Parkinson Disease, REM Sleep Behavior Disorder
Conditions
Keywords
sodium oxybate
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.
Interventions
DRUGSodium Oxybate
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).
OTHERPlacebo
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.
Sponsors
Jazz Pharmaceuticals
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, placebo-controlled trial
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of RBD Episodes in One Month (Per Patient RBD Log) | Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks) | Patients record any episode of dream enactment, such as talking, shouting, kicking, or punching, etc. |
| Number of Severe of RBD Episodes in One Month (Per Patient RBD Log) | Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks) | 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): 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). The number of injurious (severe) episodes is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Epworth Sleepiness Scale (ESS) Score | Assessed at baseline and week 12 | 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. |
| Number of Responders According to the CGI Efficacy Scale (CGI-E) | Assessed at week 12 (end of treatment period). | 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. |
| Change in Ambulatory Measures of Movements During Sleep Using Actigraphy | Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks) | Measure of activity score using in-home 4-week actigraphy |
| RBD Episode Severity and Frequency During REM Sleep by Quantitative Video-PSG (Polysomnography) Analysis Per 10 Minutes of REM Sleep | Assessed at baseline and week 12 (average approximately 8 hours to assess at each time point) | 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. |
| Number of Responders According to the CGI Improvement Scale (CGI-I) | Assessed at week 12 (end of treatment period). | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sodium Oxybate (SXB) Arm For each participant, Sodium Oxybate (SXB) starting at a 4.5g total nightly dose then titrated up weekly by 1.5g increments over 8 weeks to establish their optimal individualized dose (based on their clinical response on RBD symptoms and tolerance). Participant then receive their optimal dose for at least 4 weeks. | 12 |
| Placebo (PBO) Arm Placebo similar in appearance, smell and flavor so that it is indistinguishable from sodium oxybate. | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Side effects | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo (PBO) Arm | Sodium Oxybate (SXB) Arm |
|---|---|---|---|
| Age, Continuous | 65.8 years STANDARD_DEVIATION 7.6 | 65.4 years STANDARD_DEVIATION 7.3 | 66.1 years STANDARD_DEVIATION 8.2 |
| Body Mass Index (BMI) | 25.7 kg/m^2 STANDARD_DEVIATION 6.3 | 27.0 kg/m^2 STANDARD_DEVIATION 7.6 | 24.4 kg/m^2 STANDARD_DEVIATION 4.7 |
| Current Treatment Antidepressant | 8 Participants | 4 Participants | 4 Participants |
| Current Treatment Cholinergic | 3 Participants | 1 Participants | 2 Participants |
| Current Treatment Clonazepam | 9 Participants | 4 Participants | 5 Participants |
| Current Treatment Dopaminergic | 10 Participants | 4 Participants | 6 Participants |
| Current Treatment Melatonin | 14 Participants | 6 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 12 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| History of Injuries | 22 Participants | 12 Participants | 10 Participants |
| Insomnia | 7 Participants | 5 Participants | 2 Participants |
| Parkinson disease | 12 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 12 Participants | 12 Participants |
| RBD Symptom Duration | 9.8 years STANDARD_DEVIATION 5.8 | 8.4 years STANDARD_DEVIATION 4.3 | 11.2 years STANDARD_DEVIATION 6.9 |
| Region of Enrollment United States | 24 Participants | 12 Participants | 12 Participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 18 Participants | 9 Participants | 9 Participants |
| Sleep Apnea | 7 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 7 / 12 | 2 / 12 |
| serious Total, serious adverse events | 5 / 12 | 0 / 12 |
Outcome results
Primary
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.
Time frame: Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks)
Population: Participants with data at each time point are included in the analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sodium Oxybate (SXB) Arm | Number of RBD Episodes in One Month (Per Patient RBD Log) | Baseline | 37.5 episodes |
| Sodium Oxybate (SXB) Arm | Number of RBD Episodes in One Month (Per Patient RBD Log) | Final dose | 23.5 episodes |
| Placebo (PBO) Arm | Number of RBD Episodes in One Month (Per Patient RBD Log) | Baseline | 35.0 episodes |
| Placebo (PBO) Arm | Number of RBD Episodes in One Month (Per Patient RBD Log) | Final dose | 25.5 episodes |
Comparison: Within group analysis of change from baseline.p-value: 0.0395% CI: [-41, -2]Wilcoxon Signed Rank test
Comparison: Within group analysis of change from baseline.p-value: 0.1195% CI: [-21.5, 0]Wilcoxon Signed Rank test
Comparison: Between group analysis of change from baseline.p-value: 0.2795% CI: [-32, 11.3]Mann Whitney U test
Primary
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): 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). The number of injurious (severe) episodes is reported.
Time frame: Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks)
Population: Participants with data at each time point are included in the analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sodium Oxybate (SXB) Arm | Number of Severe of RBD Episodes in One Month (Per Patient RBD Log) | Baseline | 1.5 episodes |
| Sodium Oxybate (SXB) Arm | Number of Severe of RBD Episodes in One Month (Per Patient RBD Log) | Final dose | 0.5 episodes |
| Placebo (PBO) Arm | Number of Severe of RBD Episodes in One Month (Per Patient RBD Log) | Baseline | 1.5 episodes |
| Placebo (PBO) Arm | Number of Severe of RBD Episodes in One Month (Per Patient RBD Log) | Final dose | 1.0 episodes |
Comparison: Within group analysis of change from baseline.p-value: 0.0295% CI: [-3, 0]Wilcoxon Signed Rank test
Comparison: Within group analysis of change from baseline.p-value: 0.8395% CI: [-1, 1]Wilcoxon Signed Rank test
Comparison: Between group analysis of change from baseline.p-value: 0.0995% CI: [-3.5, 0]Mann Whitney U test
Secondary
Change in Ambulatory Measures of Movements During Sleep Using Actigraphy
Measure of activity score using in-home 4-week actigraphy
Time frame: Assessed for 28 days at baseline and during last month of treatment (total treatment period of up to 12 weeks)
Population: Analysis was not possible because the data that were collected were corrupted and uninterpretable.
Secondary
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.
Time frame: Assessed at baseline and week 12
Population: Participants with data at each time point are included in the analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sodium Oxybate (SXB) Arm | Epworth Sleepiness Scale (ESS) Score | Baseline | 8.0 score on a scale |
| Sodium Oxybate (SXB) Arm | Epworth Sleepiness Scale (ESS) Score | Final dose | 5.0 score on a scale |
| Placebo (PBO) Arm | Epworth Sleepiness Scale (ESS) Score | Baseline | 9.5 score on a scale |
| Placebo (PBO) Arm | Epworth Sleepiness Scale (ESS) Score | Final dose | 7.5 score on a scale |
Comparison: Within group analysis of change from baseline.p-value: 0.2695% CI: [-7, 2]Wilcoxon Signed Rank test
Comparison: Within group analysis of change from baseline.p-value: 0.4395% CI: [-3.5, 2]Wilcoxon Signed Rank test
Comparison: Between group analysis of change from baseline.p-value: 0.6595% CI: [-4, 3]Mann Whitney U test
Secondary
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.
Time frame: Assessed at week 12 (end of treatment period).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Oxybate (SXB) Arm | Number of Responders According to the CGI Efficacy Scale (CGI-E) | 10 Participants |
| Placebo (PBO) Arm | Number of Responders According to the CGI Efficacy Scale (CGI-E) | 6 Participants |
Comparison: Between group analysis of change from baseline.p-value: 0.08Mann Whitney U test
Secondary
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.
Time frame: Assessed at week 12 (end of treatment period).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Oxybate (SXB) Arm | Number of Responders According to the CGI Improvement Scale (CGI-I) | 10 Participants |
| Placebo (PBO) Arm | Number of Responders According to the CGI Improvement Scale (CGI-I) | 7 Participants |
Comparison: Between group analysis of change from baseline.p-value: 0.18Mann Whitney U test
Secondary
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.
Time frame: Assessed at baseline and week 12 (average approximately 8 hours to assess at each time point)
Population: Participants with data available at the respective time points are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Oxybate (SXB) Arm | RBD Episode Severity and Frequency During REM Sleep by Quantitative Video-PSG (Polysomnography) Analysis Per 10 Minutes of REM Sleep | Baseline | 13.2 episodes*severity per 10 minutes of REM | Standard Deviation 12.3 |
| Sodium Oxybate (SXB) Arm | RBD Episode Severity and Frequency During REM Sleep by Quantitative Video-PSG (Polysomnography) Analysis Per 10 Minutes of REM Sleep | Final dose | 7.2 episodes*severity per 10 minutes of REM | Standard Deviation 7.4 |
| Placebo (PBO) Arm | RBD Episode Severity and Frequency During REM Sleep by Quantitative Video-PSG (Polysomnography) Analysis Per 10 Minutes of REM Sleep | Final dose | 10.5 episodes*severity per 10 minutes of REM | Standard Deviation 10 |
| Placebo (PBO) Arm | RBD Episode Severity and Frequency During REM Sleep by Quantitative Video-PSG (Polysomnography) Analysis Per 10 Minutes of REM Sleep | Baseline | 10.1 episodes*severity per 10 minutes of REM | Standard Deviation 8.4 |
Comparison: Within group analysis of change from baseline.p-value: 0.2395% CI: [-15.2, 1.7]Unpaired T-test
Comparison: Within group analysis of change from baseline.p-value: 0.9595% CI: [-4.6, 4.5]Unpaired T-test
Comparison: Between group analysis of change from baseline.p-value: 0.2295% CI: [-16.2, 3.1]Paired T-test