminergic activity during sedation but later causing a slight, and potentially beneficial dopaminergic 
hyperactivity.   
 
11C-Raclopride scans.   
Two subjects received a baseline one hour 11C-raclopride scan.  On a separate day subjects received a 
single 4.5g Xyrem® oral dose followed by three 11C-raclopride scans: 45 minutes, six hours, and 24 
hours later.  The 45-105 minute scan coincides with a time of peak sedation, whereas the six hour time 
represents washout/early withdrawal when most/all of the Xyrem® will have been metabolized.  At 6 
and 24 hours we investigated the question whether there might be increased dopamine release as a 
result of built-up dopamine.   
 

DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
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11C-Raclopride binding potential (BPND) in whole striatum showed almost identical changes in 
both subjects: BPND levels were modestly above baseline (by 6, 13%) at the 45 minute scan and 
below baseline (-7%, -6%) at six hours, when blood GHB levels were almost undetectable.  BPND levels 
were still lower than baseline (by 6% and 8%) when scanned the next day following Xyrem®—a time 
(32 half-lives) well into Xyrem® withdrawal.   Our findings, which go well beyond animal data [6-11], 
suggest that Xyrem® can, during initial sedation, decrease dopamine release in human brain, and 
increase dopamine release during drug withdrawal.   
 
11C-DTBZ scans. DTBZ findings were, as hypothesized, generally “opposite” to those of 
raclopride.  We have promoted the novel use of 11C-DTBZ binding to the intraneuronal vesicular 
monoamine transporter (VMAT2) in dopamine neurones as an index sensitive to intra-neuronal 
dopamine [14-16] (the “flip-side” of extra-neuronal raclopride binding).  In this scenario, a hypothetical 
Xyrem®-induced buildup of intraneuronal striatal dopamine would be reflected by decreased striatal 11C-
DTBZ BPND, because of increased competition of dopamine at VMAT2.  Employing the same protocol 
as with raclopride, striatal 11C-DTBZ BPND, unlike that of raclopride, was decreased at both 45 minutes 
(-21%) and 6 hours (-14%), and normal [-3%] at 24 hours.  This suggests that Xyrem® does indeed 
cause build-up of dopamine inside its neurones.   
 
Taken together, the preliminary raclopride and DTBZ findings, provide the first hint that Xyrem® might 
induce, in the normal human brain, initial buildup of intraneuronal dopamine and decreased release, 
followed hours later by above-normal dopamine release.  We now aim to determine whether either of 
these changes occurs in brain of patients with narcolepsy, the indication for which Xyrem® is approved, 
following a single dose of the drug.    
 
 
3. OBJECTIVE AND HYPOTHESES 
Our Trial Objective is to establish, in Xyrem®-naïve patients with narcolepsy and in matched controls, 
whether a single dose of Xyrem® causes changes in striatal binding of 11C-raclopride and 11C-DTBZ 
that would suggest decreased activity of brain dopamine neurones during the initial sedation and 
increased dopaminergic activity during Xyrem® withdrawal. 
 
Our WORKING MODEL, based on our preliminary human PET brain data, is that an initial action of 
Xyrem® is to cause, during sedation (which is very fast onset with Xyrem®), depressed activity of 
nigrostriatal dopamine neurones and dopamine release together with marked intraneuronal 
biosynthesis of dopamine.  At this early time, intraneuronal concentrations of dopamine (competing with 
11C-DTBZ at VMAT2) will be high whereas extraneuronal levels of dopamine (competing with 11C-
raclopride at the dopamine receptor) will be low because (we predict) Xyrem® causes accelerated 
synthesis of dopamine while depressing activity of dopamine neurones.   
 
During drug withdrawal, dopamine that has been building up inside the neurone is released, leading to 
increased extraneuronal dopamine (accompanied by decreased raclopride binding at the dopamine 
receptor) and a normalization of dopamine levels inside the neurone.  The modestly increased 
dopamine activity might persist somewhat in drug withdrawal and be beneficial to the patient.   
 
Our HYPOTHESES, based on our pilot data and employing a five scan approach, are that, relative to 
baseline, striatal 1) 11C-raclopride binding will be increased one hour post-Xyrem® but decreased at 
seven hours, suggesting decreased and increased neuronal dopamine release, respectively, at these 
times; and 2) 11C-DTBZ binding will be decreased at five hours post-Xyrem®, suggestive of increased 
intraneuronal vesicular dopamine buildup during Xyrem® exposure.  We predict that this biphasic 
change in dopamine will occur in both narcolepsy and in healthy control study groups. 

DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
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4. TOTAL NUMBER OF SITES AND NUMBER OF CANADIAN SITES  
There will be a single Canadian site: 
1) 
Centre for Addiction and Mental Health (CAMH), Toronto, ON Canada   
 
5. STUDY PARTICIPANTS 
5.1. Sample Size 
A maximum of 15 patients diagnosed with narcolepsy, who are not currently being treated with 
stimulant drugs (e.g. Alertec®, Ritalin®, or Dexedrine®) to manage their narcolepsy, and a maximum of 
15 healthy controls, will complete all study procedures.     
 
Monte Carlo simulations [17] (>10,000) were performed using BP estimates and standard deviations 
derived from our data in normal subjects and assumed mixed models analysis and constant standard 
deviations, with full maximum likelihood for evaluation and time treated as categorical variable to 
facilitate pre-planned comparisons of outcome values.  Results indicate that a sample of 15 will provide 
sufficient power (>80%, 0.05 alpha) to detect changes (baseline vs. GHB day scans, within subject 
comparisons) of the magnitude observed in the small pilot study for both raclopride and DTBZ binding. 
 
5.2. Patient Population 
Subjects are Xyrem®-naïve adult males or females aged 19 or over. 
 
5.3. Inclusion Criteria 
General inclusion  
 
Able to sign and date informed consent 
 
Willing and able to complete trial as described in protocol 
 
Age 19 or over, both genders 
 
Willing to forgo alcohol and any other sedative-hypnotic drug 48 hours prior to and 24 hours 
after Xyrem® administration 
 
Narcolepsy inclusion criteria (in addition to criteria listed above): 
 
Must fulfill the International Classification of Sleep Disorders classification for a clinical 
diagnosis of narcolepsy with cataplexy as determined by a physician specializing in sleep 
disorders.   
 
5.4. Exclusion Criteria 
General exclusion criteria 
 
Use of any sedative hypnotics, tranquilizers, anticonvulsants, antihistamines (except non-
sedating), benzodiazepines, clonidine, or any medications known to modulate dopamine (e.g. 
dopamine agonists, antagonists, DAT inhibitors, MAO-A/B inhibitors) at start of baseline 
period 
 
Have taken any investigational drug within the past 30 days prior to consent interview  
 
Have sleep apnea, are shift workers, or have any disorder other than narcolepsy that might be 
considered to be a cause of excessive daytime sleepiness  
 
History or evidence of current or recent (within one year of consent) substance abuse or 
dependence (with exception of nicotine) per interview and urine toxicology; This will include 
especially any subject who is a heavy alcohol drinker or who cannot control their drinking 
behaviour  

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 
Any clinically significant unstable or uncontrolled medical or psychiatric disease assessed at 
physical examination or medical history including but not limited to cardiovascular, hepatic, 
renal, GI, pulmonary, neurological, or other systemic disease that might interfere with 
participation in study  
 
Clinically significant abnormal clinical laboratory urinalysis/blood findings or pre-trial EKG results 
demonstrating clinically significant abnormality  
 
Clinically significant history of head trauma, past intracranial surgery, or seizure disorder  
 
Have ever taken Xyrem® / sodium oxybate / GHB at any time  
 
Subject is on sodium-restricted diet  
 
Pregnancy or lactation and women of childbearing potential not taking adequate contraceptive 
measures [menstrual cycle status on scan days will be documented]  
 
Hypersensitivity or other contraindications to sedatives  
 
Current, past, or anticipated exposure to radiation exceeding 20mSv in the last 12 months  
 
Metal implants or paramagnetic objects within the body which may interfere with MRI  
 
Claustrophobia  
 
Succinic semialdehyde dehydrogenase deficiency  
 
Subject has any other problem that in investigators’ opinion would preclude participation in trial    
 
 
6. STUDY DESIGN AND DURATION 
6.1. Summary of Design  
Those subjects meeting inclusion/exclusion (I/E) criteria will receive, on one day, a single 11C-raclopride 
and a single 11C-DTBZ PET brain scan to provide baseline measurement, along with a 3T MRI scan for 
PET co-registration.  On a later date each subject will receive a single 3.0 g oral dose of Xyrem® 
followed by three scans: two 11C-raclopride scans at approximately one and seven hours and one 11C-
DTBZ scan approximately five hours following Xyrem® administration.  Subjects will participate in a final 
follow-up telephone call the day after taking Xyrem® for a brief interview.  
 
The pilot study design required subjects to be scanned four times (e.g., baseline; one, 6 and 24 hours 
post- Xyrem®) with raclopride and four times with DTBZ, which would require one group of subjects 
receiving four raclopride scans, and a separate group of subjects receiving four DTBZ scans—for which 
cost would be high in terms of monies, number of subjects, and radiation exposure to humans. Further, 
subjects receiving raclopride scans would not be those receiving DTBZ scans and, importantly, it would 
not be possible to correlate in individual subjects the extent of dopamine buildup inside the dopamine 
neurone (with 11C-DTBZ) with the extent of dopamine released by the neurone (with 11C-raclopride).   
 
We, and the external reviewers of our pilot data,  feel that there is value in an approach that: 1) 
“measures” both intraneuronal (DTBZ) and extraneuronal (raclopride) dopamine in the same group of 
patients in order to assess presynaptic dopamine buildup as well as dopamine release; and 2) is cost 
effective in terms of number of scans and subjects.  We will therefore follow a five scan approach: two 
baseline scans using both 11C-raclopride and 11C-DTBZ.  On a separate day subjects will receive three 
scans after ingesting Xyrem®: 11C-raclopride at approximately one and seven hours post; 11C-DTBZ at 
approximately 5 hours post-Xyrem®. 
 
The raclopride scan at one hour post- Xyrem® corresponds to the time we found the single dose of 
Xyrem® to be maximally sedating and for which we anticipate the maximal reduction of dopamine 
release.  Based on our feasibility data, at five hours post-Xyrem®, dopamine should have been “well” 
accumulated within dopamine neurones and can be assessed by a DTBZ scan.  The seven hour 11C-
raclopride scan is conducted during drug withdrawal (approximately 14 Xyrem® half-lives) and would 

DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
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correspond to the time a subject participates in morning work duties following the typical second night-
time Xyrem® dose. This subject therefore might benefit from modest dopamine hyperactivity.  Thus, this 
scan time has been selected for both “clinical” relevance and for logistical considerations. 
  
6.2. Duration 
The study duration for each subject will involve approximately one-two days medical screening, two 
PET/MRI scan days (baseline and Xyrem® day), including one MRI session for co-registration of the 
PET scans, and a follow-up telephone call the day after taking Xyrem®.  Unscheduled visits may occur 
if required (e.g. subject must return for: blood work/EKG if could not be scheduled on same day as 
screening visit, etc.).  Subject participation will likely occur over a period not longer than 5 weeks.  
Anticipated study start and finishing dates are September 1, 2015 and May 1, 2019, respectively.   
 
6.3. Details of Study Design 
6.3.1. Recruitment 
Control subjects will be recruited by print and online advertisement and invited to contact the Research 
Coordinator (RC – by phone or email), who will explain the study and answer questions posed.  If 
narcolepsy patient groups are available, the PI will speak to such groups, describe the study, and 
provide flyers/brochures explaining the study which will include a contact number for the RC.  If the 
subject is interested, RC will proceed with a telephone/email screen, asking general questions to try to 
determine whether the subject will meet I/E criteria.  If subject passes this screen they will be asked to 
come in for the screening and baseline evaluation day with RC.   
 
In addition, patients meeting criteria for a diagnosis of narcolepsy with cataplexy may be referred by a 
specialist at sleep/neurology clinics aware of the study.  The patients will be informed (through 
conversation and using the provided flyer/brochure) that there is an opportunity to participate in a PET 
study looking at the effects of a drug used to treat narcolepsy (Xyrem®) on brain dopamine.  All patients 
will be informed that their potential participation or refusal will not jeopardize their care or change their 
clinical management. The patient can then contact the RC for further information if interested, and 
proceed through telephone/email screen for eligibility.  
 
6.3.2. Schedule of Activities 
Activity 
Screening 
Visit(s) 
Baseline 
Scan Day 
Xyrem® 
Scan Day 
Follow-up 
call 
Written Informed consent 
RC 
 
 
 
Consent review 
 
RC 
RC 
RC/PI 
Demographics/Drug - Alcohol Use History 
RC 
 
 
 
Psychiatric Interview  
RC 
 
 
 
Routine Blood Work1 & EKG 
CL 
 
 
 
Urine collection/drug screen2 
RC 
RC 
RC 
 
Medical History & Physical Exam 
SP 
 
 
 
I/E determination 
PI/QI 
 
 
 
Adverse Event review/log 
 
RC/PI/QI 
RC/PI/QI 
RC/PI/QI 
MRI Scan 
 
RIC-MRI 
 
 
I.V. or catheter placement 
 
RIC-PET 
RIC-PET 
 
Record/monitor vitals 
 
 
A/QI 
 
PET Scans 
 
RIC-PET 
RIC-PET 
 
Xyrem® administration 
 
 
A/QI 
 
Blood draw for GHB level 
 
 
RIC-PET 
 
Interview regarding lingering effects of Xyrem® 
 
 
 
RC/PI 
1Routine Blood Work (at screening) includes serum chemistry (sodium, potassium, chloride, urea (BUN), creatinine, total protein, 
albumin, total bilirubin, ALT, AST, ALP, GGT, LDH, calcium, magnesium, TSH, free T4), random glucose, CBC + differential, ESR, 

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PT/INR, and serum β-HCG for all women of childbearing potential. 
2Urine drug screen includes a rapid response urine test panel 
immediately read by RC and broad spectrum analysis done by CAMH Clinical Lab. A = Anesthesiologist, CL = Clinical Lab, PI = 
Principal Investigator, QI = Qualified Investigator, RC = Research Coordinator, RIC-MRI = Research Imaging Centre MRI group, 
RIC-PET = Research Imaging Centre PET group, SP = Study Physician. 
 
6.3.3. Pre-Study Screening and Baseline Evaluation (Days 1 and 2) 
Subjects will come to CAMH for a Screening day visit, during which they will meet with RC who, after 
further explanation of the study, will take informed consent.  Each potentially eligible person who has 
signed informed consent will be assigned a Subject ID in consecutive order starting from Jazz-001.  
Should the subject meet all criteria and continue through the study, they shall keep the same ID 
throughout.  For those subjects who signed consent and subsequently fail to meet eligibility 
requirements, a minimal data set will be maintained under their Subject ID (i.e. consent form, 
demographics, assessments used to determine eligibility). 
 
The following procedures will be performed at the screening visit(s): 
- 
Obtain written informed consent 
- 
Structured clinical interview for demographics, drug use history (including alcohol and nicotine 
using AUDIT questionnaire and Fagerstrom Test) 
- 
Psychiatric interview for DSM-IV (DSM-5) Axis I disorders using SCID-NP, SIGH-SAD (Ham-D) 
- 
Urine specimen collection for: 
o Rapid Response urine test panel (results immediately assessed by RC)  
o Broad spectrum urine drug analysis (assessed by CAMH Clinical Lab) 
- 
EKG with 12-lead electrocardiogram (assessed by cardiologist) 
- 
Blood collection for: 
o Routine blood work (see schedule of events for detailed list) 
o For female subjects of childbearing age, serum pregnancy test (β-HCG) 
- 
Medical history and physical exam with study physician 
- 
For narcolepsy subjects, if consent is given, a member of the study team will collect required 
information from the subject’s referring physician in order to characterize their condition.  
 
This visit will take approximately four hours, and may be broken up over more than one day in order for 
the physician to have access to the lab results prior to performing the physical evaluation. 
 
   
 
The study physician will review all lab results once they are available, and make a recommendation for 
suitability for the study.  If permission given, the study physician may contact the subject’s family 
physician and/or review their medical records for corollary information to help alleviate any concerns 
regarding medical history or lab results if necessary.  All the above information is provided to the QI and 
PI for final eligibility determination.  If the subject qualifies and is enrolled in the study, the QI will 
provide a prescription for 3.0 g Xyrem®. RC will give the prescription to CAMH Pharmacy at least one 
week prior to the subject’s scheduled Xyrem® scan day.  
 
Subjects will be informed of their status, and if they are to continue in the study, RC will schedule the 
Baseline Scan Day appointment prior to subject leaving the screening visit (if possible).   
 
Subjects will be informed that transportation to and from CAMH for all subsequent visits will be provided 
for them (i.e., by taxi) as required. 
 

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6.3.4. Treatment/Assessment visits  
6.3.4.1. 
Day 3: Baseline PET/MRI 
During this visit the following tasks will occur: 
- 
RC meets with the subject, reviews the tasks to be completed for the day, and confirms the 
subject is willing to continue 
- 
Urine specimen collected for: 
o Rapid Response urine test panel (immediately assessed by RC, must be negative for 
contraindicated drugs) 
o Broad spectrum urine drug screen (assessed by CAMH Clinical Lab) 
o Pregnancy test in females of child bearing age (immediately assessed by RC, must be 
negative) 
- 
Subject receives a 3T MRI scan for PET co-registration (see below for details) 
- 
A single I.V. line or fine needle catheter (one per tracer) is placed in the subject’s arm for tracer 
administration 
- 
Subject receives a single 11C-raclopride scan followed by a single 11C-DTBZ PET scan at CAMH 
PET Centre (see below for details)  
- 
RC enquires about any adverse events (AEs) that the subject may have suffered as a result of 
the days activities; these are recorded on the AE log 
- 
Subject is dismissed upon completion of 2nd scan 
 
This visit should take approximately seven hours. While in the PET Centre, subjects will be provided 
with a private room where they can rest/lay down/sleep between procedures as necessary. 
 
6.3.4.2. 
Day 4: Xyrem® Administration Day 
The Xyrem® scan day should take place within one week of the Baseline scan day. 
 
During this visit the following tasks will occur: 
- 
RC meets with the subject, reviews the tasks to be completed for the day, and confirms the 
subject is willing to continue 
- 
RC enquires about any AEs since last visit; these are recorded on AE log 
- 
Subject is interviewed by RC and by anesthesiologist re: physical status and recent use of any 
medication, food, or liquids.  Subject must confirm no food (including milkshakes, smoothies 
or instant breakfast drinks) since previous night and no liquids for the past 2 hours.  If this is 
not the case, subject does not take Xyrem® 
- 
Urine specimen collection for: 
o Rapid Response urine test panel (immediately assessed by RC, must be negative for 
contraindicated drugs) 
o Broad spectrum urine drug screen (assessed by CAMH Clinical Lab) 
o Pregnancy test in females of child bearing age (immediately assessed by RC, must be 
negative) 
- 
An I.V. line is placed in the subject’s arm to allow for blood sampling and tracer injection   
- 
Subject is connected to a physiological monitor (supplied by PET Centre): vitals (HR, BP, 
Respiration rate, O2 saturation) are taken and recorded.  Vitals must be within normal range 
(assessed by anesthesiologist) for subject to receive Xyrem®. 
- 
A sample of venous blood (approximately 7 ml) is taken for baseline GHB measurement.   
- 
3.0 g liquid Xyrem® is prepared in CAMH Pharmacy, with sign-off by Pharmacist(s), RC and a 
2nd member of study staff, confirming correct dosage.  Each dosing cup will be labeled, 
sealed, and brought by Pharmacist together with RC or 2nd staff to PET scan room.   

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- 
Anesthesiologist confirms/signs that the drug has been delivered, the seal is intact, and the 
subject ingests the full dose; RC records the time dose was ingested. 
- 
A sample of venous blood is taken approximately 0.5, 1, 3, 5 and 7 hours post-Xyrem® ingestion 
for GHB measurement  
- 
Subject receives two 11C-raclopride scans starting approximately one and 7 hours post-Xyrem® 
and one 11C-DTBZ PET scan approximately five hours post-Xyrem® 
- 
Anesthesiologist will monitor subject and record the time when level of consciousness and vital 
signs have returned to normal, indicating that it is safe for subject to leave any time after that 
point.  RC will record the time that subject actually leaves the PET/MRI Centre (after the 7 
hour PET scan); by taxi or with companion who will drive them home.  Both RC and 
Anesthesiologist will sign-off on this discharge form.  
- 
RC enquires about any AEs that the subject may have suffered as a result of the days activities 
- 
After final scan and AE evaluation, subject is paid the honorarium for full completion of the 
study, reminded that he/she cannot drive or operate heavy machinery (including farm 
equipment), and should not engage in strenuous activities, consume alcohol or any sedatives, 
make important decisions or engage in any activity requiring mental alertness for the next 24 
hours.  
- 
Subject will be given a wallet card printed with study details (e.g., Xyrem® dose, date and time 
taken, precautions/warnings, contact information for study personnel) and told that this should 
be kept on them (in their wallet) as a reminder of the precautions necessary and also to 
provide emergency contact information  
- 
Subject is then discharged 
 
This visit will take approximately 10 hours. 
 
6.3.4.3. 
Telephone Follow-up 
Subject is contacted the following morning, by RC and/or PI.  The purpose of the phone call will be to 
enquire about the subject’s wellbeing since leaving the PET Centre.     
 
6.3.5. Unscheduled Visits 
Subjects may need to return to the site for an unscheduled visit (i.e. extra day for screening visit if 
time/schedule did not permit completion over 2 days), or receive a follow-up phone call for evaluation of 
conditions relating to their participation in the study or the study drug (i.e. ongoing AE that the QI has 
determined needs to be tracked).  The date and reason for these visits/phone calls will be recorded. 
 
6.4. PET and MRI scan procedure, data acquisition, and image analysis 
PET measurement of 11C-raclopride binding to the striatal brain dopamine receptor and 11C-DTBZ 
binding to VMAT2 are common, routine procedures used worldwide (e.g., see our publications ref [14, 
18] and references therein).  Briefly, PET images of 11C-raclopride (approximately 60 minute) or 11C-
DTBZ (approximately 60 minute) scans will be acquired using CPS-HRRT neuro-PET camera system 
(Siemens Medical Imaging, Knoxville, TN).  Head movement minimization is achieved with a head 
immobilization system (Tru Scan Imaging, Annapolis USA).  Transmission scans will be obtained using 
a single-photon 137Cesium (E = 662 keV) point-source, and used to correct the emission scans for the 
attenuation of 511 keV photons through tissue and head support.   
 
The PET scans will be initiated following a bolus injection of 11C-raclopride or 11C-DTBZ into an arm 
vein.  Raw data are reconstructed by filtered-back projection [19].   
 

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MRI (up to approximately one hour):  The structural MRI protocol includes the primary structural MRI 
scan to be used for PET coregistration.  This standard spin-echo proton-density weighted protocol 
(MRI; TE = Min Full, TR = 6000, field of view = 22 cm 2D, slice thickness = 2mm, NEX= 1) will be 
obtained (Signa 3Tesla GE MRI scanner, (Discovery MR750) General Electric Medical Systems, 
Milwaukee, WI) for purpose of region of interest (ROI) delineation.   
 
ROI delineation and analysis will be performed following standard operating procedure for PET ROI 
analysis.  In brief, a standard brain template will be transformed to fit individual high-resolution MRI 
scans, creating ROIs.  These will then be refined, aligned and resliced to match the dimension of the 
PET images.   The whole striatum (the primary region of interest) as well as bilateral sub-compartments 
of the striatum including ventral striatum and pre and post commissural caudate and putamen (as 
described by Mawlawi [20]) as well as reference tissues (which provide the input function), namely, 
cerebellar cortex (excluding vermis) for 11C-raclopride [18] and the occipital cortex for 11C-DTBZ [21] are 
selected as ROIs. 11C-Raclopride and 11C-DTBZ time activity curves will be obtained from the dynamic 
data and specific binding (BPND) will be estimated in each ROI.  This method has been validated to 
reliably estimate BPND for 11C-raclopride (e.g., [22]) and 11C-DTBZ[14].   
 
We will ensure that scans are not corrupted by motion artefact by de-noising and visually inspecting all 
images.  Should MRI data suggest changes in volume/shape of ROIs, partial volume effect (PVE) 
adjustment will be made.  We will report both PVE corrected and uncorrected data.   
 
7. EFFICACY VARIABLES AND ANALYSIS 
The primary endpoint is the change in 11C-raclopride or 11C-DTBZ BP in whole striatum, caudate, 
putamen, and bilateral sub-compartments of the striatum, from baseline scan vs. that at one, 5 and 7 
hour scans. 
 
The secondary endpoint is the blood concentration of GHB (expressed as the area under the curve; 
AUC) at 0.5, 1, 3, 5 and 7 hours following ingestion of GHB.  
 
8. STUDY DRUG 
8.1. Drug Formulation 
Each bottle contains 180 ml of Xyrem® at a concentration of 500 mg/ml.  Xyrem® is supplied as a kit, 
containing a press-in-bottle adapter and a 10 ml oral measuring device (plastic syringe).  The pharmacy 
will provide a 100 ml dosing bottle. 
 
8.2. Dosage Regimen 
Each subject will receive a single oral dose of 3.0 g (6 ml of a 500 mg/ml solution) diluted in 60 ml of 
water.  Subjects will lie down immediately after dosing. 
 
The pilot study 4.5 g dose was selected by Dr. Mortimer Mamelak, Toronto (a consultant who has 
extensive clinical experience in administration of Xyrem® for narcolepsy; [23-27]) as a commonly used 
therapeutic dose that is sufficient to cause sedation but can be safely administered to a Xyrem®-naïve 
subject under supervision.  Both Dr. Mamelak and PI believe that sedation will be required for Xyrem® 
to exert an effect on the dopamine system that can be assessed using 11C-raclopride or 11C-DTBZ.  
Further, it is Dr. Mamelak’s experience that many subjects receiving smaller doses similar to 2.25 g will 
not experience somnolence.  Regarding safety, we note that in one published Xyrem® multicenter trial 
in narcolepsy [28] a group of drug-naïve subjects received two 4.5 g doses (spaced 2.5-4 hours apart) 
at their homes (the trial coordinator phoned the subjects after their first night and three times weekly), 

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and the drug was well-tolerated.  In a second study also in narcolepsy patients, the patients received a 
single initial dose of 4.5 g Xyrem® in a sleep lab setting and the drug was also well-tolerated [29].  
 
The Xyrem® dose we have selected (3.0 g) to carry forward is slightly less than that used in our original 
study (4.5 g).  In the pilot study, using 4.5 g dose of Xyrem® we did encounter subjects who developed 
nausea, some with vomiting (while lying supine), after ingesting the drug.  While listed as a known 
adverse reaction, this does prevent scanning of the individuals during the earlier time points as they are 
unable to lie on their back in the scanner.  We have chosen to reduce the dose to 3.0 g, which is well 
within the range of doses used in treatment of narcolepsy as a first dose; and is less likely to induce 
nausea/vomiting in Xyrem®-naïve subjects than the 4.5 g dose. 
 
8.3. Washout Period 
Xyrem® is rapidly eliminated by metabolism with a plasma half-life of approximately 0.5 to 1 hour and 
time to peak plasma concentration of 0.5 to 1.25 hours (Xyrem® monograph).  
 
The almost certain (>95%) consequence of a single 3.0 g dose of Xyrem® is reversible sedation, 
depressed consciousness, and possibly sleep lasting approximately 15 minutes to 3.5 hours.  Vital 
signs (HR, BP, respiration rate, oxygen saturation) and level of consciousness will be regularly 
monitored immediately before (baseline measurement) and post-Xyrem® by an anesthesiologist, 
working under supervision of Dr. O'Leary, the QI.  The anesthesiologist present for the Xyrem® dose 
will also establish and sign-off (with co-sign-off by RC or PI) when the subject can safely leave (by taxi 
or driven by companion) the PET Centre (estimated 6 hours post drug).  Subject will be contacted by 
phone the following morning, by RC and/or PI for a brief interview to enquire about their wellbeing since 
leaving the PET Centre. 
 
9. CONCOMITANT MEDICATION    
Subjects will be carefully screened at the beginning of the study to ensure that they are healthy and 
safely able to take Xyrem®.  If subjects are currently on medication (including antidepressants for 
cataplexy) to treat a medical or mental illness, this condition must be stable/controlled, and they must 
be on a stable dose of said medication.  The QI will determine whether the subjects’ medications would 
be contraindicated.  On the Xyrem® Scan day, specifically disallowed drugs/medications are any 
sedative-hypnotics, or any other CNS depressants including alcohol.   
 
10. RESCUE MEDICATION AND RISK MANAGEMENT   
10.1. 
Risks from Xyrem® 
Our primary goal is the prevention of the two main predictable possible adverse events (airway 
obstruction and/or central respiratory depression from oversedation, aspiration of gastric contents).  To 
this end we first undertake to review carefully the reports of the candidates’ history and physical 
examinations before they enter the study to try to identify co-morbidities that might put the subjects at 
increased risk.  If needed, a joint discussion with the QI, Dr. O’Leary and the PI would ensue to resolve 
issues identified before enrollment would continue. 
 
While sedation is anticipated, significant respiratory depression with the dose proposed is not.  If 
present, the drug profile indicates that this would be self limiting (i.e. does not require an antidote) and 
of short duration (2-3 hours).  In this regard, data from a recent investigation of GHB overdose cases 
suggest that most such subjects coming to the ER do not actually require intubation and are managed 
conservatively by lateral positioning, either oropharyngeal or nasopharyngeal airway adjuncts, and 
close physiological and neurological monitoring [30]. 
 

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During the study when Xyrem® is administered the anesthesiologist will monitor the subject’s level of 
consciousness and vital signs. The physiological monitor in this unit will allow continuous display of 
oxygen saturation, HR, respiratory rate and intermittent blood pressures.  Based on Dr. Mamelak’s 
experience with Xyrem®, we expect that no subject will require any intervention, including oxygen.  
However a variety of ancillary airway devices will be available including the ability to give oxygen by 
nasal prongs and mask, address airway obstruction (oral and nasal airways, laryngeal masks), 
manually ventilate (Laerdal bag and mask), intubate (suction, laryngoscope, endotracheal tubes), 
medications for sedation (midazolam, propofol), muscle relaxation (succinylcholine, rocuronium), 
inotropic support and emergency management (ephedrine, epinephrine, phenylephrine).  While we do 
not expect that interventions other than simple airway management will be needed, the anesthesiologist 
will have the expertise, skill set and equipment to protect the airway and manage ventilation if called 
upon.  The spectrum of interventions that will be available is large and will be dictated by the patient’s 
condition.  
 
Per CAMH policy, a code blue call to Switchboard must be made, for example, in cases of respiratory 
arrest or significant depression of respiration or aspiration of vomit causing choking.  Again, the 
anesthesiologist has the expertise to manage these issues.  In these scenarios Switchboard would not 
be instructed to call 911 at the time of the code blue call as the resources within the unit are expected 
to meet the clinical needs.  However, the CAMH-College Street site Attending Physician/Duty 
Doctor/Medical Doctor, who proceeds to the scene, leads the code and will determine whether a 911 
call needs to be made.  An external 911 call will be made if the subject does not respond to the 
management provided by the anesthesiologist or is considered by either the anesthesiologist or 
attending medical staff to require outside intervention because of a critical condition.  An example 
would be signs of cardiac arrest or instability.  In the unlikely event that it was felt that a transfer to an 
emergency department was indicated this would be activated according to the priority of the clinical 
situation.  The anesthesiologist would accompany the patient to the ER.  
 
Based on measurement of vital signs (HR, BP, respiration rate, oxygen saturation) and level of 
consciousness, the anesthesiologist will establish and sign-off (with co-sign-off by RC or PI) when the 
subject can safely leave (by taxi) the PET Centre (estimated 6 hours post drug).  Subject will be given a 
wallet card printed with study details (e.g., Xyrem® dose, date and time taken, precautions/warnings, 
contact information for study personnel) and told that this should be kept on them (in their wallet) as a 
reminder of the precautions necessary and also as emergency contact information.  Subject will be 
contacted by phone by PI and/or RC the following morning to enquire about his/her wellbeing since 
leaving the PET Centre.   
 
There are other risks associated with Xyrem® (estimated from clinical trial data employing a variety of 
doses taken chronically) including headache, unspecified pain, confusion, diarrhea, urinary 
incontinence, and insomnia.  As GHB can be an abused drug, there is generic (we feel very low) risk 
that the subjects might “like” the GHB experience and wish to take the drug recreationally.  This risk is 
minimized by selecting subjects who do not have a history of substance abuse.   
 
10.2. 
Other risks that might result from study procedures 
There is the unknown risk of radiation exposure as part of the PET scanning procedure.  However, the 
radiation dose provided has not been found to be associated with any harm.  Subjects exceeding the 
yearly radiation dose limit (20 mSv) will be excluded from study.  There is the risk of bruising and 
discomfort from venipuncture.  Some subjects might find some questions on the screening tests (e.g., 
SCID) uncomfortable.    
 

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11. PREMATURE WITHDRAWAL/DISCONTINUATION CRITERIA 
Subjects are advised in the consent form that they are free to withdraw from the study at any time 
without prejudice, and may be withdrawn at the Investigators discretion. 
 
Trial will also be terminated should subject develop or be found to have any condition that might 
compromise subject safety (e.g., unstable vitals, presence of abused drug in urine) or confound 
interpretation of primary PET outcome measure. 
 
If the subject withdraws from the study at any time prior to Xyrem® ingestion, they will be paid a pro-
rated amount, and are free to leave at any time.  If they withdraw from the study after Xyrem® ingestion, 
the subject must remain in the PET Centre, monitored by the anesthesiologist, until such time that the 
anesthesiologist determines it is safe for the subject to leave.  Subject will then be paid a pro-rated 
amount, and allowed to leave by taxi or with companion.  All data collected up to the point that the 
subject withdraws will be used (if applicable).   
 
12. SAFETY VARIABLES AND ANALYSIS 
Prior to and following Xyrem® administration the anesthesiologist will monitor the subject’s level of 
consciousness and vital signs. The physiological monitor in the PET Centre unit will allow continuous 
display of oxygen saturation, HR, respiratory rate and intermittent blood pressures (every 15 minutes or 
more frequent if indicated). 
 
12.1. 
Adverse Events 
Adverse events will be assessed at each study visit following administration of the first PET radiotracer 
(Baseline scan day).  Study staff will question the subject directly asking: how they are feeling following 
the scans/Xyrem®; how have they been feeling since last visit.  All AEs, whether reported by the subject 
or observed by study staff/investigators, will be recorded (as a diagnosis not per symptom: i.e. common 
cold vs. sore throat, sinus congestion, etc.) on the AE log along with a brief description, start 
date/resolution date and any action taken (medications, Dr. visit, etc.).  The AE log will be initialed by 
the QI, who will make the determination on relationship of the AE to the investigational drug.  All AEs 
determined by the QI to have a causal relationship with the investigational product or as a result of 
study procedures, will be reported to CAMH REB as part of the annual ethics approval renewal 
process. Examples of this would include, but not be limited to: claustrophobia from either PET or MRI 
scanner; nausea and/or vomiting, headache – known possible reactions to Xyrem® as per Xyrem® 
monograph (depending on severity as assessed by QI).  
 
Final contact with the subjects occurs the day after Xyrem® administration, via phone call from RC 
and/or PI.  During this call, RC and/or PI will enquire about any new AEs or unresolved AEs that have 
been recorded in the subjects file.  If the AE is still unresolved, they will be marked as ongoing, and the 
QI will determine whether the AE requires any further follow-up.  This will be documented on the log, 
with follow-up calls/visits to occur if/as necessary using the unscheduled visit forms.   
 
12.2. 
Serious Adverse Events 
As defined by Health Canada, a serious adverse event (SAE) is an adverse event that: 
-  requires in-patient hospitalization or prolongation of existing hospitalization 
  
-  causes congenital malformation 
-  results in persistent or significant disability or incapacity 
-  is life threatening  
-  results in death 
 

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Important medical events that may not result in death, be life-threatening or require hospitalization, may 
be considered an SAE when, based upon medical judgment, may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
 
A Serious Unexpected Adverse Drug Reaction (SUDAR) as defined by Health Canada is a serious 
adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out 
in the investigator's brochure or on the label of the drug. 
 
If any AEs recorded are determined by the QI to be SAEs or SUADRs, they must be reported, within a 
specified time frame to: 
1) CAMH REB:  QI must complete and sign the CAMH REB Serious Adverse Events form and 
submit to the REB within 48 hours of knowledge.  The QI will include a description of the event 
in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.    
 
2) Health Canada:  As required under Food and Drug Regulations, Part C, Division 5:  
During the course of a clinical trial, the sponsor/investigator shall inform the Minister of any 
serious unexpected adverse drug reaction in respect of the drug that has occurred inside or 
outside Canada as follows: 
(a) if it is neither fatal nor life threatening, within 15 days after becoming aware of the 
information; and 
(b) if it is fatal or life threatening, within seven days after becoming aware of the information. 
 
The sponsor/investigator shall, within eight days after having informed the Minister, submit a 
complete report in respect of that information that includes an assessment of the importance 
and implication of any findings made. 
 
3) Jazz Pharmaceuticals:  The investigators will inform Jazz Pharmaceuticals of any SAEs 
occurring 
within 
the 
study 
subject 
population. 
 
Jazz 
will 
be 
copied 
(via 
AEReporting@jazzpharma.com) 
on 
the 
CAMH 
REB 
SAE 
report, 
any 
subsequent 
correspondence, and will be provided a copy of the CIOMS form I report. 
  
For expedited reporting to Health Canada and Jazz Pharmaceuticals, the investigators will use the 
CIOMS form I. 
 
13. STATISTICAL ANALYSIS 
The Biostatistical Consulting Service at CAMH, who provided the power calculations, will continue to 
advise on all statistical analyses to be conducted.  Prior to analysis, data will be screened to ensure 
that underlying assumptions for statistical procedures are met. Should any demographic characteristic 
be found to be associated with outcome measures, they will be included as covariates in subsequent 
analyses. Changes in raclopride binding in whole striatum will be tested using a mixed model, with 
raclopride binding the dependent variable and time (baseline vs. one hour post-Xyrem® and vs. 7 hours 
post- Xyrem®) as the categorical independent variable.  An unstructured covariance structure will be 
assumed.  Should a significant time effect be detected, a series of Bonferroni-adjusted pairwise 
comparisons will be carried out.  Changes in DTBZ will be assessed using a paired t-test.  
Subcompartments of striatum will be examined in a separate exploratory analysis.   An exploratory 
correlation (Pearson) will investigate relationship between DTBZ binding changes at five hours 
(dopamine buildup) vs. raclopride changes at 7 hours (release of dopamine that had been “built-up”).  
 

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14. DATA MANAGEMENT AND RETENTION 
A Case Report Form (CRF) will be completed for each subject enrolled in the study. Investigators will 
protect privacy by assigning an identification code to each (i.e. Jazz-001). A master list containing ID 
codes matched to the subject’s complete name and contact information will be held in a secure file, 
separate from the CRF. A subject screening log, noting reasons for screen failure, where applicable, 
will be maintained for all.   
 
Digital files of PET and MRI data will be considered source documents and will be stored on a 
password-locked computer. The CRF will note the day and time of the PET scan, its number in the PET 
Centre Database, the radiotracer information (injected radioactivity, specific activity, total mass, etc.) 
and a note to the effect that the scan was completed with no technical problems. 
 
Study data and other essential documents will be retained in a secure setting by the investigators for a 
period of 25 years as required by federal regulations. 
 
15. REGULATORY ISSUES  
15.1. 
Ethics Approval  
Prior to initiation, this study will have received approval from CAMH REB as well as Health Canada No 
Objection Letter (NOL).  CAMH REB approval is subject to annual renewal.  Any amendments to the 
study will require approval from the above agencies prior to implementation, except when necessary to 
eliminate immediate hazards and/or protect the safety, rights or welfare of subjects. 
 
15.2. 
Consent  
Consent to enter the study must be sought from each subject only after a full explanation has been 
given, an information sheet offered and time allowed for consideration. Signed informed consent will be 
obtained prior to conducting any study procedures (with the exception of the initial phone screen). The 
right of the subject to refuse to participate without giving reasons must be respected. All subjects are 
free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing 
further treatment.  
 
15.3. 
Confidentiality  
All personal study subject data collected and processed for the purposes of this study will be managed 
by the investigators and their staff with adequate precautions to ensure the confidentiality of those data, 
and in accordance with applicable national and local laws and regulations on personal data protection. 
The ethics committees approving this study, CAMH Monitor(s), and Health Canada will be granted 
direct access to the study subjects’ original study records for verification of clinical trial procedures 
and/or data, without violating the confidentiality of the subjects, to the extent permitted by the law and 
regulations. In any presentations of the results of this study at meetings or in publications, the subjects’ 
identity will remain confidential. 
 
15.4. 
Sponsor  
Research Imaging Centre, CAMH 
 
15.5. 
Funding  
This study is being funded through a grant from Jazz Pharmaceuticals Inc. 
 
15.6. 
Audits  
As part of the quality assurance review of this research project, this study may be subject to inspection, 
monitoring and/or audit by CAMH or Health Canada staff. 

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DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
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DOES XYREM® INFLUENCE BRAIN DOPAMINE IN PATIENTS WITH NARCOLEPSY?  
A PET IMAGING INVESTIGATION 
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