Clinical trial NCT02365870
Conditions: Anxiety Disorders Parkinson Disease
Keywords: Anxiety Disorders Parkinson Disease rotigotine
Sponsor: Johns Hopkins University
Start date: 2016-08-01; Completion date: 2019-07-01
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the effectiveness of the rotigotine transdermal patch in reducing anxiety in people with Parkinson's disease.

Detailed description:
Anxiety is a serious medical condition that worsens quality of life by negatively affecting peoples thoughts, feelings, and ability to function normally. Anxiety can affect anyone, but people with Parkinson's appear to be at a much higher risk with an estimated 40% or more suffering from anxiety. Parkinson's is a neurological disorder that causes tremor and other problems with normal movements. The disease symptoms are believed to be caused in large part by the loss of dopamine producing cells in the midbrain. Anxiety in Parkinson's may be associated with the loss of dopamine caused by the disease and therefore may respond to dopamine based treatments. This study will evaluate the effectiveness of the rotigotine transdermal patch, a dopamine replacement medication, in reducing symptoms of anxiety in people with Parkinson's disease.

Participants in this double-blind study will be randomly assigned to receive either rotigotine or a placebo patch for 8-weeks. All participants will be evaluated at the study site at baseline and weeks 2, 4, and 8. Psychiatric, cognitive, and movement assessments will be performed along with a review of anxiety symptoms. All participants will be offered continued routine psychiatric care with the study physician upon completion of the study.

Arms: arm 1: rotigotine transdermal patch 2mg to 6mg daily per 24 hour patch for 8 weeks arm 2: placebo transdermal patch 2mg to 6mg daily per 24 hour patch for 8 weeks
Interventions: intervention 1: rotigotine transdermal patch intervention 2: placebo
Intervention descriptions: intervention 1: Participants will receive the dopamine agonist rotigotine in the form of a transdermal patch to be worn daily intervention 2: Participants will receive a placebo transdermal patch to be worn daily

Protocol documents:
Prot_SAP_000.pdf: 
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Anxiety in Parkinson's: Use of 
quantitative methods to guide 
rational treatment 
 
 
 
 
 
NCT02365870 
 
 
 
 
 
 
 
April 26, 2017 
 
 
 
 
 


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Date: 04/26/17   
Principal Investigator: Greg Pontone, MD  
Application Number: NA_00092051  
  
  
  
JHM IRB - eForm A – Protocol  
  
Anxiety in Parkinson’s: Use of quantitative methods to guide rational treatment  
  
 
1.  
Abstract  
a. Provide no more than a one-page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research.  
  
Anxiety in PD aggravates physical disability and independently contributes to poor health-related 
quality of life. Clinically significant anxiety occurs in up to 40% of patients with PD, a markedly 
higher prevalence than healthy or comparably disabled persons without PD. Anxiety in PD is 
complicated by atypical presentations, comorbidity with depression, and phenomenological 
overlap with other non-motor and motor symptoms of PD. As a result, anxiety syndromes in PD 
are often poorly characterized. In my previous work, 22% of anxious patients with PD had 
clinically significant anxiety syndromes that failed to meet criteria for the established Diagnostic 
and Statistical Manual (DSM) anxiety diagnoses. These 'non-DSM' anxiety syndromes were often 
associated with fluctuations in motor symptoms resulting from the 'wearing-off' of dopamine based 
treatments. However, even when anxiety occurs in association with motor fluctuations, it is not 
clear whether it is a reaction to the change in motor function and dopamine levels or an 
independent process. In order to better target and treat anxiety syndromes in PD the relationship 
between PD-specific features and anxiety needs to be better understood.  
  
There have been no randomized controlled drug trials to treat anxiety in PD. Current management 
strategies are based on expert opinion and observational studies and recommend the anti-anxiety 
treatments typically used in the non-PD population. Yet, many of these anti-anxiety treatments 
may worsen motor function and increase fall risk in PD. Currently, there is no evidence-based 
standard to guide the pharmacologic treatment of anxiety in PD. The overlap between PD-specific 
features and anxiety suggests that certain anxiety syndromes may emerge from the 
neurodegenerative process of PD. The goal of this study is to, 1) investigate a system of 
classification for anxiety disorders that accounts for patterns of comorbidity with PD-specific 
features (e.g. wearing-off) and 2) to design and conduct an intervention that tests whether treating 
fluctuations in dopaminergic neurotransmission improves anxiety in an 8-week study of rotigotine 
vs. placebo.  
  
2. 
Objectives (include all primary and secondary objectives)  
(1) 
Using latent class analysis, investigate whether a hypodopaminergic state, 
produced by a temporary interruption of dopamine medications, is associated with a 
distinct anxiety syndrome in PD in a cross-sectional study of 200 subjects with idiopathic 
PD. Hypothesis: Certain anxiety syndromes and PD have a shared causal mechanism. 
Demonstrating that certain anxiety symptoms are associated with motor fluctuations, that is both 
anxiety and motor fluctuations are increased in hypodopaminergic states and cluster together 
based on a latent variable will support this hypothesis  


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(2) 
Conduct an 8-week intervention study of rotigotine (n=30) compared to placebo 
(n=30) for the treatment of anxiety disorders in PD that will provide estimates of effect size 
and the impact of co-occurring motor fluctuations on the treatment of anxiety. Hypothesis:  
Treatment with rotigotine for anxiety associated with motor fluctuations will result in a greater 
reduction of anxiety as compared to treatment with placebo  
  
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research)  
  
Anxiety is common in PD and associated with motor fluctuations. Anxiety is one of the most 
common non-motor symptoms in PD, occurring in up to 56% of patients, often in association with 
PD-specific features.(1,2) Anxiety syndromes are more prevalent than in healthy or comparably 
disabled individuals without PD and result in greater disability and a lower quality of life.(3-6) 
Anxiety syndromes in PD are a heterogeneous group of conditions that are characterized by either 
episodic or persistent anxiety phenomena, frequent comorbidity with depression, and atypical 
presentations when compared to anxiety syndromes in the general population.(7-9) In a previous 
study, we found that 22% of PD patients had atypical anxiety syndromes not specifically described 
by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-
IVTR).(10) The most common atypical presentation of anxiety in PD in our study and others is 
when anxiety occurs as an episodic symptom potentially related to the wearing-off of dopaminergic 
treatment and motor fluctuations.(3,10,11) "Wearing-off" is defined as a generally predictable 
recurrence of motor and non-motor symptoms as the effect of dopaminergic treatment declines over 
a given dose.(12) The loss of treatment effect leads to episodic reemergence or worsening of motor 
and non-motor symptoms typically referred to as "fluctuations". The pathophysiology of wearingoff 
is thought to be related to the progressive loss of dopamine in PD.(13) Wearing-off occurs in up to 
40% of PD patients within 4-6 years of starting levodopa therapy, although it has also been reported 
to occur much earlier, within 5-6 months, in up to 30% of patients.(14,15) Other studies suggest 
that anxiety (and depression) may be a ‘phenocopy’ of autonomic dysfunction, another common 
non-motor symptom, and not associated with fluctuations or wearing-off of dopaminergic 
medications.(16) Whether wearing-off anxiety, autonomic dysfunction related anxiety, and other 
subtypes are specific to PD and represent subgroups with distinct etiologies and treatment is not 
known.  
  
There are very few data on treatment of anxiety in PD. A recent study by the MDS non-motor task 
force concluded there are insufficient data on the treatment of anxiety in PD to establish 
evidencebased treatment standards. (17) Anxiety is associated with worse quality of life, greater 
motor impairment, more dyskinesias, and a greater frequency of motor fluctuations.(18,19) In a 
recent study, our data showed that anxiety associated with motor fluctuations was an independent 
predictor of lower self-perceived health status in PD.(10) Despite the distress and dysfunction 
caused by anxiety syndromes and their unusually high prevalence in PD there are no randomized 
controlled trials (RCTs) on which to establish evidence-based treatment. (17) In addition, many 
conventional anxiety treatments can be problematic when used in PD. Benzodiazepines and 
tricyclic antidepressants can increase the risk of falls and contribute to the risk of delirium and 
confusion in PD.(20,21) Even selective serotonin reuptake inhibitors(SSRIs), which are typically 
well tolerated in the general population, may worsen tremor and other motor symptoms in 
PD.(21,22) Therefore, a RCT of a non-traditional anti-anxiety agent that takes into account the 
potential association between anxiety and PD-related features, and a potential PD-specific 
vulnerability to side-effects is needed.  


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4.  
Study Procedures  
a. Study design, including the sequence and timing of study procedures    
(distinguish research procedures from those that are part of routine care).  
  
For objective 1: Subjects will be assessed in both the “on” and “off” motor states following the 
clinical protocol from the Core Assessment Program for Surgical Interventional Therapies in PD  
(CAPSIT-PD).(23) We use the CAPSIT-PD protocol routinely in the PDRC and movement  
disorder clinics and will include consenting individuals as part of this study. However, a portion 
of the subjects recruited will have the CAPSIT-PD protocol exclusively for this study and not as 
a part of routine clinical care. "Wearing-off" and the "off-motor state" in PD are defined as a 
generally predictable recurrence of motor and non-motor symptoms as the effect of 
dopaminergic medications stops.(12) Subjects will temporarily stop all dopaminergic 
medications for a minimum of 12-hours in order to be assessed in the “off” motor state in the 
morning. (Most individuals with PD do not take medications overnight and usually take their 
last dose between 5-9pm. Therefore most participants will only be off medications for a few 
hours more than they normally would be as the study will be conducted in the morning) The on- 
and off-state assessments are listed below. Subjects will then take their usual morning 
dopaminergic medications and after one hour, to allow them to return to their best "on" state, 
repeat the CAPSIT-PD on-off battery. In addition to the on-off testing battery, several PDrelated 
clinical features will be assessed, only in the on-state, using instruments recommended by the 
National Institute of Neurological Disorders and Stroke Common Data Element Project 
(NINDS-CDE)(24) for PD.  
  
CAPSIT-PD on- and off-state testing battery  
Each assessment will be conducted twice, once in the off-state and once after resuming PDmeds 
in the on-state  
1. Anxiety: Hamilton Anxiety Rating Scale (HAM-A)(25)  
2. Depression: 17-item Hamilton Depression Rating Scale (HAM-D)(26)  
3. Motor and non-motor fluctuations: 19-symptom wearing-off questionnaire (WOQ-19)(27)  
4. Physical Disability: Schwab and England Scale (SE)(28)  
5. Motor symptom severity: MDS-UPDRS part III(30)  
6. Symbol Digit Modalities Test(45)  
7. Stroop Color and Word Test(46)  
  
NINDS-CDE Recommended Assessments for PD-Specific Clinical Features (only for on-state)  
1. Demographics  
2. PD Medical History  
3. PD Family History  
4. PD and Non-PD Medication Log  
5. Motor: MDS-UPDRS parts I-IV  
6. Psychiatric: Structured clinical interview for DSM-IV-TR (SCID) axis I disorders, research 
version, non-patient edition (29)  
7. Cognitive: Montreal Cognitive Assessment (MoCA)(31)  
8. Other non-motor: Non-motor Symptoms Questionnaire (NMS-Quest)(35) and the Scales for  
Outcomes in Parkinson’s disease autonomic dysfunction scale (SCOPA-AUT)(32,33)  
9. Quality of life: 8-item Parkinson's Disease Questionnaire (PDQ-8)(34)  
10. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease(QUIP)(47)  


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11. Neo Five-Factor Inventory(48)  
12. Rapid Assessment of Physical Activity(RAPA)(49)  
  
For objective 2:  
The intervention will be 8 weeks in duration and include a 4-week dosage titration period and a 
4-week maintenance period. Transdermal patch. Dosing will begin at baseline on day zero with 
either 1) placebo or 2) rotigotine at 2mg/24h and will be increased following the recommended 
dose escalation schedule for PD such that subjects will increase to 4mg/24hrs in week 2, and 
6mg/24hrs in week 3. This dose of rotigotine is within the range shown to be safe and 
efficacious for the treatment of motor symptoms. 17,36,37) The timing of assessments is shown 
in Table 1. All assessments except for the physical exam, and the Clinical Global Impression for 
Anxiety Severity and change scales (CGI-S and CGI-C)(38) are part of the CAPSIT-PD on- and  
off-state testing battery, the table indicates administration points. Safety and tolerability will be 
assessed by recording adverse events.  
  
b. Study duration and number of study visits required of research participants.  
Objective 1 is one 3-hour cross-sectional visit, duration and visits for objective 2 are in Table 1  
  
  
Table 1. Assessment schedule for objective 2  
Visit Number  
Screening  Baseline  Follow-up visits  
Time  
- - -  
0  
WK2  
WK4  WK8:  
FINAL  
Diagnostic Interview or 
AIM 1 Battery  
X  
  
  
  
X  
Physical Examination  
X  
  
  
  
X  
MDS-UPDRS I-IV  
X  
  
  
  
X  
MoCA  
X  
  
  
  
X  
CGI-Severity  
X  
X  
  
  
  
CGI-Change  
  
  
X  
X  
X  
HAM-A  
X  
X  
X  
X  
X  
HAM-D  
X  
X  
X  
X  
X  
SCOPA-AUT, NMS  
X  
X  
X  
X  
X  
  
c. Blinding, including justification for blinding or not blinding the trial, if applicable.  
  
For the clinical trial in objective 2: double-blinded, randomized, placebo controlled, 8-week 
intervention study of rotigotine vs. placebo for the treatment of anxiety in PD. The study is 
double-blinded to reduce the risk of bias in rating anxiety response to treatment as both the 
subject and investigators will be rating anxiety using self-reports and investigator-administered 
scales.  
  
d. Justification of why participants will not receive routine care or will have current therapy 
stopped.   
  
Patients will receive routine care and will NOT have current therapy stopped.  
  
e. Justification for inclusion of a placebo or non-treatment group.  


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Absence of current standard treatment for anxiety in PD justifies inclusion of a placebo group. 
Anti-anxiety drugs based on serotonin, norepinephrine, and benzodiazepine mechanisms are the 
current standard in non-PD populations and are used in PD without sufficient evidence of 
efficacy and may be associated with side effects.  
  
f. Definition of treatment failure or participant removal criteria.  
  
Rotigotine is an evidence based treatment for motor symptoms and motor complications of 
treatment in PD and deemed to be of "acceptable risk without specialized monitoring".(17) 
Rotigotine does carry the risk of nausea, vomiting, application site reactions, dizziness, 
anorexia, hyperhidrosis, insomnia, lower extremity edema, somnolence and dyskinesia. 
Rotigotine is a treatment routinely used as part of clinical care in PD. If impulse control 
disorders occur the subject will taper and stop the study drug, their treating neurologist will be 
notified, and they will be referred for psychiatric treatment. Subjects will be examined for lower 
extremity edema at screening and at each follow-up visit. If edema occurs subjects will be asked 
if they wish to discontinue the study drug. Subjects will be asked about excessive somnolence at 
each visit. If somnolence is severe and interferes with daily functioning, tapering and 
discontinuation of the study drug will be recommended.  
  
Subjects in the intervention study will be medically screened prior to enrollment and will be 
monitored at the designated intervals for any adverse events. Subjects who are acutely suicidal 
or an imminent risk to themselves will be excluded. Subjects will be removed from the study if 
they request removal, if the team believes it is unsafe to continue, if they experience significant 
distress for any reason, or if the patient becomes imminently suicidal. Subjects will be 
monitored closely by an experienced clinical team, available 24-hours per day.  
  
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely.  
  
After termination of the intervention study, prematurely or scheduled, a summary letter will be sent 
to the patient’s treating clinicians detailing the patient’s participation in the study, the patient’s 
response, aftercare plans, and any other relevant information. The study medication or placebo will 
be tapered and stopped, unless, in the case of participant on study drug, their treating doctor wishes 
to continue rotigotine and take over prescribing it as part of their routine care. Subjects will be 
offered follow-up psychiatric care in our clinic as well as assistance in obtaining care elsewhere, 
including by providing consultation to their primary clinician/neurologist. All adverse events will 
be reported to the JHH IRB.  
  
 
5.  
Inclusion/Exclusion Criteria  
Subjects for both objectives will be English-speaking adult men and women including minority 
groups, ages 21 years or older, with idiopathic PD, based on UK Brain Bank Criteria.(39) Subjects 
with a diagnosis of dementia or a Montreal Cognitive Assessment (MoCA) (30) <23 will be 
excluded to reduce the chance of enrolling individuals with Lewy body dementia. Additional 
inclusion and exclusion criteria for objective 2 are in Table 2.  
Table 2. Additional inclusion and exclusion criteria for objective 2 8-week intervention study  
Inclusion Criteria  


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1. Diagnosis of DSM Anxiety Disorder and as part of this intervention study, we will include all anxiety subtypes provided 
treatment with medication is indicated in standard clinical psychiatric practice  
2. Stable medical history and general health. If non-postmenopausal female, must be non-pregnant and using a medically 
acceptable form of contraception during the study if sexually active  
3. On stable anti-parkinsonian therapy for 2 weeks before enrollment and expected to be able to remain on stable therapy 
for the 8-week study.  
4. If treated for depression, must be on stable anti-depressant for 2 weeks before enrollment and expected to be able to 
remain on stable therapy for the 8-week study.  
5. *[Not on anti-anxiety therapy (unless it is for another indication, i.e. REM Sleep Behavior Disorder) at time of 
enrollment OR able to be tapered safely off these medications as determined by the t ½ of prescribed medication at 
the time of screening]*  
Exclusion Criteria  
1. *[Exclude subjects with dementia as diagnosed by DSM criteria or MoCA <23 and subjects with less than a 1 year 
duration of PD to help exclude subjects who may have Lewy body dementia (62)]*  
2. Lifetime diagnosis of schizophrenia, bipolar disorder, impulse control disorder (ICD), or major depression with psychotic 
features  
3. Current alcohol or substance use disorder, as defined by DSM  
4. Acute suicidality or need for inpatient psychiatric hospitalization  
5. Psychotic symptoms so severe as to warrant treatment with antipsychotic medications in the opinion of the patient’s 
physician  
6. Medical conditions such as current malignancy or hematological, endocrine, cardiovascular, renal, hepatic, 
gastrointestinal, or other non-PD neurological disease that is medically debilitating and/or CNS affecting (e.g., 
uncontrolled diabetes mellitus or thyroid disease). If there is a history of such disease and it has been stable for > one 
year, then subject may be included if investigator judges their participation as safe.  
7. Patient currently treated with psychotherapy for anxiety/depression  
8. Current treatment with another dopamine agonist  
  
  
  
  
 
6.  
Drugs/ Substances/ Devices  
a. The rationale for choosing the drug and dose or for choosing the device to be used.  
  
Rotigotine is an evidence-based treatment for motor symptoms and motor complications of 
treatment in PD and deemed to be of "acceptable risk without specialized monitoring". Dosing 
will begin at baseline on day zero with either 1) placebo or 2) rotigotine at 2mg/24hrs and will 
be increased following the recommended dose escalation schedule for PD such that subjects 
will increase to 4mg/24hrs in week 2, and 6mg/24hrs in week 4.]* This dose of rotigotine is 
within the range shown to be safe and efficacious for the treatment of motor symptoms in PD.  
  
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed.  
  
N/A  
  
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.   
  
N/A  
  


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7.  
Study Statistics  
a. Primary outcome variable. Hamilton Anxiety Rating Scale(HAM-A)  
b. Secondary outcome variables. 17-item Hamilton Depression Rating Scale (HAM-D), 
19symptom wearing-off questionnaire (WOQ-19), Schwab and England Scale (SE), MDS-
UPDRS part III  
c. Statistical plan including sample size (n=200) justification and interim data analysis.  
For objective 1: We will conduct a latent profile analysis (LPA) using the following observed 
variables (measured in the on-state) as latent profile indicators: age of PD onset, LEDD, 
HAMA, HAM-D, WOQ-19, SE, UPDRS part III, and MoCA score, to model unobserved (i.e. 
latent) profiles. LPA is a type of latent class analysis that uses continuous indicator variables. 
Using LPA we will determine 1) the number of classes/profiles that best fits symptom profiles 
of observed values, 2) the proportion of the sample that belongs in each class/profile (e.g. class 
prevalences), and 3) the means of each latent profile, conditioned upon membership in each 
class. We will then test whether specific subject characteristics (age, gender, variability of 
symptoms between on- and off-states (as change scores), and motor fluctuations), from the 
battery above predict differential membership in the identified latent profiles via latent profile 
regression. With latent profile regression, predictors of latent profile membership are modeled 
via multinomial logistic regression. Statistical power for latent profile regression was 
determined via monte carlo simulation,(42) assuming 3 classes/profiles with prevalences of  
30%, 10%, and 60%. We would have 80% or greater power to detect a log odds ratio for an 
association between a standardized predictor and latent profile membership of 1.17 for profile 1 
(prevalence of 30%) and 1.71 for profile 2 (prevalence of 10%), with profile 3 as the reference 
class. Antidepressant, anti-anxiety, and other psychiatric medication use will be controlled for in 
the analysis.  
  
For objective 2: The primary outcome variable is the HAM-A. Power was calculated based on 
an enrollment of 60 subjects total, equally distributed between treatment and control groups, 
with a 10% dropout by the final time-point, and a standard deviation of 8.55 (which is a pooled 
estimate calculated from different anxiety subtypes in PD patients assessed using the 
HAMA.(43) The within subject/between time-point correlation was assumed to be 0.5 with a 
compound symmetric correlation structure, and the alpha level was set at .05. Power 
calculations were based on the formula of Jung and Ahn,(44) which calculates power for the 
difference in slope (i.e. the difference in response trajectory) between treatment and control 
groups for a longitudinal clinical intervention. Based on the assumptions specified, we would be 
able to detect an effect size of .69 from baseline to 8 weeks for the two groups with 80% power. 
This proposal is for a proof of concept study that will provide important initial estimates which 
may be used to 1) assess the potential efficacy of this novel anxiety intervention and thus 
provide necessary data for a "go-no-go" decision for a more definitive hypothesis-testing trial, 
and 2) provide estimates of effect size and variance needed to properly design such a trial.  
  
Screening for objective 1: Screen failures are expected to be rare for objective 1 as there are 
only 3 criteria for exclusion: 1) UK Brain Bank criteria for PD, 2) English speaking, and 3) 
nondemented. In our longitudinal study of Parkinson’s disease, which has autopsy confirmation 
at study end, the rate of accurate clinical diagnosis of PD is approximately 90%. The presence 
of dementia has a similar accuracy and will be further screened using the MoCA with a cut off 
of <23. The drop-out rate is also expected to be low as objective 1 takes place in one 3-hour 
visit.  Screening for objective 2: Objective 2 will require 60 subjects who can be recruited from 
the n=200 from objective 1. Based on our preliminary data, 30% of subjects with a DSM 
anxiety disorder and comorbid depression and up to 53% with anxiety disorders only will not be 


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on any treatment for anxiety. In addition, we have included a protocol for enrolling individuals 
whose anxiety is not adequately controlled on their current therapy.(item 4 inclusion criteria)  
  
Subjects for objective 2 will be preferentially recruited from objective 1 for maximum 
efficiency. In the unlikely event that none of the subjects for objective 2 come from objective 1 
the total number of subjects needed for both is n=260. We will be conducting post consent 
screening and will allow for ~15% screen fail rate and estimate that the maximum number of 
subjects consented will not exceed 300.   
  
d. Early stopping rules.   
  
Participants will be removed from the study if they request removal, if the team believes it is 
unsafe to continue, if they experience significant distress for any reason, or if the patient 
becomes imminently suicidal. Subjects will be monitored closely by an experienced clinical 
team, available 24-hours per day.  
  
 
8.  
Risks  
a. Medical risks, listing all procedures, their major and minor risks and expected frequency.  
  
All members of the research team will make every effort to implement the protocol procedures 
in a sensitive and supportive manner. Only subjects who are medically stable will participate in 
these studies. Dr. Pontone will provide close clinical monitoring during all aspects of the study.  
  
Clinical assessments and questionnaires: Subjects will be informed prior to beginning the 
evaluation to please notify the examiner if they experience any distress. If this occurs, the 
examiner will stop the evaluation. To minimize the chance of this happening, subjects will be 
provided breaks and positive feedback and research staff will provide assistance with form 
completion if needed. We will conduct psychiatric and motor assessments in a standardized 
fashion. These approaches are standard for patient assessment in clinical practice and are 
generally not associated with more severe complications. Frequency: rare  
On- and off-motor state testing: As mentioned above we will follow the standard clinical 
protocol established in the Core Assessment Program for surgical Interventional Therapies in 
PD.(66) Subjects will be closely monitored for discomfort or distress. For subjects who 
experience distress the off-state testing will be stopped and their usual Parkinson's medications 
will be resumed. For subjects unable to tolerate the full 12 hour off-state, it is recommended that 
the longest tolerable wash-out be determined and to use this period for all subsequent 
assessments. For our study, subjects who fail to tolerate washout of 8 hours or more will be 
excluded to minimize the potential for patient distress while preserving the goal of optimal 
washout of dopaminergic medication. Frequency: rare  
Rotigotine drug treatment: Rotigotine carries the risk of impulse control disorders, lower 
extremity edema, and excessive somnolence. Prior to enrollment in the intervention study 
subjects will be screened for impulse control disorders and subjects with any current or past 
impulse control disorders will be excluded from the study. During the course of the study 
subjects will be specifically asked about impulse control disorders at each visit. If impulse 
control disorders occur the subject will taper and stop the study drug, their treating neurologist 
will be notified, and they will be referred for psychiatric treatment. Subjects will be examined 
for lower extremity edema at screening and at each follow-up visit. If edema occurs subjects 
will be asked if they wish to discontinue the study drug. Subjects will be asked about excessive 


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daytime somnolence at each visit. If daytime somnolence is severe and interferes with daily 
functioning, tapering and discontinuation of the study drug will be recommended.  
  
Subjects in the intervention study will be medically screened prior to enrollment and will be 
monitored at the designated intervals for any adverse events. For females of childbearing age, 
negative urine pregnancy test prior to study will be required. Subjects who are acutely suicidal 
or an imminent risk to themselves will be excluded. Subjects will be removed from the study if 
they request removal, if the team believes it is unsafe to continue, if they experience significant 
distress for any reason, or if the patient becomes imminently suicidal. Subjects will be 
monitored closely by an experienced clinical team, available 24-hours per day.  
  
We will have direct contact with the patient’s neurologist and will convey clinically relevant 
information in a summary report or by direct phone or personal contact, as is our standard 
practice for our other PDRC clinical research protocols. If the screening exam is negative or the 
participant declines, this will be indicated. Dr. Pontone will also review the patient’s responses 
for evidence of any information that should be addressed immediately by the patient’s treating 
clinicians. In particular, this would include suicidality or other severe psychiatric symptoms. 
After termination of the intervention study, a summary letter will be sent to the patient’s treating 
clinicians detailing the patient’s participation in the study, the patient’s response, aftercare 
plans, and any other relevant information. Subjects will be offered follow-up psychiatric care in 
our clinic as well as assistance in obtaining care elsewhere, including by providing consultation 
to their primary clinician/neurologist. All adverse events will be reported to the JHH IRB. 
Frequency: 10% of subjects on rotigotine experience impulse control issues at some point 
during treatment, daytime somnolence severe enough to be clinically significant is not common, 
and edema is rare.  
  
b. Steps taken to minimize the risks.   
  
Answered in item a above.  
  
c. Plan for reporting unanticipated problems or study deviations.  
  
All adverse events and study deviations will be compiled and reported quarterly to the IRB. 
Serious Adverse Events (defined as those which are life-threatening, or require hospitalization) 
will be reported within 24 hours to the IRB.  
  
d. Legal risks such as the risks that would be associated with breach of confidentiality.  
  
We will comply with applicable laws and regulations regarding subject data privacy. We will 
use the health information only as permitted in accordance with the provisions of the Health 
Insurance Portability and Accountability Act and the regulations promulgated thereafter. If 
necessary, we will revise our protocol to meet those regulations. Patient identifications will 
remain anonymous to study staff until the patient indicates willingness to participate. With 
approval from the participant, medical and neurological records will be reviewed by the 
investigator or research assistant in order to complete and confirm aspects of the database. 
Research data will be kept in locked files and information on computer databases will be coded 
to protect patient identity. Subjects will not be identified in publications.  
  


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e. Financial risks to the participants. N/A  
  
 
9.  
Benefits  
 
a.  
Description of the probable benefits for the participant and for society.  
  
Potential benefits to participants is better recognition of anxiety disturbances that can occur in 
PD. Benefits also include awareness that participation in the study is a significant contribution 
toward finding a better understanding of the mechanistic underpinnings of anxiety syndromes 
that may be specifically associated with PD and to the development of an evidenced based 
treatment for anxiety in PD. Clinically relevant information that would otherwise have remained 
undetected but is revealed through this assessment will be conveyed to their treating clinicians.  
  
 
10.  
Payment and Remuneration  
a.  
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol.  
  
Objective 1: Participants will be provided $10 for travel costs or valet parking (valued at 
$10).  
  
Objective 2: Participants will be provided $25 at completion plus paid valet parking or travel 
costs ($10) for each visit.  
  
 
11.  
Costs  
a.  
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them.  
  
There will be no costs to the participants.  
  
  
  
  
  
  
  
  
References  
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