Treatment of REM Sleep Behavior Disorder (RBD) With Sodium Oxybate

Study Overview
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Brief Summary
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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
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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.

Official Title
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Sodium Oxybate in Treatment-Resistant REM Sleep Behavior Disorder (RBD): A Randomized Placebo-Controlled Trial

Conditions
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REM Sleep Behavior Disorder, Parkinson Disease

Intervention / Treatment
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* Drug: Sodium Oxybate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 40-85 years old With or without Parkinson's disease Experiencing RBD episodes on average at least 2x/week or 8x/month Able to report RBD episodes themselves or via a partner witness 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 BMI > 35 Untreated or uncontrolled OSA (4%AHI>15) Cognitive impairment resulting in inability to comply with treatment instructions Pregnancy

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sodium Oxybate (SXB) arm<br>Sodium Oxybate (SXB) will be dispensed to the participants. | Drug: Sodium Oxybate<br>* 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).<br>|
| Placebo Comparator: Placebo (PBO) arm<br>Placebo will be dispensed to the participants. | Other: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of RBD Episodes in One Month (Per Patient RBD Log) | Patients record any episode of dream enactment, such as talking, shouting, kicking, or punching, etc. | Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks) | 
| Number of Severe of RBD Episodes in One Month (Per Patient RBD Log) | Patients record any episode of dream enactment, such as talking, shouting, kicking, or punching, etc. Severity is scored from 1 to 3 (1: least severe, 3 most severe): 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...; 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; injurious: any contact with bed partner (hitting or grabbing), wall or furniture, any fall or leaving bed (doving out, walking, jumping). The number of injurious (severe) episodes is reported. | Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Responders According to the CGI Efficacy Scale (CGI-E) | Clinical Global Impression-Efficacy index (CGI-E) is a 4x4 rating scale that assesses the therapeutic effect (Marked, Moderate, Minimal, Unchanged or worse) of treatment medication and associated side effects (none, do not significantly interfere with patient's functioning, significantly interfere with patient's functioning, Outweigh therapeutic effect). Therapeutic effect: Marked and Side effects: None is the best. Therapeutic effect: Unchanged or worse and Side effects: outweigh therapeutic effect is the worst. Each combination of an estimated therapeutic effect and side effect is assigned a score from 1-16, 1 being the best, 16 being the worst. Participants scoring below 4 were considered to be responders. | Assessed at week 12 (end of treatment period). | 
| Number of Responders According to the CGI Improvement Scale (CGI-I) | Clinical Global Impression-Improvement scale (CGI-I) is a 7-point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1. Very much improved, 2. Much improved, 3. Minimally improved, 4. No change, 5. Minimally worse, 6. Much worse, 7. Very much worse. 1 is the best and 7 is the worst. Participants scoring below 4 were considered to be responders. | Assessed at week 12 (end of treatment period). | 
| Epworth Sleepiness Scale (ESS) Score | Epworth Sleepiness Scale (ESS) is a scale to assess patients' general level of sleepiness. Patients choose the most appropriate number (0=would never doze, 1=slight chance of dozing, 2=moderate chance of dozing, 3=high chance of dozing) for the each situation: Sitting and reading, Watching TV, Sitting and inactive in a public place, As a passenger in a car for an hour, Lying down to rest in the afternoon, Sitting and talking to someone, Sitting quietly after a lunch, While stopped for a few minutes in the traffic in a car. 0-10: Normal range, 10-12: Borderline, 12-24: Abnormal. Participants recorded their scores for 28 days at baseline and during the 28 days leading up to week 12; scores were then averaged to calculate the score for each time point per participant, and then the median for all participants is reported. | Assessed at baseline and week 12 | 
| RBD Episode Severity and Frequency During REM Sleep by Quantitative Video-PSG (Polysomnography) Analysis Per 10 Minutes of REM Sleep | The average number of dream-enactment episodes (resulting in motor behaviors, or movements) weighted for severity. Frequency and severity were calculated as the sum of RBD episodes (frequency) times severity (mild = 1; moderate = 5, severe = 10) occurring over one night's sleep, then averaged to calculate the number of episodes per 10 minutes of REM sleep. | Assessed at baseline and week 12 (average approximately 8 hours to assess at each time point) | 
| Change in Ambulatory Measures of Movements During Sleep Using Actigraphy | Measure of activity score using in-home 4-week actigraphy | Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sodium oxybate