Conditions: Huntington Disease Chorea
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and benefit of risperidone for the treatment of chorea (involuntary movements) in Huntington's disease. Risperidone is commonly used in clinical practice to treat chorea, however, it has not been approved by the Food and Drug Administration (FDA) to treat chorea. This study will examine 1) whether the investigators see MRI changes with risperidone treatment and 2) whether sensors applied to the participants body can measure chorea and detect changes in chorea.

Detailed description:

Arms:
arm 1: Participants will initiate risperidone 0.5 mg nightly the day after the baseline visit. Dose assessment will occur at pre-specified intervals during the titration phase (week 2, 3, 4, 6, 7). The investigator will increase the dose by 0.5 mg at the week 2, week 3, week 4, and week 6 visits until either optimal chorea benefit has been obtained, an intolerable adverse event occurs, or the maximum allowable dose (3.0 mg) is reached.

Interventions: intervention 1: Risperidone intervention 2: BioStamp nPoint device
Intervention descriptions: intervention 1: capsule or tablet, 0.5 mg intervention 2: MC10 has developed the BioStamp nPointTM, a FDA 510(k) cleared medical device. This multimodal, reusable and rechargeable biosensor uses flexible and stretchable electronics to enable unobtrusive wear on the body and monitoring in the home. The sensors have accelerometry, gyroscopy, and ECG/EMG capabilities. A docking station enables wireless recharging and data collection.

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
Risperidone for the treatment of HunƟngton’s disease chorea 
NCT04201834 
November 7, 2019 


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Risperidone for the treatment of Huntington’s disease chorea
Principal Investigator – Ruth Schneider, MD
Co-Principal Investigator – Fred Marshall, MD


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS
4
1.0        PURPOSE OF STUDY 
8
2.0       BACKGROUND AND RATIONALE
8
3.0
ADMINISTRATIVE ORGANIZATION
11
4.0      STUDY DESIGN
11
4.1 Subject Population
4.2 Study Drug
4.3 MC10 Sensors
4.4 Neuroimaging
5.0     INCLUSION AND EXCLUSION 
16
5.1 Inclusion Criteria
5.2 Exclusion Criteria
6.0
RECRUITMENT METHODS
17
7.0
CONSENT PROCESS
18
8.0  
STUDY PROCEDURES
19
8.1
Schedule of Activities
8.2
Study Visits
8.3
Study Assessments
8.4
Electronic Medical Record
8.5
Return of Research Results
9.0
RISKS TO SUBJECTS
31
9.1
General
9.2
Study Drug
9.3
MC10
9.4
Neuroimaging
10.0
POTENTIAL BENEFITS TO SUBJECTS
33
11.0
COSTS FOR PARTICIPATION
33
12.0     PAYMENT FOR PARTICIPATION
33
13.0 
SUBJECT WITHDRAWALS
34
14.0    PRIVACY AND CONFIDENTIALITY OF SUBJECTS 
34
AND RESEARCH DATA    
14.1
MC10
15.0    DATA/SAMPLE STORAGE FOR FUTURE USE
35
16.0    DATA AND SAFETY MONITORING PLAN
35
16.1
Adverse Event Definition


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16.2
Serious Adverse Event
16.3
Recording Adverse Events
16.4
Responsibilities for Reporting Serious Adverse Events
16.5
Assessment of Severity
16.6
Assessment of Relationship
16.7
Monitoring Plan
17.0    DATA ANALYSIS PLAN
38
17.1
Sample Size
17.2
Statistical Analysis Plan
18.0    REFERENCES
40


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PROTOCOL SYNOPSIS
FULL STUDY TITLE
Risperidone for the treatment of Huntington’s disease chorea
CLINICAL PHASE
Phase II
INVESTIGATORS/ 
STUDY GROUP
Ruth Schneider (PI), Fred Marshall (Co-PI), Giovanni Schifitto 
(Co-I), Jamie Adams (Co-I), Christopher Tarolli (Co-I), Nasir 
Udin (Co-I)
STUDY OBJECTIVE
1) To determine the preliminary efficacy and safety of risperidone 
for the treatment of HD chorea.
2) To assess whether frontostriatal structural and functional 
connectivity is predictive of risperidone clinical response and 
whether clinical response is associated with increased functional 
connectivity.
3) To assess the ability of wearable accelerometers to detect 
chorea severity and the responsiveness of wearable 
accelerometers to the effect of risperidone treatment.
STUDY RATIONALE
Chorea is present in over 90% of individuals with HD, negatively 
impacts quality of life, causes functional disability, and is a 
treatment priority for individuals living with HD. While there are 
two FDA-approved treatments for HD chorea, tetrabenazine and 
deutetrabenazine, the majority of HD experts eschew these costly 
medications in favor of atypical antipsychotics, for which there is 
little evidence from controlled trials.    Clinical trial data is needed 
to support the safety and efficacy of antipsychotics, such as 
risperidone, for the treatment of HD chorea. 
The inclusion of neuroimaging will enable a better understanding 
of the brain networks that sub-serve chorea and the potential 
identification of neuroimaging predictors of clinical response. The 
inclusion of wearable sensors will further the development of a 
novel outcome measure by assessing their responsiveness to 
chorea treatment.
STUDY SITES
University of Rochester 
STUDY PERIOD 
18 months
STUDY POPULATION 
AND NUMBER OF 
SUBJECTS
12 to 16  participants with manifest HD and UHDRS TMC ≥ 8
STUDY DESIGN
This is a single-center, blinded-rater, open-label dose response 
study of risperidone for the treatment of HD chorea.  
MAIN INCLUSION/ 
EXCLUSION 
CRITERIA
  Inclusion Criteria:
1.
Manifest HD (DCL 4 + CAG repeat ≥ 37 or family history of 
HD)
2.
UHDRS TMC ≥ 8
3.
UHDRS Total Functional Capacity ≥ 5


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4.
Subject willing and able to provide written informed consent 
OR legally authorized representative provides written 
informed consent 
5.
Between 18 and 65 years of age
 
   Main Exclusion Criteria: 
6.
Use of antipsychotic, levodopa, amantadine, dopamine 
agonist, monoamine oxidase inhibitor, or other disallowed 
medication in the 30 days prior to the baseline visit
7.
Prior non-response to risperidone or intolerability to 
risperidone (in the investigator’s opinion)
8. Allergy or hypersensitivity to risperidone
9.
Dysphagia that in the investigator’s opinion would preclude 
participation in the study
10. Active suicidal ideation or psychiatric condition that in the 
investigator’s opinion would preclude participation in the 
study 
11. QTc > 460 msec for women or >450 msec for men on 12-lead 
EKG
12. History of cardiac arrhythmia or congenital long QT syndrome
13. Significant renal impairment (creatinine clearance < 30 
mL/min as estimated by the Cockgroft-Gault formula) or 
hepatic impairment (AST or ALT > 2.5 times upper limit of 
normal OR alkaline phosphatase or total bilirubin > 2 times 
upper limit of normal)
14. Active drug or alcohol abuse or dependence
15. Pregnant or breast-feeding
16. Any contraindication to MRI (e.g. pacemakers, aneurysm clips, 
metallic prostheses, shrapnel fragments, claustrophobia)
17. History of active (clinically significant) skin disorder that 
would interfere with sensor adherence
18. History of allergic response to adhesives
19. Pacemaker, AICD, or other implantable stimulator
20. Use of an investigational drug in the 30 days prior to the 
baseline visit
21. Inability to complete study activities, as determined by the 
study team
22. Clinically significant parkinsonism as determined by expert 
investigator assessment
DOSAGE
Participants will initiate risperidone 0.5 mg nightly the day after 
the baseline visit. Dose assessment will occur at pre-specified 
intervals during the titration phase (week 2, 3, 4, 6, 7). The 
investigator will increase the dose by 0.5 mg at the week 2, week 
3, week 4, and week 6 visits until either optimal chorea benefit 
has been obtained, an intolerable adverse event occurs, or the 
maximum allowable dose (3.0 mg) is reached. The investigator 
should consult with the participant (and care partner) and use all 
available study information in determining whether the optimal 
dose has been reached.  To ensure that the participant is on a 


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stable dose by week 8, the dose at week 7 may be decreased but 
should not be increased.
The maximum dosage reached should be maintained during the 
maintenance phase (week 8-week 12). Reductions and 
discontinuation of study drug will be allowed at any time during 
the study in the setting of an adverse event.  Following the week 
12 visit, participants may choose to remain on drug at the 
discretion of their treating clinician, but otherwise will complete a 
short taper with follow-up by phone at week 13.
DURATION OF 
TREATMENT
12 weeks
PRIMARY OUTCOME 
MEASURE(S)
The primary outcome measure is UHDRS TMC score, as assessed 
by blinded expert-rater review of video recordings. 
SECONDARY 
OUTCOME 
MEASURE(S)
Efficacy:
1. UHDRS component and total scores
2. Clinical global impression of change (CGI) (investigator)
3. Patient global impression of change (PGI)
4. Chorea Index as measured by MC10 wearable sensors
5. Quantifiable chorea score as measured by Q-Motor
Safety and Tolerability:
1. Adverse events and serious adverse events
2. UHDRS parkinsonism score
3. Epworth Sleepiness Scale
4. QTc on 12-lead EKG
5. Barnes Akathisia Scale
6. Weight and vital signs
7. Lipids, CBC with differential, CMP (with fasting glucose)
Cognition and Psychiatric Features
1. Columbia Suicide Severity Rating Scale
2. Problem behaviors assessment short form
3. Hospital anxiety and depression scale
4. Apathy Scale
5. Montreal Cognitive Assessment
NEUROIMAGING
Neuroimaging will include examination of brain grey and white 
matter atrophy, functional connectivity (via resting state fMRI, rs-
fMRI), and structural connectivity (via diffusion MRI, dMRI) at two 
time points, between screening and baseline (off drug) and between 
week 8 and week 12 (maintenance phase, on drug).  
All imaging will be conducted on a research dedicated 3T whole-
body Siemens Prisma scanner (Erlangen, Germany), equipped 
with a 64-channel receive-only head coil and body coil 
transmission, and high-performance gradients of max strength 
80mT/m and slew rate of 200mT/m/s. The MRI protocol 
includes 3D T1w MPRAGE [TR/TE = 1400/2.34 ms; 1 mm 


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isotropic resolution] and T2w SPACE sequence [TR/TE = 
3200/444 ms; 1 mm isotropic resolution] anatomical images, 
single-shell dMRI [64 diffusion-encoded (b=1000 s/mm2) and 5 
reference (b = 0 s/mm2) images; TR/TE = 4300/69 ms; 1.5 mm 
isotropic resolution] and rs-fMRI [TR/TE = 993/43 ms, number 
of volumes = 300, 2 mm isotropic resolution] using EPI 
sequences. 
SENSORS
During the screening and week 8 visits, participants will be fitted 
with 3 MC-10 BioStamp nPoint wearable sensors (chest, arm, 
leg), prior to completing in-clinic motor assessments.  Following 
each of these visits, participants will wear the sensors at home for 
1 week.
SAFETY 
CONSIDERATIONS
According to the package insert, in risperidone clinical trials the 
most common adverse reactions (≥10%) were somnolence, 
increased appetite, fatigue, rhinitis, upper respiratory tract 
infection, vomiting, coughing, urinary incontinence, increased 
saliva, constipation, fever, parkinsonism, dystonia, abdominal 
pain, anxiety, nausea, dizziness, dry mouth, tremor, rash, 
akathisia, and dyspepsia.
To minimize the risk of side effects, we will follow a slow titration 
and limit the total daily dose to 3.0 mg.  Safety and tolerability 
will be closely monitored by study investigators. If an 
intolerability or adverse event occurs, depending on the severity 
of the event, investigators may decide to decrease the study drug 
or to discontinue the study drug.  Participants will be able to 
withdraw from the study at any time.  
SAMPLE SIZE 
CONSIDERATIONS
There are no prior clinical trials from which to estimate an effect 
size for risperidone and this represents a convenience sample. We 
are relying on data from studies of existing treatments to inform 
power analysis and the identification of a chorea effect less robust 
than existing treatments would dampen enthusiasm for 
risperidone.  In a clinical trial of tetrabenazine, over 12 weeks 
there was a 5.0-unit change (SD 3.7 units) in total maximal 
chorea score.11 A sample size of 11 participants will provide > 98% 
power to detect a 5.0 unit difference or greater, using a one-
sample t-test at the 5% significance level.  A sample size of 12 
participants will account for an estimated 8% drop-out rate.  


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1. PURPOSE OF STUDY 
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease 
characterized by psychiatric features, cognitive impairment, and motor abnormalities 
that affects approximately 40,000 individuals living in North America.1  Chorea is 
present in over 90% of individuals with HD,2 negatively impacts quality of life, causes 
functional disability, and is a treatment priority for individuals living with HD.3 While 
there are two FDA-approved treatments for HD chorea, tetrabenazine and 
deutetrabenazine, the majority of HD experts eschew these costly medications in favor 
of atypical antipsychotics,4 for which there is little evidence from controlled trials.    
Clinical trial data is needed to support the safety and efficacy of antipsychotics, such as 
risperidone, for the treatment of HD chorea.  Moreover, our approach to treatment and 
assessment of response to treatment would be enhanced by a better understanding of 
the brain networks that sub-serve chorea and the use of novel outcome measures that 
enable in-home assessment.  
Aim 1: To determine the preliminary efficacy and safety of risperidone for the 
treatment of HD chorea.   
Hypotheses: 
1A) There will be a 5.0 unit difference or greater between baseline and week 12 in the 
primary outcome measure of the Unified Huntington’s Disease Rating Scale Total 
Maximal Chorea (UHDRS TMC) score 
1B) Risperidone treatment is tolerable, as defined by ≥9 of 12 participants completing 12 
weeks on study drug (any dose). 
Aim 2: To assess whether frontostriatal structural and functional connectivity is 
predictive of risperidone clinical response and whether clinical response is associated 
with increased functional connectivity.  
Hypotheses:
2A) Decreased structural and functional connectivity of the frontostriatal pathways will 
be associated with chorea severity and thus predict the observed response to risperidone
2B) Clinical response to risperidone will be associated with increased functional 
connectivity
Aim 3: To assess the ability of wearable accelerometers to detect chorea severity and 
the responsiveness of wearable accelerometers to the effect of risperidone treatment.
Hypotheses: 
3A) Wearable sensors will measure chorea severity as determined by the Chorea Index 
and correlate with traditional measures (e.g. UDHRS).


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3B) Wearable sensors will detect changes in chorea as determined by the Chorea Index 
in response to risperidone treatment with at least as much sensitivity as traditional 
assessments (e.g, UHDRS TMS, UHDRS chorea subscores).
2. BACKGROUND AND RATIONALE 
While two vesicular monoamine transporter type 2 (VMAT-2) inhibitors, tetrabenazine 
and deutetrabenazine, have received FDA approval for the symptomatic treatment of 
chorea in HD following pivotal double-blind, randomized, placebo-controlled studies,5,6 
they are prohibitively expensive.  According to the Institute for Clinical and Economic 
Review, the annual wholesale acquisition cost for deutetrabenazine (36 mg daily dose) is 
$90,071 and for tetrabenazine (25 mg daily dose) is $19,885-$76,087.7  This stands in 
stark contrast to the calculated annual cost of $35 for risperidone (2 mg daily dose).8 
Antipsychotic drugs are routinely used in clinical practice for the treatment of HD 
chorea and expert-established clinical practice guidelines recommend antipsychotic 
drugs as first-line treatment for chorea in the setting of depression, psychosis, 
aggression, and/or non-compliance.4,9  The majority of HD experts favor antipsychotic 
drugs as the first-line treatment for HD chorea;4 our recent poll of 22 Huntington 
Disease Society of America (HDSA) Centers of Excellence Center Directors revealed that 
12 (54.5%) favor atypical antipsychotics (most commonly risperidone) and 9 (41%) favor 
VMAT-2 inhibitors.10  Of those who preferred VMAT-2 inhibitors, the most commonly 
cited reason was the existence of clinical trial data.  
There have been few clinical trials of atypical antipsychotic drugs for HD 
chorea.11,12,13,14,15,16,17 There have not been any prior prospective clinical trials of 
risperidone.  However, several case reports and case series support the potential benefit 
of risperidone for the treatment of chorea.18,19,20,21 Moreover, in a retrospective chart 
review study, Duff et al compared 17 individuals with HD treated with risperidone 
against 12 individuals with HD not treated with any antipsychotic medication.22 The 
mean (SD) risperidone dose was 2.5 (1.9) mg daily (range 0.75-6.0 mg) and the mean 
time between pre-treatment evaluation and post-treatment evaluation in the 
risperidone group was 14.8 (8.2) months (control group 11.0 (3.7) months). While the 
control group had significant worsening of UHDRS23 total motor scores, the risperidone 
group had stable UHDRS total motor scores.  Désaméricq et al examined the effects of 
antipsychotic and tetrabenazine treatment in a large observational, prospective cohort 
(Huntington French-Speaking Group).24 63% of 956 were treated with an antipsychotic 
(with 13% on risperidone) or tetrabenazine and when comparing long-term outcomes 
between the different groups, no differences in rate of decline of motor or behavioral 
function were identified.  Differences in cognitive decline were seen, with benzamide 
antipsychotics (e.g. amisulpride, levosulpiride) associated with the greatest cognitive 
decline. Schultz et al examined the effects of risperidone, olanzapine, and tetrabenazine 
treatment in another large, observational, prospective cohort (Enroll-HD).25 The mean 
(SD) risperidone dose was 1.76 (1.6) mg daily and olanzapine dose was 6.95 (5.88) mg 
daily. Changes in UHDRS total motor score were comparable between these groups and 
the tetrabenazine group suggesting comparable chorea benefit. 


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Neuroimaging
The pathological hallmark of HD is degeneration of striatal medium spiny neurons, but 
there is also widespread cortical atrophy, and chorea is thought to reflect dysfunction of 
the cortico-striatal motor circuit.26 Neuroimaging studies have shown that motor 
dysfunction is associated with caudate atrophy,27 altered motor cortico-striatal 
circuits,28 altered cortico-cortical networks,29 degeneration of the corpus callosum 
body,30 and decreased insular functional connectivity.31   Different neuroimaging 
metrics correlate with HD genetic burden,32 motor function,33 and clinical progression34 
and offer promise as longitudinal disease biomarkers.  
Clinical experience demonstrates that there is heterogeneity in response to HD chorea 
treatment.  Some patients have chorea that is refractory to treatment with VMAT-2 and 
antipsychotic medications; others demonstrate differential improvement with one class 
compared to the other. Different motor phenotypes have been recognized in HD35 and it 
may be that clinical heterogeneity in response to chorea treatment reflects underlying 
neurobiological differences. Research in schizophrenia suggests that changes in 
functional connectivity occur with antipsychotic treatment36 and that differences in 
cortical thickness37 and white matter tract integrity38 may predict response to 
antipsychotic treatment.  
Here, we propose to take advantage of advanced analytical approaches to fully evaluate 
structural and functional connectivity, identify predictors of clinical response to 
risperidone treatment and examine neuroimaging changes associated with risperidone 
treatment.
Wearable Sensors Background (MC10)
HD research and care have also been hampered by the limitations of existing clinical 
measures and a lack of objective measures of chorea. The UHDRS29 is commonly used 
in clinical trials to assess motor function but the scale has several limitations: it is 
categorical, subjective, must be administered by a trained rater, and some items exhibit 
poor interrater reliability.39  New objective disease measures are needed.  Objective 
quantitative-motor (Q-motor) assessment40 is sensitive to HD clinical progression41, and 
has been used in clinical trials42 but must be performed in a clinic setting. Wearable 
sensors, which enable unobtrusive monitoring in the home environment, may be an 
ideal tool for assessing HD motor function.  Preliminary work has established the 
feasibility of wearable sensors in HD,43,44 which can objectively measure motor features 
of HD, but further work is needed to establish their sensitivity to detect chorea and 
responsiveness to treatment.
MC10 has developed the BioStamp nPointTM, a FDA 510(k) cleared medical device.  This 
multimodal, reusable and rechargeable biosensor uses flexible and stretchable 
electronics to enable unobtrusive wear on the body and monitoring in the home. The 
sensors have accelerometry, gyroscopy, and ECG/EMG capabilities. A docking station 
enables wireless recharging and data collection (Figure 1). 


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UR investigators have completed a 12-month study in which individuals with HD, 
prodromal HD, and healthy controls wore the MC10 sensors in clinic and at home. 
Analysis of accelerometer data has resulted in the development of a novel metric for 
quantifying truncal chorea, referred to as the Chorea Index,45 which correlates with the 
truncal chorea rating on the UHDRS, both in clinic and at home. Analysis also resulted 
in quantifying gait metrics and activity patterns (amount of time spent sitting, standing, 
walking and lying down), which were significantly different between individuals with 
HD and control participants.45
  
3. ADMINISTRATIVE ORGANIZATION  
Participating URMC departments/centers include the Department of Neurology and the 
Center for Advanced Brain Imaging & Neurophysiology (UR CABIN).
4. STUDY DESIGN
This is a single-site, blinded-rater, open-label dose response study of risperidone for the 
treatment of HD chorea that incorporates brain MRI with novel methods of structural 
and functional connectivity data integration and wearable sensors. The study will 
include a titration phase and a maintenance phase. Risperidone dosage assessment, 
with consideration to chorea benefit and tolerability, will occur at regular intervals 
during the titration phase until the optimal dosage has been reached.  During the 
maintenance phase, the participant’s optimal dosage will be continued. The primary 
outcome measure is the UHDRS total maximal chorea (TMC) score, as assessed by 
expert-rater review of video recordings. All expert-rater assessments of video recordings 
will be performed at the time of subject study completion, and raters will be blinded to 
the study visit.  
Screening Phase (7-45 days)
All participants determined to be eligible will have the MC10 sensors placed at the 
conclusion of the screening visit and be instructed to wear the sensors for 1 week 
following the visit.  If they are later found to be ineligible on the basis of screening 
laboratory results or an inability to discontinue a disallowed medication, they will be 


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instructed to remove and return the wearable sensors.  Participants will also be 
scheduled for a brain MRI, which will occur prior to the baseline visit.
Titration Phase (8 weeks)
Risperidone will be initiated at 0.5 mg daily the day after the baseline visit with a 
planned increase to 0.5 mg twice daily after 7 days.  The dose will be assessed at pre-
specified intervals for the duration of the titration phase (week 2, week 3, week 4, week 
6, and week 7).  The investigator will increase the dose by 0.5 mg at the week 2, week 3, 
week 4, and week 6 visits until optimal chorea benefit has been obtained, the participant 
experiences an intolerable adverse event, or the maximum allowable dosage (3.0 mg 
daily) is reached. To ensure that the participant is on a stable dose by week 8, the dose at 
week 7 may be decreased but should not be increased. The MC10 sensors will be placed 
at the week 8 visit and participants will be instructed to wear the sensors for 1 week 
following the visit (during the maintenance phase). 
Maintenance Phase (4 weeks)
The maximum dosage reached should be maintained during the maintenance phase 
(week 8-week 12), however, reductions/discontinuation will be allowed in the setting of 
an adverse event.  The second brain MRI should occur during the maintenance phase. 
Following the week 12 visit, participants may choose to remain on drug at the discretion 
of their treating clinician, but otherwise will complete a short taper with follow-up by 
phone.
4.1. SUBJECT POPULATION
a) Number of Participants:  We anticipate screening 16 individuals in order 
to meet our enrollment goal of 12 subjects. Evaluable subjects who withdraw 
from the study prior to initiating drug treatment may be replaced to meet 
the enrollment goal.
b) Gender and Age of Participants:  There will not be any enrollment 
restrictions based upon gender.  Participants must be between 18 and 65 
years of age.
c) Racial and Ethnic Origin:  There will not be any enrollment restrictions 
based upon race or ethnic origin.
Huntington’s disease is characterized by a triad of motor abnormalities, 
psychiatric symptoms, and cognitive impairment.  As such, we will allow adults 
with decisional impairments to participate.  In the case of absence of consent 
capacity, we will obtain informed consent from a legally authorized 
representative. This is described under more detail in Section 7.
4.2. STUDY DRUG
4.2.1 Study Drug


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Risperidone is a selective monoamergic antagonist with high affinity for 
serotonin 5HT2, dopamine D2 receptors, α1 and α2 adrenergic receptors, and H1 
histaminergic receptors. In adults, it is FDA-approved for use in bipolar 
disorder and schizophrenia.  While commonly used in clinical practice, it is 
considered investigational for HD chorea.  As per FDA policy 
(https://www.fda.gov/media/79386/download), this study is exempt from IND 
requirements because:

risperidone is lawfully marketed in the U.S

we do not intend to report the investigation to the FDA in support a 
new indication or change in labeling of risperidone

we do not intend to use the investigation to support a change in the
advertising for risperidone

the study does not involve a route of administration, dose, or patient 
population that significantly increases the risk associated with 
risperidone
Risperidone does carry a black box warning for increased mortality in elderly 
patients with dementia-related psychosis.  Given this, elderly patients over the 
age of 65 will be excluded. The study is designed, in part, to assess the 
tolerability of risperidone in this population. Adverse events will be closely 
monitored. The risperidone label can be found at 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020272s056,02
0588s044,021346s033,021444s03lbl.pdf
4.2.2 Study Drug Packaging, Distribution, and Accountability
The Investigational Drug Service at the University of Rochester will manage the 
packaging and distribution of the study drug in conjunction with the study 
team.  0.5 mg tablets of the study drug will be purchased in bulk.  The study 
drug will be repackaged into labeled bottles. The Investigational Drug Service 
will dispense bottles.  Medication labels will be provided by the Investigational 
Drug Service and labeling will include the study number, route of 
administration, quantity, directions for use, storage conditions, and additional 
space for information to be completed by a study team member (dispensing 
date, participant number). The drug will be stored at the site in a locked storage 
area with controlled temperature (59°- 77° F).
At each in-person visit participants will receive an adequate supply of study 
drug to ensure that participants have a sufficient supply of study drug to last 
until their next visit.  Participants will be asked to return all study bottles.
4.2.3 Study Drug Dose Adjustment
The maximum allowable dose and dose levels were selected in accordance with 
prescribing guidelines and clinical experience. Participants will initiate 
risperidone 0.5 mg nightly (level 1) the day after the baseline visit with a pre-


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planned increase to 0.5 mg twice daily after 7 days. Dose assessment will occur 
at pre-specified intervals during the titration phase. At the week 2, 3, 4, and 6 
visits, the investigator will increase the dose by 0.5 mg (Table 1) until either 
optimal chorea benefit has been obtained, an intolerable adverse event occurs, 
or the maximum allowable dose is reached. The investigator should consult 
with the participant (and care partner) and use all available study information 
in determining whether the optimal dose has been reached. To ensure that the 
participant is on a stable dose by week 8, the dose at week 7 may be decreased 
but should not be increased. The investigator may decrease the dose or 
discontinue the study drug in the event of an adverse event. 
Table 1: Risperidone Dose Levels
Dose Level
Total Daily 
Dose
Morning Dose
Evening Dose
1*
0.5 mg
None
0.5 mg
2
1.5 mg
0.5 mg
1 mg
3
2 mg
1 mg
1 mg
4
2.5 mg
1 mg
1.5 mg
5
3 mg
1.5 mg
1.5 mg
*With increase to 0.5 mg twice daily after 7 days.
The drug should be taken orally and can be taken with or without food. For 
twice daily administration, the doses should be spaced approximately 12 hours 
apart. A drug diary will be used to provide instructions on how to take the 
medication and to help with adherence. 
After the week 12 visit, participants on study drug will begin a short taper off of 
study drug. Participants with a total daily dose of ≥2.5 mg will be instructed to 
decrease to 1mg twice daily for 3 days then decrease to 0.5 mg twice daily for 3 
days then stop. Participants with a total daily dose of 1.5-2 mg will be instructed 
to decrease to 0.5 mg twice daily for 3 days then stop. Participants with a total 
daily dose of 0.5-1 mg will be instructed to stop the drug without a taper.
Participants who discontinue study drug and do not withdraw their consent, 
will continue to be followed in the study.
4.2.4 Allowed Medications
CYP2D6 inhibitors (e.g. fluoxetine, bupropion, and paroxetine), cimetidine, and 
ranitidine, which may result in increased serum concentrations, will be 
permitted as titration is being performed slowly and our maximal total daily 
dose is only 3.0 mg. 
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbital), which may 
result in decreased serum concentrations of risperidone, will be allowed.


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Vesicular monoamine transporter-2 inhibitors will be allowed but stable 
dosages for 30 days prior to the baseline and for the duration of the study will 
be required. We recognize that the vesicular monoamine transporter-2 
inhibitors have been associated with QT prolongation; the mean increase in 
QTc interval with tetrabenazine 50 mg is 8 msec 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021894lbl.pdf) and the mean 
increase in QTc interval with deutetrabenazine 24 mg is 4.5 msec 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208082s000lbl.pdf).  Given 
that risperidone treatment may also be associated with QT prolongation, we 
will obtain baseline and follow up EKGs and will keep the maximum total daily 
dose to 3 mg. In addition, we are excluding those > 65 years of age and with a 
history of cardiac arrhythmias or congenital long QT syndrome. 
4.2.5 Disallowed Medications
The following medications will not be allowed from 30 days prior to the study 
and for the duration of the study:

Selective and non-selective monoamine oxidase inhibitors

Typical or atypical antipsychotics

Levodopa (any formulation)

Dopamine agonists

Valproate

Furosemide

QT Prolonging Drugs (Table 2)
Table 2: QT Prolonging Drugs
Amiodarone
Levomethadyl
Arsenic trioxide
Mesoridazine
Azithromycin
Methadone
Bepridil
Moxifloxacin
Chloroquine
Pentamidine
Chlorpromazine
Probucol
Clarithromycin
Procainamide
Disopyramide
Quinidine
Dofetilide
Sevoflurane
Domperidone
Sotalol
Droperidol
Sparfloxacin
Erythromycin
Thioridazine
Flecainide
Vandetanib
Halofantrine
Vardenafil
Ibutilide
Escitalopram and citalopram will be allowed with the following dose restrictions. The 
maximum total daily dose of citalopram will be 20 mg for individuals who are ≥ 60 


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years of age, are known CYP2C19 poor metabolizers, or are taking certain CYP2C19 
inhibitors (cimetidine, omeprazole, esomeprazole, lansoprazole, fluconazole, fluoxetine, 
fluvoxamine, and ticlopidine). For all others, the maximum total daily dose of 
citalopram will be 40 mg. The maximum total daily dose of escitalopram will be 10 mg 
for individuals who are ≥ 60 years of age and 20 mg for all others.
Participants will be permitted to discontinue a disallowed medication in order 
to enroll in the study. Any discontinuation of disallowed medications for the 
purpose of enrollment in the study will be done only after the participant has 
completed the informed consent process, and all reductions and 
discontinuations will be completed under the guidance of the clinical 
investigator and/or the patient’s treating neurologist. Participants 
discontinuing a disallowed medication must remain off the disallowed 
medication for 30 days prior to the Baseline visit and must remain off the 
disallowed medication for the entirety of the Titration and Maintenance periods 
in the study. 
Concomitant medications will be collected at each visit and verified in the 
electronic medical record whenever possible. If treatment with a disallowed 
medication is required, the study drug should be discontinued and the 
participant should continue in the study off of the study drug.  The study drug 
may be restarted after the disallowed medication is stopped.
4.2.6 Pregnancy and Nursing
Female participants of childbearing potential will be advised to use adequate 
birth control as there is insufficient data regarding the effects of risperidone on 
the fetus. Adequate birth control methods include surgical sterilization, a 
partner who has had a vasectomy, oral contraceptives, condom plus spermicidal 
cream/jelly, cervical cap plus spermicidal cream/jelly, diaphragm plus 
spermicidal cream/jelly, intrauterine device (in place for at least 3 months) plus 
spermicidal cream/jelly, or contraceptive implant or injection.  Abstinence is 
considered an acceptable contraceptive regimen.  
If a participant becomes pregnant during the study, it is important that they 
notify a   study team member immediately.  In such an event, the study drug 
must be discontinued immediately.  The participant may continue in the study 
off of study drug.  All attempts will be made to follow the participant until 
delivery.  
      4.3  MC10 SENSORS
MC10 has developed the BioStamp nPointTM, a FDA 510(k) cleared medical 
device.  This multimodal, reusable and rechargeable biosensor uses flexible and 


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stretchable electronics to enable unobtrusive wear on the body and monitoring 
in the home. The sensors have accelerometry, gyroscopy, and ECG/EMG 
capabilities. A docking station enables wireless recharging and data collection
The study team at the University of Rochester will receive the wearable sensor 
patches from MC10 and store the sensors in a secure office, accessible only to 
research study team members with access. All records pertaining to supply 
receipt, distribution, and return will be maintained by the research team. 
The sensors will be applied at the screening and week 8 visits, as described in 
Section 8.2. After completing all sensor activities, the sensors should then be 
removed and, with the docking station, mailed back in pre-paid packaging or 
returned in-person.  
Sensor data will be used to calculate a Chorea Index score, or average amount of 
chorea over a given period of time, using algorithms from our previous work. 
We will also analyze activity patterns and gait.
      4.4   NEUROIMAGING
All imaging will be conducted on a research dedicated 3T whole-body Siemens 
Prisma scanner (Erlangen, Germany), equipped with a 64-channel receive-only 
head coil and body coil transmission, and high-performance gradients of max 
strength 80mT/m and slew rate of 200mT/m/s. The MRI protocol includes 3D 
T1w MPRAGE [TR/TE = 1400/2.34 ms; 1 mm isotropic resolution] and T2w 
SPACE sequence [TR/TE = 3200/444 ms; 1 mm isotropic resolution] 
anatomical images, single-shell dMRI [64 diffusion-encoded (b=1000 s/mm2) 
and 5 reference (b = 0 s/mm2) images; TR/TE = 4300/69 ms; 1.5 mm isotropic 
resolution] and rs-fMRI [TR/TE = 993/43 ms, number of volumes = 300, 2 mm 
isotropic resolution] using EPI sequences. 
Neuroimaging will occur at two time points, between screening and baseline 
(off drug) and between week 8 and week 12 (maintenance phase).  
5. INCLUSION AND EXCLUSION CRITERIA
5.1    INCLUSION CRITERIA

Manifest HD (Diagnostic Confidence Level 4 + CAG repeat ≥ 37 or family 
history of HD)

UHDRS Total Maximal Chorea (TMC) ≥ 8

UHDRS Total Functional Capacity ≥ 5

Subject willing and able to provide written informed consent OR legally 
authorized representative provides written informed consent*

Between 18 and 65 years of age


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*A care partner will be required to attend all visits for all subjects with a TFC 5-7 at 
screening OR when consent was provided by a legally authorized representative.  
5.1   EXCLUSION CRITERIA

Use of antipsychotic, levodopa, dopamine agonist, monoamine oxidase 
inhibitor or other disallowed medication in the 30 days prior to the 
baseline visit (see Section 4.2.5)*

Prior non-response to risperidone or intolerability to risperidone (in the 
investigator’s opinion)

Allergy or hypersensitivity to risperidone

Dysphagia that in the investigator’s opinion would preclude participation 
in the study

Active suicidal ideation or psychiatric condition that in the investigator’s 
opinion would preclude study participation 

QTc > 460 msec for women and QTc > 450 msec for men on 12-lead EKG

History of cardiac arrhythmia or congenital long QT syndrome

Significant renal impairment (creatinine clearance < 30 mL/min as 
estimated by the Cockgroft-Gault formula) or hepatic impairment (AST or 
ALT > 2.5 times upper limit of normal OR alkaline phosphatase or total 
bilirubin > 2 times upper limit of normal)

Active drug or alcohol abuse or dependence

Pregnant or breast-feeding

Any contraindication to MRI (e.g. pacemakers, aneurysm clips, metallic 
prostheses, shrapnel fragments, claustrophobia)

History of active (clinically significant) skin disorder that would interfere 
with sensor adherence

History of allergic response to adhesives

Pacemaker, AICD, or other implantable stimulator

Use of an investigational drug in the 30 days prior to the baseline visit

Inability to complete study activities, as determined by the study team

Clinically significant parkinsonism as determined by expert investigator 
assessment
*Participants currently taking a disallowed medication will be allowed to 
reduce and discontinue the disallowed medication in order to qualify for study 
participation. Disallowed medications must be discontinued at least 30 days 
prior to the baseline visit. 
6. RECRUITMENT METHODS
We anticipate that the majority of participants will be identified within the clinical 
practices of faculty in the UR Department of Neurology.  To minimize undue 
influence, discussion of research participation should occur after all clinical care 
related activities have been completed.  Potential participants may also be asked to 


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spread the word about the study and share our contact information with any other 
individuals who may wish to enroll in the study. We will use multiple methods to 
identify potential participants; beyond recruiting from clinical practices, other 
sources will include support groups, interest registries, and affinity organizations. 
Recruitment avenues include:
 (1) We may use the eRecord “My Reports” function to regularly generate lists of 
patients seen in the UR neurology department with a diagnosis of Huntington’s 
disease.  The research team will give each neurology provider a list of their identified 
patients and the date of their next upcoming clinic visit so that he or she may 
consider whether their patient may be appropriate for participation.  
(2) The study will be posted on appropriate clinical research registries including, but 
not limited to, HD Trial Finder, Research Match, and the UR Health Research 
website.  
(3) We will reach out to individuals who expressed interest in participating in future 
research studies through avenues including the UR Department of Neurology Study 
Interest Registry (STUDY00000537), and the CTSI Volunteer Registry 
(STUDY00001978).  
(4) We will reach out to local patient advocacy groups and other health-related 
community organizations to increase awareness and engage potential participants.  
We will promote the study at regional symposiums and other events. Additional 
efforts may be made to promote the study in the local news media and social media 
outlets.
(65 We may use i2b2, TriNetX, or another appropriate informatics tool to identify 
Huntington’s disease patients seen at the UR movement disorders clinic and then 
send an RSRB-approved recruitment letter and research brochure to the identified 
patients.  
The study team will track recruitment metrics such as how potential participants 
learned about the trial, referral source, number who are found to be ineligible, 
reasons for ineligibility, number who decline, reasons for nonparticipation of 
potentially eligible participants (when available), and number who enroll.  This 
information will be reviewed monthly to identify any problems and develop 
strategies to enhance recruitment.
7. CONSENT PROCESS
Interested potential participants will be contacted by a study coordinator who will 
provide a brief overview of the study, assess their interest, and schedule them for a 
screening visit, at which time eligibility will be confirmed and written informed 
consent will be obtained.  Written informed consent and HIPAA authorization will 
be obtained using an IRB-approved consent form.  The study coordinator obtaining 
consent will be trained in human subject’s protection according to University of 


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Rochester IRB procedures.  
Capacity to consent to the study will be determined by the study coordinator during 
the consent process. As delineated in the consent form, capacity will be determined 
based on the potential participant’s understanding of why the study is being done, 
what will happen during the study, possible risks and benefits, alternatives to 
participation in the study, how personal information will be protected, and what to 
do if there is a problem or question.
Investigators and study team members will ensure that prospective participants have 
sufficient knowledge and understanding of the details of the study to allow them to 
make an informed decision whether or not to participate.  Prospective participants 
will be provided with an opportunity to ask questions.  Every effort will be made to 
provide potential participants with a copy of the consent form prior to the screening 
visit.
Prospective participants will also be asked to consent to future contact to update 
their contact information and inform them about future studies (STUDY00000537).  
Participants may decline to consent to this aspect and still participate in the study.
Documentation of consent will be stored in a secure filing cabinet at the UR and will 
only be accessible to members of the UR study team.  A copy of the consent form will 
be provided to the participant upon obtainment of consent.  Consent 
acknowledgment will be electronically recorded in REDCap. If an individual is 
unable or unwilling to consent, the individual will be excluded from the study but 
their routine clinical care will not be affected.
Consent Process for Adults with Decisional Impairment:
If an individual is not capable of giving consent to participate, we will obtain 
informed consent from a legally authorized representative.
8. STUDY PROCEDURES


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8.1
SCHEDULE OF ACTIVITIES
Screening     
(-7-60 days )
Baseline 
(Week 0)
Week 2 
(±-3 days)
Week 3
(±3 days)
Week 4      
(±3 days)
Week 6       
(±-3 days)
Week 7      
(±3 days)
Week 8 
(±-3 days)
Week 12 
(±-3 days)
Week 13     
(±-3 days)
PW Visit
TITRATION
MAINTENANCE
Clinic
Clinic
TC
Clinic
TC
Clinic
TC
Clinic
Clinic
TC
Clinic
Informed Consent
X
Eligibility
X
Confirm HD Diagnosis
X
Demographics
X
Health History
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
Vital Signs + Physical 
Measurements
X
X
X
X
X
X
X
Physical Exam
X
12-lead EKG
X
X
X
Chemistry/Hematology
X
X
X
Pregnancy Test
S
U
U
C-SSRS
X
X
X
X
X
X
UHDRS-Motor (VR)
X
X
X
X
X
X
X
UHDRS-Cognition
X
X
X
X
X
X
UHDRS-Behavior
X
X
X
X
X
X
UHDRS-Functional 
Assessment
X
X
X
UHDRS-Independence
X
X
X
UHDRS-TFC
X
X
X
X
PBA-Short form
X
X
X
X
X
X
HADS
X
X
X
X
X
X
Epworth Sleepiness 
Scale
X
X
X
X
X
X
Barnes Akathisia Scale
X
X
X
X
X
X
Apathy Scale
X
X
X
X
X
X
MoCA
X
X
X
Q-Motor
X
X


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S Serum pregnancy test for women of childbearing potential
U Urine pregnancy test for women of childbearing potential
1Should occur prior to baseline visit.
2Should occur prior to week 12 visit.
8.2
STUDY VISITS
8.2.1 Screening Visit
Prior to completing any study activities, written informed consent will be 
obtained.  The study coordinator and investigator will assess potential 
participants for study eligibility.  Participants will be assigned a unique 
participant identification number. If a participant is being withdrawn from a 
medication to qualify for the study (detailed in Section 4.2.5), the consent form 
must be signed prior to the initiation of the withdrawal. 
Evaluations:

Informed Consent

Eligibility Criteria Review

Confirm HD Diagnosis

Demographics

Health History

Concomitant Medications

Vital Signs + Physical measurements

Physical Examination

12-lead EKG

Chemistry/hematology

Pregnancy test (serum, for women of childbearing potential)

UHDRS-Motor (VR)

UHDRS-TFC
MC10 Activities: 
Application of MC10 wearable sensors
Lying position activity
10 meter walk test (VR)
Wear sensors x 1 week
Assess Adverse Events
X
X
X
X
X
X
X
X
X
Assess Dose
X
X
X
X
X
X
X
Assess Drug Adherence
X
X
X
X
X
X
CGI
X
X
X
X
X
X
PGI
X
X
X
X
X
X
Neuroimaging
X1
X2
MC10 WEARABLE SENSORS
Apply Sensors
X
X
Lying Position Activity
X
X
10 Meter Walk test (VR)
X
X
Wear sensors x 1 week
X
X
Daily journal x 1 week
X
X


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Daily journal x 1 week
Three sensors will be applied using double-sided adhesives to the chest, arm 
and leg.  The arm and leg sensor will be applied to the most affected side as 
determined by the investigator.  In the case of symmetric symptoms, the arm 
and leg sensors will be placed on the dominant side. The sensors will be applied 
before the performance of standard clinical motor assessments (UHDRS-
Motor), which will be video-recorded and logged into the BioStamp NPoint 
Investigator Application. Videos will be stored in Box. For the lying position 
activity, participants will be asked to lay in each of four positions (supine, 
prone, and on both sides) for approximately 30 seconds.
After the visit, participants will wear the sensors and complete a daily journal 
for one week. For 6 days, participants will wear the sensors during waking 
hours and recharge them nightly. Beginning on Day 7, participants will wear the 
sensors continuously for 24 hours. This will permit the capture of sleep data. 
On Day 8, after 24 hours of continued use, participants will remove the sensors 
and return them with the docking station either by pre-paid packaging or in-
person.  In the journal, participants will record the predominant activity that 
they engage in (sitting, standing, walking, lying down) for every hour of the day 
during the recording period and any falls.
Neuroimaging will be scheduled to occur at least 1 week following the screening 
visit (following completion of the wearable sensory portion of the Screening 
phase), but prior to the baseline visit. 
Screen Fails: All screening tests/procedures are for research purposes only. 
Data gathered during the screening process will be retained.
8.2.2 Baseline Visit
The baseline visit will occur within 7-45 days of the screening visit.  Prior to the 
baseline visit, laboratory study results obtained at the screening visit must be 
reviewed and eligibility confirmed, neuroimaging must be obtained, the first 
wearable sensor period must be completed, and all disallowed medications 
must have been discontinued for ≥30 days.  Participants will be supplied with 
study drug and the first dose of study drug should be taken the following 
morning.
Evaluations:

Concomitant Medications Update

Vital Signs + Physical measurements

Pregnancy test (urine, for women of childbearing potential)

C-SSRS

UHDRS-Motor (VR)

UHDRS-Cognition


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Version Date: 11/7/19

UHDRS-Behavior

UHDRS-Functional Assessment

UHDRS-Independence

PBA-Short form

Hospital Anxiety and Depression Scale

Epworth Sleepiness Scale

Barnes Akathisia Scale

Apathy Scale

MoCA

Q-Motor

CGI

PGI

Assess Adverse Events
8.2.3 Week 3 Visit
The Week 3 visit should occur within 21 ± 3 days of the baseline visit.  
Previously dispensed study drug bottles will be collected and new study drug 
bottles dispensed.
Evaluations:

Concomitant Medications Update

Vital Signs + Physical measurements

C-SSRS

UHDRS-Motor (VR)

UHDRS-Cognition

UHDRS-Behavior

PBA-Short form

Hospital Anxiety and Depression Scale

Epworth Sleepiness Scale

Barnes Akathisia Scale

Apathy Scale

Assess Adverse Events

Assess Dose (Section 8.3.24)

Assess Drug Adherence

CGI

PGI
8.2.4 Week 6 Visit
The Week 6 visit should occur within 42 ± 3 days of the baseline visit.  
Previously dispensed study drug bottles will be collected and new study drug 
bottles dispensed.
Evaluations:


Page 25 of 45
Version Date: 11/7/19

Concomitant Medications Update

Vital Signs + Physical measurements

12-lead EKG

Chemistry/hematology, (at investigator’s discretion) approximately two 
tablespoons  

C-SSRS

UHDRS-Motor (VR)

UHDRS-Cognition

UHDRS-Behavior

PBA-Short form

Hospital Anxiety and Depression Scale

Epworth Sleepiness Scale

Barnes Akathisia Scale

Apathy Scale

Assess Adverse Events

Assess Dose

Assess Drug Adherence

CGI

PGI
8.2.5 Week 8 Visit
The Week 8 visit should occur within 56 ± 3 days of the baseline visit.  
Previously dispensed study drug bottles will be collected and new study drug 
bottles dispensed.
Evaluations:

Concomitant Medications Update

Vital Signs + Physical measurements

Pregnancy test (urine, for women of childbearing potential)

C-SSRS

UHDRS-Motor (VR)

UHDRS-Cognition

UHDRS-Behavior

PBA-Short form

Hospital Anxiety and Depression Scale

Epworth Sleepiness Scale

Barnes Akathisia Scale

Apathy Scale

MoCA

Q-Motor

Assess Adverse Events

Assess Dose

Assess Drug Adherence


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Version Date: 11/7/19

CGI

PGI
MC10 Activities: 
Application of MC10 wearable sensors
Lying position activity
10 meter walk test (VR)
Wear sensors x 1 week
Daily journal x 1 week
Three sensors will be applied using double-sided adhesives to the chest, arm 
and leg.  The arm and leg sensor will be applied to the most affected side as 
determined by the investigator.  In the case of symmetric symptoms, the arm 
and leg sensors will be placed on the dominant side. The sensors will be applied 
before the performance of standard clinical motor assessments (UHDRS-
Motor), which will be video-recorded and logged into the BioStamp NPoint 
Investigator Application. For the lying position activity, participants will be 
asked to lay in each of four positions (supine, prone, and on both sides) for 
approximately 30 seconds.
After the visit, participants will wear the sensors and complete a daily journal 
for one week. For 6 days, participants will wear the sensors during waking 
hours and recharge them nightly. Beginning on Day 7, participants will wear the 
sensors continuously for 24 hours. This will permit the capture of sleep data. 
On Day 8, after 24 hours of continued use, participants will remove the sensors 
and return them with the docking station either by pre-paid packaging or in-
person.  In the journal, participants will record the predominant activity that 
they engage in (sitting, standing, walking, lying down) for every hour of the day 
and any falls.
Neuroimaging should occur between the week 8 and week 12 visit. A urine 
pregnancy test should be obtained prior to neuroimaging for all women of 
childbearing potential.
8.2.6 Week 12 Visit
The Week 12 visit should occur within 84 ± 3 days of the baseline visit.  
Previously dispensed study drug bottles will be collected. Participants will be 
instructed how to taper off of study drug.
Evaluations:

Concomitant Medications Update

Vital Signs + Physical measurements

12-lead EKG

Chemistry/hematology (approximately two tablespoons) 

C-SSRS


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Version Date: 11/7/19

UHDRS-Motor (VR)

UHDRS-Cognition

UHDRS-Behavior

UHDRS-Functional Assessment

UHDRS-Independence

UHDRS-TFC

PBA-Short form

Hospital Anxiety and Depression Scale

Epworth Sleepiness Scale

Barnes Akathisia Scale

Apathy Scale

MOCA

Assess Adverse Events

Assess Drug Adherence

CGI

PGI
8.2.7 Telephone Visits (Week 2, Week 4, Week 7, Week 13)
The Week 2 visit should occur within 14 ± 3 days of the baseline visit. The Week 
4 visit should occur within 28 ± 3 days of the baseline visit.  The week 7 visit 
should occur within 49 ± 3 days of the baseline visit. If scheduling requires two 
separate phone calls for each telephone visit, one with the study coordinator 
and one with the investigator, this will be allowed.  
Evaluations:

Concomitant Medications Update

Assess Adverse Events

Assess Dose
The Week 13 visit should occur within 91 ± 3 days of the baseline visit.  At this 
visit, the coordinator will assess drug adherence and verify that the participant 
has completed their study drug taper. This visit does not need to occur for any 
participants who did not require a study drug taper.  Coordinators may also use 
this visit to follow up on any unresolved adverse events. 
8.2.8 Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the 
subject’s request or as deemed necessary by an investigator. The date and 
reason for the unscheduled visit will be recorded.  The following evaluations 
may be performed, as deemed necessary by the investigator.
Evaluations:

Concomitant Medications Update


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
Vital Signs + Physical measurements

Physical Examination

12-lead EKG

Chemistry/hematology (approximately two tablespoons)

Pregnancy Test

C-SSRS

UHDRS-Motor 

UHDRS-Cognition

UHDRS-Behavior

Assess Adverse Events

Assess Dose

Assess Drug Adherence
8.2.9 Premature Withdrawal Visit
Subjects may withdraw from the study at any time. In the event of a premature 
study withdrawal (either participant or investigator initiated), a premature 
withdrawal visit should occur. Reasons for premature withdrawal will be 
documented. At the time of the visit, participants will be instructed to 
discontinue their study drug, if they have not done so already.  If the participant 
is unwilling or unable to come in for a premature withdrawal visit, a telephone 
visit (evaluations described in Section 8.2.6) should be performed whenever 
possible.
Evaluations:

Concomitant Medications Update

Vital Signs + Physical measurements

C-SSRS

UHDRS-Motor (VR)

UHDRS-Cognition

UHDRS-Behavior

UHDRS-Functional Assessment

UHDRS-Independence

UHDRS-TFC

PBA-Short form

Hospital Anxiety and Depression Scale

Epworth Sleepiness Scale

Barnes Akathisia Scale

Apathy Scale

Assess Adverse Events

Assess Drug Adherence

CGI

PGI
8.3
STUDY ASSESSMENTS


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8.3.1 Study Duration
The individual’s participation in the study will last for approximately 14-20weeks.  
The overall anticipated duration of the study is 18 months.
8.3.1 Participant Information 
Demographics, health history, and concomitant medications will be obtained at 
screening.  Concomitant medications will be updated at each study visit.
Medical and Safety Assessments
8.3.2 Physical Examination
A brief physical examination will be performed by the investigator at the 
screening visit. This will include examination for parkinsonism. 
8.3.3 Physical Measurements and Vital Signs
Participant height, weight, respiratory rate, blood pressure, heart rate, and 
temperature will be collected by a study coordinator at the screening visit.  
Weight, respiratory rate, blood pressure, heart rate, and temperature will be 
collected at subsequent in-person visits. 
Sitting blood pressure and heart rate will be measured after 3 minutes of rest. 
Readings will be repeated every 3 minutes until two consecutive readings are 
similar to ensure that baseline has been reached. Standing blood pressure and 
heart rate will be measured after 3 minutes of standing by a study coordinator.
8.3.4 Electrocardiogram
A 12-lead electrocardiogram will be obtained by a trained study coordinator.  
ECG readings will be provided by a cardiologist.
8.3.5 Chemistry and Hematology
A fasting comprehensive metabolic panel, fasting lipid panel, and complete blood 
count with differential will be obtained at screening and week 12.  At the 
investigator’s discretion (e.g. in the event of leukopenia identified on baseline 
CBC or a reported history of drug-induced leukopenia), labs may also be repeated 
at week 6. All blood tests will be obtained on-site and sent to URMC Labs for 
processing. Screening labs may be repeated one time if abnormal to confirm 
eligibility. Each blood draw will be approximately two tablespoons in size. 
8.3.6 Pregnancy Screening


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A serum pregnancy test will be obtained at screening for all women of child-
bearing potential.  All blood tests will be obtained on-site and sent to URMC Labs 
for processing. A urine pregnancy test will be obtained at baseline (prior to drug 
initiation) and week 8 (prior to neuroimaging) for all women of child-bearing 
potential.  
8.3.7 Adverse Events
Soliciting of adverse events will be non-specific. Participants will be asked the 
question, “Do you feel different in any way since your last research study visit?” 
All adverse events occurring after the screening visit will be reported.  All 
subsequent adverse events will be reported regardless of suspected relationship 
to the study device.  Adverse events not previously documented in the study will 
be recorded in the adverse event section in the case report form.  The nature of 
each individual event, date and time of onset, duration, severity, and relationship 
to treatment will be established by the investigator.  Likely alternative etiologies 
should be recorded for events considered unrelated to study device.  
Adverse events already documented in the CRF, at a previous visit, and 
designated as ‘continuing’ should be reviewed at each visit.  If an adverse event is 
resolved, then the documentation in the CRF must be completed to that effect.   If 
an adverse event changes in frequency or severity during a study period, then a 
NEW record of that event will be initiated.  A record of all adverse events will be 
reviewed periodically by the study investigators.  The documentation and 
classification of adverse events is further reviewed in Section 16.
8.3.10 Epworth Sleepiness Scale (ESS)
The ESS is a validated, self-administered scale for the assessment of excessive 
daytime sleepiness.46 The study coordinator will instruct the participant on how 
to complete this questionnaire and will subsequently review the questionnaire for 
completion.
8.3.11 Barnes Akathisia Scale
The Barnes Akathisia Scale, which has been used in clinical trials of tetrabenazine 
for HD chorea, includes objective observation and subjective questions to assess 
for the presence and severity of drug-induced akathisia.47
Huntington’s Disease Motor Assessments
8.3.12 Confirmation of Diagnosis of Manifest Huntington’s Disease
Manifest HD, defined as UHDRS Diagnostic Confidence Level (DCL) 4 + CAG 
repeat ≥ 37 or family history of HD will be confirmed by an investigator. No 
genetic testing will be done as a part of this study.


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8.3.13 Unified Huntington’s Disease Rating Scale (UHDRS)
The UHDRS is a validated assessment of HD.48 The complete UHDRS includes 
the following assessments: motor, cognitive, behavioral, functional, 
independence, and total functional capacity. The cognitive assessment includes 
the verbal fluency test, symbol digit modalities test, and stroop interference test 
(color naming, word reading, interference). Ideally, the same rater should 
complete a given section at each visit.  The UHDRS Motor will be video-recorded.  
Videos will be independently rated by raters blinded to the study visit.
8.3.14 Clinical Global Impression (CGI) and Patient Global Impression (PGI) 
Scales
The CGI is an observer-rated scale that measures impression of severity (CGI-S) 
and change (CGI-C). The CGI-C is rated on a 7-point scale from 1 (very much 
improved) to 7 (very much worse).  The CGI-S and CGI-C will be completed by an 
investigator. Similarly, the PGI is a patient-rated scale that measures impression 
of change (PGI-C).  The PGI-C will be completed by the participant and reviewed 
by a study coordinator.
8.3.15 Quantitative Motor (Q-Motor) Assessments
Q-Motor assessments are performed using force transducers and a grip device 
that includes a position sensor.  The following tasks will be performed separately 
on each side: digitomotography (speeded finger tapping), 
dysdiadochomotography (pronation-supination), manumotography and 
choreomotography (grip force and chorea analysis), and pedomotography 
(speeded foot tapping). The Q-Motor takes approximately 15-3- minutes to 
administer.  Data transfer will be performed using a secure web based platform. 
8.3.16 10 Meter Walk Test
The 10 meter walk test is a validated measure of walking function. The test asks 
individuals to walk a total of 10 meters with the time taken to walk over the 
middle 6 meters recorded to allow for acceleration and deceleration. The test is 
performed at normal walking speed and participants are allowed to use assistive 
devices if they typically walk with them. Administration of the 10-meter walk will 
be video-recorded.
8.3.17 Wearable Sensor Daily Journal 
Participants will maintain a daily journal in which they record the predominant 
activity that they engage in (sitting, standing, walking, lying down) for every hour 
of the day during the recording period, as well as any falls.  Participants will 
complete this journal for 1 week following the screening visit and the week 8 visit 
(during the time when they are wearing the sensors).
Huntington’s Disease Psychiatric and Cognitive Assessments


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8.3.18 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a validated tool that will be used to screen for suicidal ideation and 
behavior and assess the level of risk.49  It will be administered by a trained rater.
8.3.19 Problem Behavioral Assessment – short (PBA-s)
The PBA-s is a validated, semi-structured interview with 11 items that is designed 
to assess the severity and frequency of common behavioral problems in HD.50  It 
will be administered by a trained rater.
8.3.20 Montreal Cognitive Assessment (MoCA)
The MoCA assesses visual-spatial and executive function, language, short-term 
memory, attention, abstraction, and orientation.  It will be administered by a 
trained coordinator.
8.3.21 Hospital Anxiety and Depression Scale (HADS)
The HADS is a self-rated measure with anxiety and depression subscales that is 
recommended for screening in HD.51 The study coordinator will instruct the 
participant on how to complete this questionnaire and will subsequently review 
the questionnaire for completion.
8.3.22 Apathy Scale (AS)
The AS is a clinician-rated scale, that has been used in other HD studies and is 
recommended for screening for apathy in HD.51 The AS assesses the presence and 
severity of apathy.52  
 
Study Drug Assessment
            8.3.23 Drug Adherence Assessment
Participants will be asked to use a dosing diary to track study drug adherence. 
Participants will also be verbally asked whether they have missed any doses since 
their last visit and will be instructed to bring previously dispensed study drug 
bottles to each in-person visit.  Pill counts will be performed by the study 
coordinator and the results recorded on a standard data form to monitor 
participant adherence.  At the end of the study, all returned study medication will 
be counted and compared to the data form.  Any discrepancies will be resolved 
and the data form will be updated as necessary.
8.3.24 Dose Assessment
During the titration phase, the investigator will assess the dose at week 2, week 3, 
week 4, and week 6 and increase the dose by 0.5 mg until either optimal chorea 


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benefit has been obtained, an intolerable adverse event occurs, or the maximum 
allowable dose is reached. The investigator should consult with the participant 
(and care partner) and use all available study information in making this decision 
(see Section 4.2.3). 
During the maintenance phase, the maximal dose reached should be continued 
unless an adverse event occurs that warrants dose reduction or discontinuation.
 
8.4   Electronic Medical Record
When relevant, the participant’s electronic medical record may be reviewed to 
obtain/verify participant information. Information concerning participation in this 
study will be included in the participant’s electronic medical record. Lab test 
results may also be included in the participant’s electronic medical record.
8.5    Return of Research Results
Most research results will not be provided to the participant.  There will be two 
exceptions.  1) Results of laboratory studies and EKGs may be provided at the 
discretion of an investigator.  Incidental findings that might have health 
consequences for the participant will be communicated to the participant and 
his/her primary care provider and/or primary neurologist.
2) Conditions can be diagnosed from having access to research quality brain MRI. 
Our scans are not read by a neuro-radiologist and the subjects are explicitly told 
that the experiment will not provide information as to their health status. 
However, if the researcher suspects something abnormal, they will seek advice 
from a qualified neuroradiologist. Interested individuals who sign a release form 
may receive an electronic format image of their brain.
9. RISKS TO SUBJECTS
9.1 General
1) Participants may find it uncomfortable to respond to some of the questions 
contained in the evaluations.  Participants will not be required to answer any 
questions that make them uncomfortable.  All study personnel will be 
appropriately trained in the administration of study assessments.  
2) Blood draws may cause pain, redness, bruising, or infection at the site of the 
needle stick. The study team member conducting the blood draw will be 
appropriately trained.
3) Breach of confidentiality is a potential risk. To minimize the risks of breach of 
confidentiality, all study data will be maintained in secure systems.  Additionally, 
any paper documents with identifiable information will be stored in a secure 
location and all information sharing will occur in a secure and HIPAA-compliant 


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manner.  If a breach of confidentiality occurs, the participant(s) and investigators 
will be immediately notified and appropriate steps will be taken to minimize the 
risk of a future breach of confidentiality occurring.  
      9.2 Study Drug
According to the FDA label:
 “The most common adverse reactions in clinical trials (≧10%) were somnolence, 
appetite increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, 
coughing, urinary incontinence, saliva increased, constipation, fever, 
parkinsonism, dystonia, abdominal pain, anxiety, nausea, dizziness, dry mouth, 
tremor, rash, akathisia, and dyspepsia. The most common adverse reactions that 
were associated with discontinuation from clinical trials (causing discontinuation 
in >1% of adults and/or >2% of pediatrics) were somnolence, nausea, abdominal 
pain, dizziness, vomiting, agitation, and akathisia.”
Additional recognized risks include:
o
Orthostatic hypotension
o
Hypersensitivity reactions
o
Neuroleptic malignant syndrome
o
Tardive dyskinesia
o
Hyperglycemia
o
Hyperprolactinemia
o
Leukopenia/neutropenia
o
Prolonged QT syndrome
o
Cognitive impairment
o
Dysphagia
o
Priapism
Risperidone is routinely used in clinical practice for the management of chorea in 
Huntington’s disease. To minimize the risk of side effects, we will follow a slow 
titration and limit the total daily dose to 3.0 mg.  Safety and tolerability will be 
closely monitored by study investigators.  Safety evaluation, described in detail in 
Section 8.3, will include vital signs, orthostatic vital signs, Barnes Akathisia Scale, 
multiple cognitive assessments, Epworth Sleepiness Scale, electrocardiogram, 
and chemistry/hematology. If an intolerability or adverse event occurs, 
depending on the severity of the event, investigators may decide to decrease the 
study drug or to discontinue the study drug.  Participants will be able to withdraw 
from the study at any time.
      9.3 MC10
1) When placing any adhesive onto skin, irritation or redness may occur.  If skin 
irritation develops after the visit while wearing the sensors, participants will be 
instructed to remove the sensors and contact the study team.  Individuals with an 


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active (clinically significant) skin disorder or an allergic response to adhesives 
will not be eligible to participate in the MC10 component.
2) Video recordings will be transmitted in encrypted form and stored in Box, a 
secure, HIPAA compliant database at the University of Rochester. Participants 
may be identified from these videos, as they include views of the face and full 
body; however, the study team will be instructed to minimize the use of the 
participant’s name during the recording portion of the visit.  Although data will 
be stored in secure servers in a HIPAA compliant manner at the University of 
Rochester, there is still the potential of a breach in confidentiality of study data. 
Study data will be maintained after the end of participation in the study; 
however, all study-related videos will be deleted within 5 years of study 
completion.
    9.4 NEUROIMAGING
There is no immediate risk from exposure to magnetic fields of 3 Tesla. Possible 
anxiety may result from claustrophobia or dizziness experienced by the subjects 
when placed in the magnet.  During the imaging portion of the experiment, 
subjects must remain in the bore of the magnet, which is approximately 3 feet in 
diameter.  Also, the scanning coil closely encloses the subject's anatomy being 
imaged.  These two factors may increase the likelihood of claustrophobia.  Should 
the subject feel discomfort, the experiment will be terminated upon their request.
In rare cases, contact with the MRI transmitting and receiving coil or conductive 
materials such as wires, or skin-to-skin contact that forms conductive loops, may 
result in excessive heating and burns during the experiment.  The operators of the 
MRI scanner will take steps, such as using foam pads when necessary, to minimize 
these risks.  The subjects will be informed of the risk and instructed to 
immediately report any heating sensations.  In the rare event that this would 
occur the experiment will be terminated and if necessary we will have the subject 
seek medical treatment.
Subjects will be screened for magnetic material before each study.  Subjects with 
pacemakers, aneurysm clips (metal clips on the wall of large artery), metallic 
prostheses (including heart valves and cochlear implants) or shrapnel fragments 
are at risk in an MR environment.  Welders and metal workers are also at risk for 
injury because of possible small metal fragments in their eyes. Those at risk will be 
excluded from the study.
The effect of exposure to MRI scanning on an unborn child is unknown.  Exposure 
to MRI scanning might be harmful to a pregnant female or an unborn child.  
There are no established risks at this time, but the subjects will be informed that 
there is a possibility of a yet undiscovered pregnancy related risk.


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MRI scanning produces a loud tone that can cause damage to the inner ear if 
appropriate protection is not used.  Adequate protections in the form of earplugs 
or close fitting silicon-padded headphones will be provided.
10.
POTENTIAL BENEFITS TO SUBJECTS
Participants may experience an improvement in chorea as a result of participation in 
this study, however, risperidone is readily available and may be prescribed in the 
context of routine clinical care.
11. COSTS FOR PARTICIPATION
Neither the participant nor the participant’s insurance will incur any cost as a result 
of participation in this study.
12.PAYMENT FOR PARTICIPATION 
Participants will receive $100 for each week that they wear the sensors and complete 
the accompanying daily journal (for up to $200). Participants will be compensated 
after return of the sensors and charging station. Participants will receive $50 for 
completion of each neuroimaging session (for up to $100). Participants will be 
compensated via checks.  
13.SUBJECT WITHDRAWALS
Participants will be advised in the written informed consent forms that they have the 
right to withdraw from the study at any time without prejudice.  Participants may be 
withdrawn by the investigator/sponsor for any reason they see fitting or appropriate, 
e.g.:
(1) Non-compliance with study drug or procedures
(2) Receipt of disallowed medications that cannot be discontinued
(3) An adverse event which in the investigator’s judgment puts the participant at risk
(4) Illness that prevents continued trial participation
(5) Termination of study funding
Premature withdrawal will be defined as withdrawal from the study prior to 
completion of the week 12 visit.  If a participant who has started the study withdraws 
or is withdrawn from the study prematurely, every effort should be made to complete 
the premature withdrawal visit. Reasonable effort should be made to contact any 
participant lost to follow-up during the course of the study in order to complete 
study related assessments and retrieve any outstanding data. Those withdrawn may 
be replaced.  All reasons for subject withdrawals from the study will be recorded in 
the source documentation.  If a participant withdraws from the study, data and 
information that was collected prior to withdrawal may still be used and shared with 
others.   


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14. PRIVACY AND CONFIDENTIALITY OF SUBJECTS AND RESEARCH 
DATA
Data management and storage for patient-reported outcome measures and 
traditional in-clinic measures will be performed using REDCap, which is designed 
specifically for use in research and restricts access to study data.  REDCap was 
developed in a manner consistent with HIPAA security requirements and is 
recommended to University of Rochester researchers by the URMC Research Privacy 
Officer and Office for Human Subject Protection.  REDCap servers are housed in a 
local data center at the University of Rochester and all web-based information 
transmission is encrypted.  
All participant data will be identified solely by a unique subject ID to allow 
participant data to be linked and analyzed by the broader research community. 
Subject names or personal identifiers will not appear on any research materials. 
Participant confidentiality will be assured through a multi-layered approach, entirely 
compliant with HIPAA regulations. All study documents will be labeled using the 
participant’s unique subject ID number. All records pertaining to the study will be 
kept in a secure location with limited access and destroyed according to institutional 
guidelines.  
Participants may be re-contacted, but only if they consent to future contact.
      14.1  MC10
All data transmitted from the devices to investigators will have participant identifiers 
to minimize association with personal information.  Data on the sensors are raw, tri-
axial acceleration and ECG data with no identifying information.  The data collected 
by each wearable sensor is stored locally on non-volatile memory. It will be 
transmitted to a custom-built mobile application requiring an authorized user login 
via Bluetooth technology, then encrypted using the high-grade, industry-standard 
Advanced Encryption Standard (AES) algorithm and stored on the local SQLite 
mobile database. Upon connection to either a WiFi or cellular network, data will be 
uploaded to MC10’s secure cloud, where it may be accessed by the University of 
Rochester. Patient identities and health information will not be transmitted to 
MC10. 
Data management and storage for the raw data collected from the wearable sensors 
will occur via MC10’s secure, collaborative web-based study portal, which enables 
24/7 data access, staff-specific encrypted login credentials, and cloud-based storage 
and backup. Participants will only be identified by participant identifier in the MC10 
database. Qualified researchers at the University of Rochester and MC10 will have 
access to de-identified raw sensor data. 
Since assessments will be video-recorded in clinic, images of study participants will 
be seen by the research team at the University of Rochester. The videos will be stored 
on secure servers in the University of Rochester’s Box account in a folder only shared 


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with the UR research team members. All UR research team members will undergo 
Human Subjects Research training.
15.DATA / SAMPLE STORAGE FOR FUTURE USE
Data obtained during this study (device data, patient-reported outcomes, and 
clinician-derived outcomes) will be banked for future research use. All patient-
reported and clinician-derived outcomes will be stored in a secure database 
(REDCap) only accessible by research team members.  The data will only be shared 
with researchers that are a part of this study using a HIPAA compliant, secure, 
encrypted mechanism, through REDCap or a cloud-like service like Box.com or other 
secure data transfer procedure.  
16.DATA AND SAFETY MONITORING PLAN
Safety and tolerability will be closely monitored by study investigators.  If an 
intolerability or adverse event occurs, depending on the severity of the event, 
investigators will decide whether to decrease study drug or to discontinue the study 
drug.  If during the administration of the C-SSRS or PBA-S, suicidal ideation or 
suicidal behavior is identified, the investigator will determine the most appropriate 
next step. The most appropriate next step may include recommendation to contact 
their primary care provider and/or mental health provider, referral to the national 
suicide prevention hotline, or referral to the Comprehensive Psychiatry Emergency 
Program, among other options. Participants will be able to withdraw from the study 
at any time.
     16.1 Adverse Event Definition
An adverse event is any symptom, sign, illness, or event which develops or 
worsens during the course of the study, whether or not the event is considered 
related to study drug.
16.2 Serious Adverse Event 
A serious adverse event is defined as any adverse medical event that results in 
any of the following outcomes:
•
death;
•
is life-threatening;
•
requires inpatient hospitalization or prolongation of existing 
hospitalization;
•
results in persistent or significant disability/incapacity;
•
is a congenital anomaly/birth defect; or
•
requires medical or surgical intervention to prevent permanent 
impairment or damage.


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In addition, any event which the investigator regards as serious or which would 
suggest any significant hazard, contraindication, side effect or precaution that 
may be associated with the use of the drug should be reported as a serious 
adverse event  
16.3 Recording Adverse Events
At each participant visit the site study staff will assess adverse events by 
recording all voluntary complaints of the participant and by assessment of 
clinical features.  At each study visit, the participant should be questioned 
directly regarding the occurrence of any adverse events since his/her last visit.  
Soliciting of adverse events should be non-specific and participants should be 
asked the question, “Do you feel different in any way since starting the new 
treatment?”
All adverse events, whether observed by an investigator, elicited from or 
volunteered by the participant, should be documented on an Adverse Event CRF. 
Each adverse event will include a brief description of the experience, the date of 
onset, the date of resolution, the duration and type of experience, the severity, the 
relationship to investigational product (i.e., drug or device), contributing factors, 
and any action taken with respect to the study drug/device.  This should also 
include the investigator’s opinion of the possible relationship between the 
adverse event and the study drug or participation in the study.  Likely alternative 
etiologies should be recorded for events considered unrelated to study drug. 
Adverse events already documented at a previous visit and designated as 
‘continuing’ should be reviewed at each visit.  The investigator is obliged to follow 
participants with adverse events until the event has resolved, the condition is 
considered medically stable, or the participant is no longer available for follow 
up. Participants who discontinue the study drug due to adverse events will be 
treated and followed according to established acceptable medical practice. A 
follow up telephone call will be made to all participants who have unresolved 
adverse events 30 days from the date of the final study visit.  If an adverse event 
is resolved, the documentation in the CRF must be completed to that effect.   If an 
adverse event changes in frequency or severity during a study period, a NEW 
record of that event will be initiated.  A record of all adverse events will be 
reviewed periodically by the study investigators.
The recording of adverse events will begin to occur once the participant signs 
informed consent and continue until the participant completes the study or 
withdraws from participation. 
16.4 Responsibilities for Reporting Serious Adverse Events
The investigator should record all serious adverse events that occur during the 
study period on an Adverse Event CRF.  Details included will be the same as 
those documented for adverse events (as detailed above).  The investigator or 


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their designee will fill out the MedWatch FDA 3500 form for serious adverse 
events.  This will include: an identification that serious event criteria have been 
met; a detailed description of the event and other relevant information; the 
current status of the event; if the subject has died, the date of death and autopsy 
report, if available; and the investigator’s current opinion of the relationship 
between the event and the study drug/participation in the study.  
The recording of adverse events will begin to occur once the participant signs 
informed consent and continue until the participant completes the study or 
withdraws from participation. 
The investigator will comply with regulations and RSRB policy regarding the 
reporting of adverse events.  
16.5     Assessment of Severity
Clinical adverse events will be graded on a three-point scale (mild, moderate, 
severe) and reported on the CRF and in the log.  The definitions are as follows:
MILD
no limitation of usual activities
MODERATE some limitation of usual activities
SEVERE
inability to carry out usual activities
16.6    Assessment of Relationship
For each adverse event, the relationship to the study drug will be coded as 
follows:
       DEFINITE
Causal relationship is certain (i.e., the temporal relationship 
between drug exposure and the adverse event onset/course is reasonable, there is 
a clinically compatible response to de-challenge, other causes have been 
eliminated and the event must be definitive pharmacologically or 
phenomenologically using a satisfactory re-challenge procedure, if necessary).
       PROBABLE
High degree of certainty for causal relationship (i.e., the 
temporal relationship between drug exposure and the adverse event onset/course 
is reasonable, there is a clinically compatible response to de-challenge [re-
challenge is not required] and other causes have been eliminated or are unlikely).
       POSSIBLE
Causal relationship is uncertain (i.e., the temporal 
relationship between drug exposure and the adverse event onset/course is 
reasonable or unknown, de-challenge/re-challenge information is either 
unknown or equivocal and while other potential causes may or may not exist, a 
causal relationship to the study drug does not appear probable).
       UNLIKELY
Not reasonably related, although a causal relationship 
cannot be ruled out (i.e., while the temporal relationship between drug exposure 


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and the adverse event onset/course does not preclude causality, there is a clear 
alternate cause that is more likely to have caused the adverse event than the study 
drug).
      UNRELATED 
No possible relationship (i.e., the temporal relationship 
between drug exposure and the adverse event onset/course is unreasonable or 
incompatible, or a causal relationship to study drug is implausible).
16.7      Monitoring Plan
The principal investigators will be responsible for the overall conduct of this 
small, single-center study.  A neurologist, who is not involved in the conduct of 
the study, will be appointed to independently monitor the safety of study 
participants.  If a serious adverse event occurs, a detailed report will be sent to 
the independent monitor.  The independent monitor will periodically review 
adverse events.  Following study initiation, adverse events will be reviewed 
following enrollment of the first 3 participants and then every three months or 
more frequently if deemed necessary by the independent monitor.  The 
independent monitor will document the results of each review and the RSRB will 
be notified of all monitoring activity outcomes.  As this is a small, single-center 
study no interim statistical analyses will be conducted.
17.DATA ANALYSIS PLAN
17.1    Sample Size
There are no prior clinical trials from which to estimate an effect size for 
risperidone and this represents a convenience sample. We are relying on data 
from studies of existing treatments to inform power analysis.  In a clinical trial 
of tetrabenazine, over 12 weeks there was a 5.0-unit change in total maximal 
chorea score with a standard deviation of 3.7 units.11 A sample size of 11 
participants will provide > 98% power to detect a 5.0 unit difference or greater, 
using a one-sample t-test at the 5% significance level.  A sample size of 12 
participants will account for an estimated 8% drop-out rate.  Below, we account 
for other potential scenarios:
17.2   Statistical Analysis Plan
The primary analysis will use a mixed model repeated measures (MMRM) 
approach, which will be applied to all post-baseline measures collected up to 
and including the week 12 visit. The primary outcome measure will be the 
Treatment 
effect
SD
Power
Alpha
Drop-out
N
4.0
3.7
0.80
0.05
10%
10
4.0
3.7
0.90
0.05
8%
12
3.4
3.7
0.80
0.05
8%
12
3.0
3.7
0.69
0.05
8%
12


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change from baseline in UHDRS TMC score at each visit (i.e. 4, 8, and 12 
weeks) with the week 12 change as the time point of primary interest.  The 
model will include the baseline value of the outcome variable, week (as a 
categorical factor), and the interaction between the baseline value and week.  
An unstructured covariance matrix will be assumed to model the within-subject 
variability. The Least Squares Means with 95% confidence intervals will be 
obtained for each week. Missing values will be accounted for by utilizing a 
maximum likelihood-based approach as part of the MMRM missing at random 
assumption.  Secondary outcome measures (and safety measures) will be 
analyzed in a similar fashion.  Responders will be defined as those “much 
improved” or “very much improved” on the CGI or PGI. Safety analyses will 
include tabulating adverse events with corresponding 95% two-sided 
confidence interval. Serious adverse events (if any) attributable to risperidone 
treatment will be described in detail.  The primary measure of tolerability will 
be the proportion of participants who complete 12 weeks on study drug; we 
hypothesize that ≥75% (≥9 of 12 participants) will complete the study.
We will characterize the frontostriatal structural connectivity via probabilistic 
tractography53,54 using the striatum as the seed and the frontal 
cortex as the target, as shown in Fig. 1. The probabilistic 
tractography will be reconstructed from dMRI and T1w data 
using the previously reported algorithm.55,56,57 A similar ROI-
based approach will be used for functional connectivity from rs-
fMRI data using FEAT and FIX tools in FSL 
(https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/). In addition, we will 
investigate the whole brain structural and functional 
connectome across subjects.58,59,60 Additional exploratory 
analyses will assess cortical thickness and volumetric 
assessment of basal ganglia. Briefly, cortical thickness will be 
measured using FreeSurfer (https://surfer.nmr.mgh.harvard.edu/); using the 
3D T1w images whole brain volume, whole GM, cortical GM and whole WM 
volumes will be obtained using FSL SIENAX while separate volumes of the 
basal ganglia structures will be obtained using FSL FIRST. All the volumes will 
then be normalized relative to whole head volume for each subject. Note both 
dMRI and rs-fMRI images will be preprocessed using FSL-based custom 
pipelines and spatially normalized to MNI template prior to the first and second 
level analyses.  A general linear model will be used to compare regional 
neuroimaging patterns between risperidone responders and non-responders. 
Education level, age, sex, and cognitive performance will be included as 
covariates.  To examine associations between neuroimaging metrics and 1) 
continuous clinical outcomes (such as the UHDRS TMC) we will use Pearson 
and Spearman correlation coefficients as appropriate and 2) dichotomous 
clinical outcomes we will use t-tests or chi-square tests as appropriate.  
Corrections for multiple comparisons will be made using a post-hoc family-wise 
error (Bonferroni) correction. 
Figure 1: Structural connectivity 
with tractography: Tracts (green) 
connecting striatum (orange) and 
frontal cortex (blue).


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The Chorea Index will be generated through analysis of wearable sensor 
accelerometer data and will be compared to the clinician-rated UHDRS truncal 
chorea score using correlation analysis.  The mean change in the Chorea Index 
from baseline to week 8 along with the corresponding 95% confidence interval 
will be determined. The association between the Chorea Index and the UHDRS 
TMS score will be assessed using correlation analysis for the individual scores 
as well as the week 8 change.   
Exploratory analyses: The association between the Chorea Index and Q-Motor 
score will be assessed using correlation analysis for the individual scores as well 
as the week 8 change. [Wearable sensors will detect changes in activity pattern 
and gait metrics in response to risperidone treatment.] Using MC 10 and 
University of Rochester developed algorithms, we will compare the amount of 
time participants spend sitting, standing, lying down and walking before and 
after treatment with risperidone.  We will also compare gait metrics (gait speed, 
step length, step duration, steps per day) before and after treatment.
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