Clinical trial NCT04006925
Conditions: REM Sleep Behavior Disorder Parkinson Disease
Keywords: sodium oxybate
Sponsor: Stanford University
Start date: 2019-09-10; Completion date: 2022-02-01
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is the first clinical trial using sodium oxybate for the treatment of REM sleep behavior disorder (RBD). Sodium oxybate is a drug approved by FDA for the treatment of narcolepsy which has been used "off label" to treat patients with severe RBD. This drug has shown to be effective and well tolerated in patients with RBD (Shneerson, 2009; Liebenthal, 2016; Moghadam, 2017).

Detailed description:
Rapid eye movement sleep behavior disorder (RBD) is a condition resulting in violent dream-enactment during sleep which affects millions of individuals in the United States, however therapies for RBD are limited and cause significant side effects. As a result, despite using a combination of drugs, a large number of patients with RBD continue to act out violent dreams causing severe self-injuries or injuries to their bed partners. Prior studies and our experience have shown that sodium oxybate can be effective in these cases of treatment-resistant RBD. This study would therefore evaluate the efficacy and tolerance of sodium oxybate in this patient population.

This study is an 8-week trial comparing sodium oxybate versus placebo randomly assigned to patients with treatment-resistant RBD, i.e. individuals who have insufficiently responded or tolerated melatonin and clonazepam. The study uses a double-blind design (participants, staff, and investigators will not know which drug between active drug and placebo is given to participants), and will measure treatment efficacy based on patients, partners and clinicians report, and objective outcomes based on in-home actigraphy and in-lab polysomnography before and after intervention.

Arms: arm 1: Sodium Oxybate (SXB) will be dispensed to the participants. arm 2: Placebo will be dispensed to the participants.
Interventions: intervention 1: Sodium Oxybate intervention 2: Placebo
Intervention descriptions: intervention 1: Sodium Oxybate will be titrated up weekly by 1.5g nightly dose increments from an initial 4.5g total nightly dose (which could be given in two unequal doses if needed, or one single dose no greater than 4.5g) to an optimal individual dose based on clinical response on RBD symptoms and tolerance, to a maximum nightly dose of 9g ("flexible dose" period lasting up to 8 weeks). The optimal dose will then be continued for at least 4 weeks ("stable dose"). intervention 2: Placebo will be similar in appearance, smell and flavor to the subjects, so that the investigators and participants will be unable to distinguish it from sodium oxybate.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Sodium Oxybate in Treatment-Resistant REM Sleep Behavior Disorder 
(RBD): A Randomized Placebo-Controlled Trial 
Study Protocol 
NCT04006925 
July 8, 2020 


 
Sodium Oxybate in Refractory REM Sleep Behavior Disorder: A Randomized 
Controlled Study. 
 
 
Summary 
 
Rapid eye movement sleep behavior disorder (RBD) is a condition resulting in violent 
dream-enactment during sleep which affects millions of individuals in the United States, 
however therapies for RBD are limited and cause significant side effects. As a result, 
despite using a combination of drugs, a large number of patients with RBD continue to 
act out violent dreams causing severe self-injuries or injuries to their bed partners. Prior 
studies and our own experience at Stanford have shown that sodium oxybate (SXB) can 
be effective in these cases of refractory RBD. This study would therefore evaluate the 
efficacy and tolerance of SXB in this patient population. 
 
We propose to conduct an 8-week trial comparing SXB versus placebo randomly 
assigned to patients with refractory RBD, i.e. individuals who have insufficiently 
responded or tolerated melatonin and clonazepam. To strengthen the study design, we 
will use a double-blind design, and not only measure treatment efficacy based on 
patients, partners and clinicians report–as done in most studies; we will record RBD 
objective outcomes with actigraphy, a recently validated objective tool for tracking RBD 
activity "in vivo". In addition, our study will include the gold standard PSG-based REM 
activity based on video and EMG activity before and after intervention. 
In summary, this study would not only address an important question from a clinical and 
public health perspective, it would also be the first double-blind randomized controlled 
study measuring a treatment response based both on clinical and physiological outcomes. 
We believe that this particular design should pave the way for future trials in RBD.  
 
 
Scientific Basis/Rationale 
 
Rapid eye movement (REM) sleep behavior disorder (RBD) is a neurological condition 
resulting in loss of muscle atonia during REM sleep (also called REM sleep without 
atonia, RWA) leading to violent and injurious dream-enactment behaviors1. The 
prevalence of RBD is estimated to be 0.5-1% in the general population2,3, which 
represents over 2 million individuals in the United States. RBD is strongly associated 
with synucleinopathies, namely Parkinson's disease (PD), dementia with Lewy bodies 
(DLB) and multiple system atrophy (MSA). In the remaining individuals, RBD is called 
"isolated", but is in most cases a prodromal symptom of neurodegenerative disease. 
While first episodes of dream-enactment can occur decades before neurodegenerative 
disease, the median time between a formal diagnosis of RBD and phenoconversion is less 
than 10 years4. Other than safety measures, the current evidence suggests melatonin 
(MLT) or clonazepam (CLZ) as treatment "options" due to incomplete efficacy and 
possible side effects5. The efficacy of CLZ is estimated to be about 80% in the largest 
case series, but this drug is often associated with limiting side effects. The data on MLT 


in RBD is scarce, but suggests that although better tolerated, it may not be superior to 
CLZ in terms of efficacy5,6. As a result, a large fraction of patients with RBD continue to 
experience frequent breakthrough episodes despite often using a combination of CLZ and 
MLT. Other effective treatment options are limited and have even lower level of 
evidence. Off label use SXB has shown good efficacy in 3 case reports on 4 cases of 
refractory RBD, including one at the Stanford Sleep Medicine Center7–9. The first report 
describes a 66 year-old patient with over 2 years of frequent violent RBD episodes 
resulting in multiple injuries and falls in whom SXB initiated at 3g uptitrated to 4.5g 
nightly resulted in cessation of his episodes after 5 days at the higher dose. This effect 
was sustained during the 12 month follow-up period7. A 68 year-old man with PD 
(Hoehn and Yahr score 3) with 20-year history of RBD was referred to the Stanford 
Sleep Center after exacerbation of RBD following deep brain stimulation leading to 
violent dream-enactment several times weekly. Patient had failed multiple regimens 
including high dose MLT and could not tolerate CLZ. SXB was titrated up to 5g nightly, 
resulting in cessation of RBD episodes for two months. Three breakthrough episodes 
prompted further increase to 6g nightly dose after which RBD was controlled again8. 
Two additional non-parkinsonian patients aged 68 and 51 with refractory RBD were 
placed on SXB at doses of 4.5g (in a single dose) and 3g (in two doses) nightly. This lead 
to marked reductions in severity and frequency of RBD symptoms with elimination of 
most violent episodes and sustained efficacy throughout the 5 year follow-up period9.  
The mechanism by which SXB reduces RBD is unknown, but could involve reduction in 
sleep fragmentation, or direction modulation of sleep/wake motor control as seen in 
narcolepsy with cataplexy, where at higher dose it has shown to have a restorative effect 
on muscle atonia during REM sleep10. In patients with narcolepsy, with more than 16 
years of postapproval use, SXB reduces symptoms of sleepiness and cataplexy with 
favorable long-term efficacy and safety profile11. SXB has been shown to be beneficial in 
a few other conditions such as fibromyalgia12, binge-eating disorder13 and symptoms of 
sleepiness associated with PD14,15. An open label study using SXB (mean nightly dose 
7.8g) in 27 subjects with PD suggested subjective reduction in sleepiness, fatigue and 
overall improved sleep quality as compared to prior to treatment14, while a double blind 
placebo-controlled crossover trial in 12 patients with PD resulted in improved sleep 
quality and reduced daytime sleepiness as measured by mean sleep latency test with 
mean SXB dose of 4.8g15. A drop-out rate of 10% due to side effects was reported in both 
studies.  
 
Taken together, this suggests that SXB may be a viable treatment option in patients with 
isolated RBD or RBD associated with PD, who have failed MLT and CLZ due to lack of 
efficacy or intolerance.  
 
 
Hypothesis 
 
We hypothesize that nightly dose of SXB will result in reduction of RBD severity and 
frequency per patients report and objective polysomnographic and actigraphic (wrist-
worn device) measures, over an 8-week double blind intervention comparing SXB and 
placebo (PBO). Additionally, we hypothesize that SXB improves sleep quality, and 


reduces daytime sleepiness in subjects with RBD associated with a neurodegenerative 
condition.  
 
 
Primary Objective 
 
1. Reduction in RBD episodes frequency and severity (RBD log) 
 
Secondary Objectives 
 
1. Improvement in clinical global impression scores per patient and clinician (CGI-
efficacy scale, CGI-E, and CGI-impression scale, CGI-I, respectively) 
2. Reduction of RWAi by PSG 
3. Reduction in movements severity and frequency during REM sleep by 
quantitative video-PSG analysis16 
4. Changes in overall subjective sleepiness by Epworth sleepiness scale (ESS) and 
one hour after rise time by Karolinska scale 
5. Tolerance and side effects to SXB and PBO 
 
Exploratory Objectives 
 
1. Reduction in "activity score" and "activity index" as measured by actigraphy17 
2. Reduction in periodic limb movement (PLM) arousal index 
3. Improved sleep quality by Pittsburgh Sleep Quality Index (PSQI) 
4. Effects on mood measured by PHQ-9 
5. Effects on anxiety measured by GAD-7 
6. Effect on orthostatic heart rate and blood pressure (response to orthostatic 
maneuver) 
 
 
Trial Design 
 
The total duration of this randomized, double-blind, placebo-controlled trial will be 2 
years. For each participant the total duration of the study will be 14 weeks, including 8 
weeks of intervention with SXB or PBO, preceded by a 4-week period of collection of 
baseline data, and followed by a 2-week period of data collection post-intervention.  
Subjects taking MLT or any other medication capable of affecting RBD other than 
clonazepam (CLZ) will maintain their regimen at fixed dose throughout the 14-week 
duration of the study. Those taking CLZ will proceed to reduction and discontinuation of 
CLZ, followed by a 2-week washout period prior to receiving study drug. If unable to 
discontinue CLZ prior to study drug, they will reduce CLZ to lowest acceptable dose by 
the end of the 4-week baseline period followed by cross-taper with SXB during the first 2 
weeks of flexible dosing.  
In each arm, dosage of SXB and PBO will be titrated up weekly (this weekly titration 
will occur via phone calls by the PI on days 2-6 after each new dose change) by up to 
1.5g nightly dose increments from an initial 4.5g total nightly dose (which could be given 


in two unequal doses if needed, or one single dose no greater than 4.5g) to an optimal 
individual dose based on clinical response on RBD symptoms and tolerability, to a 
maximum nightly dose of 9g ("flexible dose" period lasting up to 8 weeks). The optimal 
dose for each participant will then be continued for at least 4 weeks ("stable dose"). 
 
 
Flowchart 
 
 
MOCA: Montreal Cognitive Assessment 
 
PSG: Polysomnography 
CGI: Clinical Global Impression questionnaires 
 
 
• Day 1 (Visit #1 = Initial visit with research coordinator):  
o Verification of inclusion and exclusion criteria 
o Enrollment (if not performed prior) 
o Physical Exam (MoCA,  
o PSQI, PHQ-9, GAD-7, SCOPA-AUT, Epworth sleepiness scale 
o provide RBD logs and sleep diary for the 14 following weeks, 2 blank 
Karolinska scales, and two actigraphy devices (Philips Actiwatch2) to be 
worn on dominant wrist and ankle for one month  


o instructions on when to complete Karolinska scale #1 (Day 21-27, one 
hour after waking up the day prior to sleep study) from home  
o Instructions on clonazepam taper, when applies 
o pregnancy testing for female subjects of childbearing age, when applicable 
o collection of adverse events (AEs) 
o MD (PI, coPI) will be available as needed via telephone or remote video 
conference system 
 
• Day 1-28 (phone calls, weekly, when applicable): guidance on downtitration of 
CLZ  
 
• Day 28 ± 7 days: 1st video-PSG wearing home actigraphy device (Philips 
Actiwatch2) and additional wrist and ankle high-frequency actigraphy device 
(Xiaomi Amazfit Arc) 
 
• Day 29 (One day after Day 28 ± 7 days, Visit #2 = Randomization visit with 
research coordinator):  
o Collection of 1-month RBD log and sleep diary 
o Collection of Karolinska scale #1 
o Collection of all actigraphy devices 
o Epworth sleepiness scale 
o Randomization 
o Subjects receive SXB or PBO and instructions on titration schedule 
o pregnancy testing for female subjects of childbearing age, when applicable 
o collection of adverse events (AEs) 
o MD (PI, coPI) will be available as needed via telephone or remote video 
conference system 
 
 
Day 30-84 ± 7 days (phone calls): Every week after each new dose the subject 
will be called (including when the dose will remain stable), these phone calls will 
be made between day 2-6 to discuss response, record adverse events, and 
determine the next weeks titration dose.   
 
• Day 57-85 ± 7 days (Visit #3 = Interim visit with research coordinator): 
o Collection of 1-month RBD log and sleep diary 
o Epworth sleepiness scale 
o PSQI, PHQ-9, GAD-7  
o Completion of CGI-E by participants 
o Completion of CGI-I by clinician 
o Physical Exam (including MoCA, orthostatic vital signs) 
o instructions on when to complete Karolinska scale #2 (Day 78-84, one 
hour after waking up the day prior to sleep study) from home  
o Participants provided with two actigraphy devices (Philips Actiwatch2) to 
be worn on dominant wrist and ankle for one month 
o pregnancy testing for female subjects of childbearing age, when applicable 


o Collection of AEs, side effects 
o MD (PI, coPI) will be available as needed via telephone or remote video 
conference system 
 
 
• Day 84-112 ± 7 days: 2nd video-PSG wearing home actigraphy device (Philips 
Actiwatch2) and additional wrist and ankle high-frequency actigraphy device 
(Xiaomi Amazfit Arc) 
 
• Day 85-113  (One day after Day 84-112 ± 7 days, Visit #4 = Final Visit with 
research coordinator): 
o Collection of high-frequency actigraphy device (Xiaomi Amazfit Arc) 
o Collection of 1-month RBD log and sleep diary 
o Collection of AEs, side effects 
o Collection of Karolinska scale #2 
o Epworth sleepiness scale 
o PSQI, PHQ-9, GAD-7, SCOPA-AUT 
o Completion of CGI-E by participants 
o Completion of CGI-I by clinician 
o Physical Exam (including MoCA,  
o Verification of any protocol deviation (e.g., change in drug regimen that 
could affect RBD outcome) 
o Discontinuation of treatment 
o MD (PI, coPI) will be available as needed via telephone or remote video 
conference system 
 
 
• Day 99-127 ± 7 days (Visit #5 = Follow-up Visit with research coordinator):  
o Collection of AEs 
o Collection of actigraphy devices  
o Collection of 2-week RBD log and sleep diary 
o Compensation 
o End of study 
o MD (PI, coPI) will be available as needed via telephone or remote video 
conference system 
 
 
 
Treatment Regimen 
 
Being diagnosed with "refractory RBD", all participants will have received and failed 
prior treatments with CLZ and MLT prior to being eligible for the study. Treatment 
failure is defined as insufficient efficacy, or intolerance to treatment limiting the 
possibility of uptitration or leading to discontinuation, resulting in persistent of RBD 
episodes averaging 2 per week or 8 per month or greater.  
 


At study entry, we expect most participants to currently being treated with CLZ and/or 
MLT. Subjects taking MLT or any other medication capable of affecting RBD other than 
CLZ will maintain their regimen at fixed dose throughout the 14-week duration of the 
study. In subjects treated with CLZ, CLZ will be titrated down and discontinued 2 weeks 
prior to start of study drug, or when unable to be discontinued, cross-tapered during the 
first 2 weeks of receiving study drug until reaching the lowest possible CLZ dose, which 
will then be continued until the end of the stable dosing period 
 
Participants will be randomized in a double-blind manner to either SXB or PBO. The 
duration of the intervention in both conditions will be no longer than 12 weeks, including 
up to 8 weeks of flexible dosing and 4 weeks of stable dosing. Treatment will be initiated 
with 4.5g dose of SXB or PBO, given nightly in two doses 2.5-4h apart according to the 
standard protocol used in narcolepsy. PBO will be similar in appearance, smell and flavor 
to the subjects, so that the investigators and participants will be unable to distinguish it 
from SXB. The dose will be increased or decreased by 0.5 - 1.5g weekly increments until 
reaching the optimal dose based on clinical response and tolerance, not exceeding 9g 
nightly. Evidence has shown that patients with RBD treated with sodium oxybate respond 
to nightly doses ranging from 3-6 g. Among these subjects, some have benefited from a 5 
gram nightly dose. This flexibility in dosage is determined on an individual basis, in 
which the final dose must be both effective and tolerated. Dosage flexibility is essential  
as this older population with prodromal or overt signs of neurodegeneration may not 
require or tolerate the higher dosages used in patients with narcolepsy. Although the 
“default” regimen will be two equally divided doses 2.5-4hours apart, if required, the 
drug will be given in two unequal doses, or in one single dose, with no single dose 
allowed to be greater than 4.5g. Once optimal dose reached, fixed dose will be continued 
for at least 4 weeks and discontinued over one night. During the two weeks following 
discontinuation, data will continue to be collected. Patients will be allowed to resume 
usual treatment, including CLZ. 
 
In this study, the choice of flexible dosing for patients receiving SXB is based on a few 
factors. From the 4 case reports summarized above, effective doses of SXB in patients 
with refractory RBD ranged from 3g to 6g nightly, one patient requiring uptitration of his 
initial 5g dose to 6g. No adverse events or side effects were reported by the authors. In 
patients with narcolepsy, the efficacy of SXB is dose-dependent, showing superior 
efficacy with 9g nightly dose compared to 6g. Taken together, this data suggests that 
higher SXB doses will be more likely to control RBD symptoms, however with a higher 
risk of side effects. In the two studies evaluating SXB efficacy and tolerance in patients 
with PD using flexible dosing, final mean doses were 7.8g and 4.8g14,15.  
Our study will include a mixed group of participants, some with a neurological diagnosis 
of PD and some otherwise healthy individuals. We identify risk of dizziness and falls as 
the most concerning risk in patients with a diagnosis of synucleinopathy, as this could be 
aggravated by SXB. We will therefore carefully exclude from this study any participant 
who already suffers from balance impairment resulting in falls or requiring an ambulating 
device, as well as any patient with symptomatic orthostatic hypotension. Taken all these 
considerations into account, and given the expected interindividual variability regarding 


optimal dose of SXB, we chose flexible dosing for highest clinical benefit while 
minimizing the risk of side effects. 
 
The total amount of SXB for the 12 participants randomized to active drug is: 5,292g. 
The total amount of PBO for the 12 participants randomized to placebo drug is: 5,292g. 
 
Option for “Rescue” Open Label Extension Period 
 
All participants, should they decide to drop out of the study, may become eligible for a 
“Rescue” open label extension period, during which they will receive open label active 
drug sodium oxybate in an unblinded fashion. This will provide patients the opportunity 
of experiencing benefit from the study drug. Such participants would then receive 
ascending doses of sodium oxybate, according to the protocol, and will also be asked to 
present for visits and second polysomnography starting at visit 2, otherwise required by 
the protocol until the end of the study. 
 
Inclusion Criteria 
 
• Adult patients aged 40 to 85 years 
• Women may be included only if they have a negative β-HCG test at screen; are sterile  
(documented hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, or 
congenitally sterile) or postmenopausal (no menses for 12 months without alternative 
medical cause). 
• Women with childbearing potential whose male partners are potentially fertile must 
use one of the following highly effective birth control methods for the duration of the 
study (ie, starting at screening) and for 30 days after last dose of study drug  
o estrogen-progestin oral contraceptive pills, patches, or vaginal ring 
o progestogen pills, implant or injection 
o intrauterine device (IUD) 
o intrauterine hormone-releasing system ( IUS)  
o bilateral tubal occlusion 
o vasectomised partner (the sole sexual partner who has received medical 
assessment of the surgical success)or 
o abstain from heterosexual intercourse 
• 
In individuals without a diagnosis of Parkinson's disease (PD), PSG-
 
confirmed “definite RBD” per the International Classification of Sleep 
 
Disorders, 3rd edition (ICSD-3)  
• 
In individuals with a diagnosis of PD, either PSG-confirmed diagnosis of RBD 
 
("definite RBD") or history of dream-enactment ("probable RBD") 
• 
RBD episodes ≥ 2/week or ≥ 8/month (defined as vocalization and/or limb 
 
or body movements attributed to dream-enactment) 
• 
Reliable reporting by bed witness in the absence of patient awareness 
 
 
Exclusion Criteria 


 
• 
History of falls during ambulation in the last 6 months despite adequate 
 
neurologic treatment 
• 
Requirement of an ambulatory device at home 
• 
Inadequately treated symptomatic orthostatic hypotension (syncopal episode in 
 
the last 6 months) 
• 
BMI > 35 
• 
Untreated or uncontrolled OSA (4% desaturation AHI>15) 
• 
Liver impairment 
• 
Renal impairment 
• 
Congestive heart failure  
• 
Uncontrolled hypertension 
• 
Treatment with valproic acid 
• 
Current history of NREM parasomnias or parasomnia overlap syndrome (at least 
 
2 episodes in the last 6 months) 
• 
Diagnosis of narcolepsy 
• 
Cognitive impairment resulting in inability to comply with treatment instructions 
•  
 Diagnosis of any dementia including dementia with Lewy bodies 
• 
Diagnosis of multiple system atrophy 
• 
RBD attributed to a CNS lesion 
• 
PD Hoehn and Yahr stage 4 and 5 
• 
Any change of PD regimen during the study period 
• 
Current alcoholism or prior history of drug abuse 
• 
Pregnancy 
• 
Epilepsy currently treated with sedating antiepileptic drugs;  
• 
Concomitant use of other CNS depressants, including but not limited to opioid 
analgesics, benzodiazepines other than clonazepam, muscle relaxants, and/or 
illicit CNS depressants 
• 
Current depression (at least PHQ-9 score = 10), history of psychosis 
• 
Any change of antidepressant regimen during the study period 
• 
Chronic severe RLS (iRLS>20) (at least 3 days per week) 
• 
Succinic semi-aldehyde dehydrogenase deficiency (SSADH) 
 
 
Primary Endpoint 
• Number of RBD episodes in one month (RBD log), last month of treatment 
compared to 1-month baseline 
 
 
Secondary Endpoints 
• Severity of RBD episodes in one month (RBD log), last month of treatment 
compared to 1-month baseline. Severity is scored from 1 to 3 (1: least severe, 3 
most severe): 
1. non injurious behaviors: facial expressions, non-aggressive vocalizations 
(mumbling, gentle talking, casual conversation, singing, laughing...), twitches, 
gentle shaking, non-aggressive movements of fingers, arms or legs...; 


2. potentially injurious: punching, kicking, arm flailing or thrashing around, at 
least one limb or head out of bed, sitting up in bed, crawling, attempting to 
stand up or leave bed, near falls, cursing, screaming, shouting, yelling, or any 
behavior requiring bed partner to wake up participant; 
3. injurious: any contact with bed partner (hitting or grabbing), wall or furniture, 
any fall or leaving bed (doving out, walking, jumping). 
• CGI efficacy scale (CGE-E): 4-point therapeutic effect scale and 4-point side 
effect scale, jointly filled by patient and partner on last day of treatment 
• CGI improvement scale (CGI-I): 7-point improvement scale filled by clinician on 
last day of treatment 
• RWAi according SINBAR criteria comparing PSG pre-intervention to PSG post-
intervention 
• video-PSG analysis of REM related vocalizations and movements (“simple” 
versus “complex”) as per Sixel-Döring and colleagues16 
• Sleep outcomes: EDS, Karolinska 1 h after awakening 
 
Exploratory Endpoints 
• “Activity index” as recorded by actigraphy17 (percentage of 30-second epochs 
with an activity score above zero) last month of treatment compared to 1-month 
baseline 
• Sleep outcomes: PSQI  
• Cognitive outcome: MoCA 
• Mood and Anxiety: PHQ-9 and GAD-7 
• Orthostatic vital signs 
 
 
Sample Size Justification/Statistical Analysis 
 
Sample size calculation was made for the outcome of number of RBD episodes per 
month. Based on the data published by Brunetti et al.18, the number of RBD episodes 
decreased from 11.2 +-5.2 at baseline to 10.3 +-3.7 per month in the placebo arm. To 
detect an effect size of 50% reduction in the number of RBD episodes per month 
([placebo-active]/placebo) with a power of 80% and alpha of 5%, the number of 
participants would need to be 10 per arm. Based on prior studies using SXB in subjects 
with PD, a conservative drop out rate of 15-20% could be anticipated14,15, which would 
require to enroll at least 24 participants, i.e. 12 participants per arm. 
 
Reporting to Jazz Pharmaceuticals 
 
The Investigator/Sponsor will comply with all relevant regulatory safety reporting 
responsibilities.  Additionally, the Investigator/Sponsor will report to Jazz 
Pharmaceuticals all Serious Adverse Events (SAEs) (initial and follow up) experienced 
by any patient who has received a Jazz Pharmaceuticals Inc (JP) medicinal product, 


regardless of the suspected causal relationship between the event and the Jazz 
Pharmaceuticals medicinal product.  All SAEs must be submitted in English within one 
(1) business day of initial receipt via email or fax to 
.   
 
Any pregnancy occurring in a female subject or in a male subjects female partner will be 
reported to Jazz Pharmaceuticals, Inc within one (1) business day of initial receipt via 
email or fax to 
.  
 
In addition, all other AEs will be reported to the JP Pharmacovigilance Department in 
summary or line-item form upon JP's request and/or at the conclusion of the study. 
 
 
 
 
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SAP_001.pdf: 
Sodium Oxybate in Treatment-Resistant REM Sleep Behavior Disorder 
(RBD): A Randomized Placebo-Controlled Trial 
Statistical Analysis Plan 
NCT04006925 
January 11, 2023 
 
Statistical analysis (using SAS 9.4, Cary, NC) was by intention-to-treat for the primary efficacy analysis, 
comparison of baseline characteristics, safety and tolerance and per-protocol (PP) for 
secondary/exploratory analyses. PP analysis included all participants who completed titration and the 4-
week treatment period. Sample size calculation was based on a prior randomized controlled study by 
Brunetti et al.25 To detect an effect size of 50% reduction in the number of RBD episodes per month 
([placebo - active] / placebo) with a power of 80% and alpha of 5%, the number of participants needed 
to be 10 per arm. Anticipating a dropout rate of 20%, 24 participants required to be enrolled.  
 
We tested the primary hypothesis that SXB is superior to placebo in reducing the number of RBD 
episodes from baseline, as observed in the last month of treatment using linear mixed effects models 
with random intercepts. Models were parameterized in two ways to estimate separate group 
trajectories and between-group differences in change over time. Cohen’s d was calculated as a measure 
of treatment effect size.  Similar hypotheses were tested on secondary and exploratory outcomes. 
Within- and between-group differences were assessed with paired- and unpaired t-tests, or with the 
Wilcoxon Signed Rank and Mann-Whitney U tests for nonnormal data. Bootstrapped percentile-based 
95% confidence intervals were calculated based on 10,000 randomly resampled datasets. Participants 
scoring below 4 on the CGI-I and CGI-E were classified as “responders”; chi-square tests were performed 
to compare the proportion of responders between groups. All statistical tests were conducted using a 2-
sided alpha level of 0.05. For secondary/exploratory analyses, bootstrapped percentile-based 95% 
confidence intervals were calculated based on 10,000 randomly resampled datasets. Descriptive 
statistics on safety data are provided for all randomized participants (intention-to-treat), by treatment 
group and study phase.