Trial Outcomes & Findings for Effects of Cholinergic Augmentation on Measures of Balance and Gait (NCT NCT02206620)

NCT ID: NCT02206620

Last Updated: 2019-11-14

Results Overview

Increased body sway while standing may be markers for increased risk of falling in Parkinson's disease. Sway was measured with an inertial sensor attached to the waist. Participants did this task on a foam pad. We reported the delta in the donepezil and placebo phases \[post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase\].

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 49 participants
• Primary outcome timeframe: Six weeks
• Results posted on: 2019-11-14

Participant Flow

Participant milestones

Measure	Donepezil, Then Placebo Donepezil 5 mg per day for weeks 1-3. 10 mg/day for weeks 4-6. Then 6 week washout followed by 6 weeks of placebo. Placebo (identical appearing capsules), two capsules per day for 2 weeks and four capsules per day for the following 2 weeks.	Placebo, Then Donepezil Placebo (identical appearing capsules), two capsules per day for weeks 1-3 and four capsules per day for 4-6 weeks followed by washout for 6 weeks and then crossover to donepezil for six weeks. Donepezil 5 mg per day for 2 weeks, then 10 mg/day for the following 2 weeks.
Phase I - First Intervention (6 Weeks) STARTED	22	27
Phase I - First Intervention (6 Weeks) COMPLETED	21	26
Phase I - First Intervention (6 Weeks) NOT COMPLETED	1	1
Washout (6 Weeks) STARTED	21	26
Washout (6 Weeks) COMPLETED	21	26
Washout (6 Weeks) NOT COMPLETED	0	0
Phase II - Second Intervention (6 Weeks) STARTED	21	26
Phase II - Second Intervention (6 Weeks) COMPLETED	21	24
Phase II - Second Intervention (6 Weeks) NOT COMPLETED	0	2

Reasons for withdrawal

Measure	Donepezil, Then Placebo Donepezil 5 mg per day for weeks 1-3. 10 mg/day for weeks 4-6. Then 6 week washout followed by 6 weeks of placebo. Placebo (identical appearing capsules), two capsules per day for 2 weeks and four capsules per day for the following 2 weeks.	Placebo, Then Donepezil Placebo (identical appearing capsules), two capsules per day for weeks 1-3 and four capsules per day for 4-6 weeks followed by washout for 6 weeks and then crossover to donepezil for six weeks. Donepezil 5 mg per day for 2 weeks, then 10 mg/day for the following 2 weeks.
Phase I - First Intervention (6 Weeks) Withdrawal by Subject	1	1
Phase II - Second Intervention (6 Weeks) Withdrawal by Subject	0	2

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	All Study Participants n=49 Participants Donepezil was taken for 3 weeks at 5mg/day (1 tablet/day) and then increased to 10mg/day (2 tablets/day) for another 3 weeks. The same was done for the placebo (1 tablet for the first 3 weeks, then 2 tablets for the following 3 weeks). There was a washout period of 6 weeks between the interventions. Participants were randomized to start with donepezil or placebo.
Age, Continuous	69 years STANDARD_DEVIATION 7 • n=49 Participants
Sex: Female, Male Female	14 Participants n=49 Participants
Sex: Female, Male Male	35 Participants n=49 Participants
Disease Duration	7 years STANDARD_DEVIATION 5 • n=49 Participants
MoCA	26 scores on a scale STANDARD_DEVIATION 3 • n=49 Participants
MDS-UPDRS Part III	43 units on a scale STANDARD_DEVIATION 12 • n=49 Participants

PRIMARY outcome

Timeframe: Six weeks

Increased body sway while standing may be markers for increased risk of falling in Parkinson's disease. Sway was measured with an inertial sensor attached to the waist. Participants did this task on a foam pad. We reported the delta in the donepezil and placebo phases [post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase].

Outcome measures

Measure	Donepezil n=49 Participants Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil	Placebo n=49 Participants Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil
Delta Medio-lateral Postural Sway Range (Foam)	0.007 m/s^2 Standard Deviation 0.045	-0.004 m/s^2 Standard Deviation 0.028

PRIMARY outcome

Timeframe: Six weeks

Population: Variability of stride time was calculated from the stride time time-series as the coefficient of variation (CV, 100 multiplied by the SD of the stride times divided by the mean of each subject's stride times)

Variability in stride time time and an increase with dual tasking is another marker for increased fall risk in Parkinson's disease. Stride time variability was measured with inertial sensors attached to both feet. The delta for each phase is reported [post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase].

Outcome measures

Measure	Donepezil n=49 Participants Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil	Placebo n=49 Participants Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil
Delta of the Variability of Stride Time While Walking	-0.32 percentage of gait cycle time Standard Deviation 4.07	-0.038 percentage of gait cycle time Standard Deviation 3.98

SECONDARY outcome

Timeframe: Six weeks

Population: The average and standard deviation (SD) of the SAI at the end of each treatment is reported

Short-latency afferent inhibition (SAI) by a peripheral stimulation is a transcranial magnetic stimulation method to evaluate cortical cholinergic activity. Short-latency afferent Inhibition will be used to determine if our subjects with Parkinson's disease have evidence of reduced cholinergic tone which correlates with their measures of postural and gait instability. We report the SAI at the end of each phase (post-placebo phase and post-donepezil phase). SAI is reported in motor-evoked potential (MEP).

Outcome measures

Measure	Donepezil n=49 Participants Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil	Placebo n=49 Participants Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil
Short-latency Afferent Inhibition is a Marker of Cortical Cholinergic Activity	72.5 percentage of the unconditioned MEP Standard Deviation 26.9	74.3 percentage of the unconditioned MEP Standard Deviation 23.8

SECONDARY outcome

Timeframe: Six weeks

Attention Network Test (ANT) is 15 minute computerized test or reaction times with various cues and targets designed to assess alerting, orienting and executive control of attention. Deficits of attention are related to fall risk and may be affected by donepezil.

The delta of the Orienting Network Efficiency is reported for each phase (pre- and post-donepezil phase and pre- and post-placebo phase).

Details: In accordance with Fan et al. (2002), the subtraction method was applied to isolate the efficiency of the three attentional networks as follows: for the alerting network efficiency: mean RT NC trials - mean RT DC trials; for the orienting network efficiency: mean RT CC trials - mean RT SC trials; and for the executive network efficiency: mean RT I trials - mean RT C trials. For both the alerting and orienting effects, higher subtraction scores indicate greater efficiency; by contrast, the more efficient the executive network is, the lower the subtraction score.

Outcome measures

Measure	Donepezil n=49 Participants Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil	Placebo n=49 Participants Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil
Attention Network Test	-19.5 ms Standard Deviation 16.3	-5.1 ms Standard Deviation 5.9

Adverse Events

Donepezil, Then Placebo (Phase I)

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Placebo, Then Donepezil (Phase I)

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Donepezil, Then Placebo (Washout)

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo, Then Donepezil (Washout)

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Donepezil, Then Placebo (Phase II)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Placebo, Then Donepezil (Phase II)

Serious events: 0 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Measure	Donepezil, Then Placebo (Phase I) n=22 participants at risk Participants took a donepezil 5mg tablet each day for 3 weeks, then increased the dose to 10mg (2 tablets each day) for 3 weeks. (This was followed by 6 weeks of a washout period and then taking the placebo in the same format -- 3 weeks of one tablet, followed by 3 weeks of 2 tablets to replicate the dosage increase.)	Placebo, Then Donepezil (Phase I) n=27 participants at risk Participants took the placebo at one tablet each day for 3 weeks, then increased the dosage to 2 tablets each day for 3 weeks. (This was followed by 6 weeks of a washout period and then taking donepezil in the same format -- donepezil 5mg tablet each day for 3 weeks, followed by 3 weeks of an increased dose of 10mg (2 tablets each day).)	Donepezil, Then Placebo (Washout) n=21 participants at risk There were 6 weeks of a washout period after participants had taken donepezil for 6 weeks.	Placebo, Then Donepezil (Washout) n=26 participants at risk There were 6 weeks of a washout period after participants had taken the placebo for 6 weeks.	Donepezil, Then Placebo (Phase II) n=21 participants at risk After the washout period, participants took the placebo in the same format as the donepezil -- 3 weeks of one tablet, followed by 3 weeks of 2 tablets to replicate the dosage increase.	Placebo, Then Donepezil (Phase II) n=26 participants at risk Then participants took donepezil in the same formats the placebo -- the donepezil 5mg tablet each day for 3 weeks, followed by 3 weeks of an increased dose of 10mg (2 tablets each day).
Respiratory, thoracic and mediastinal disorders Pulmonary Embolus	0.00% 0/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.8% 1/26 • Number of events 1 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.

Other adverse events

Measure	Donepezil, Then Placebo (Phase I) n=22 participants at risk Participants took a donepezil 5mg tablet each day for 3 weeks, then increased the dose to 10mg (2 tablets each day) for 3 weeks. (This was followed by 6 weeks of a washout period and then taking the placebo in the same format -- 3 weeks of one tablet, followed by 3 weeks of 2 tablets to replicate the dosage increase.)	Placebo, Then Donepezil (Phase I) n=27 participants at risk Participants took the placebo at one tablet each day for 3 weeks, then increased the dosage to 2 tablets each day for 3 weeks. (This was followed by 6 weeks of a washout period and then taking donepezil in the same format -- donepezil 5mg tablet each day for 3 weeks, followed by 3 weeks of an increased dose of 10mg (2 tablets each day).)	Donepezil, Then Placebo (Washout) n=21 participants at risk There were 6 weeks of a washout period after participants had taken donepezil for 6 weeks.	Placebo, Then Donepezil (Washout) n=26 participants at risk There were 6 weeks of a washout period after participants had taken the placebo for 6 weeks.	Donepezil, Then Placebo (Phase II) n=21 participants at risk After the washout period, participants took the placebo in the same format as the donepezil -- 3 weeks of one tablet, followed by 3 weeks of 2 tablets to replicate the dosage increase.	Placebo, Then Donepezil (Phase II) n=26 participants at risk Then participants took donepezil in the same formats the placebo -- the donepezil 5mg tablet each day for 3 weeks, followed by 3 weeks of an increased dose of 10mg (2 tablets each day).
Gastrointestinal disorders Anorexia	0.00% 0/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.7% 1/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.7% 2/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
Gastrointestinal disorders Nausea	27.3% 6/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.4% 2/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.8% 1/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	9.5% 2/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	30.8% 8/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
Gastrointestinal disorders Diarrhea	9.1% 2/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.7% 1/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	11.5% 3/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
Gastrointestinal disorders Constipation	4.5% 1/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.4% 2/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.7% 2/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
Gastrointestinal disorders Abdominal Pain	4.5% 1/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.7% 1/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.8% 1/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Insomnia	13.6% 3/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	18.5% 5/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	4.8% 1/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.8% 1/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	4.8% 1/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	23.1% 6/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Vivid Dreams	9.1% 2/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.4% 2/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.7% 2/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
Musculoskeletal and connective tissue disorders Fatigue	18.2% 4/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.7% 1/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	9.5% 2/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	11.5% 3/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
Musculoskeletal and connective tissue disorders Muscle Cramps	13.6% 3/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	11.1% 3/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	9.5% 2/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	4.8% 1/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	19.2% 5/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Light Headedness	13.6% 3/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	14.8% 4/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.7% 2/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	4.8% 1/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	11.5% 3/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Headache	9.1% 2/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Hallucinations	9.1% 2/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	4.8% 1/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.8% 1/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	4.8% 1/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.8% 1/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Memory Disturbances	4.5% 1/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.4% 2/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.8% 1/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Increased Saliva	4.5% 1/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.7% 1/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Decreased Saliva	0.00% 0/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.4% 2/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
Renal and urinary disorders Urinary Frequency	9.1% 2/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	14.8% 4/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	15.4% 4/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
Respiratory, thoracic and mediastinal disorders Upper Respiratory Tract Infection	18.2% 4/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	11.1% 3/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	3.8% 1/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	0.00% 0/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.
General disorders Other	18.2% 4/22 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	18.5% 5/27 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	9.5% 2/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	7.7% 2/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	4.8% 1/21 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.	26.9% 7/26 • Adverse Events were collected through study completion, an average of 18 weeks. Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial. The adverse events are reported below per intervention for each Arm/Group of the study.

Additional Information

Dr. Martina Mancini

Oregon Health & Science University

Phone: 5034182602

Email: mancinim@ohsu.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place