The Tolerability of Buspirone for the Treatment of Anxiety in Parkinson's Disease
Phase: PHASE2
Conditions: Parkinson Disease, Anxiety
Sponsor: University of Rochester

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NCT02803749
The Tolerability of Buspirone for the Treatment of Anxiety in Parkinson’s Disease 
Principal Investigator – Irene Richard, MD 
Co-Principal Investigator – Ruth Schneider, MD 
Funding: Michael J Fox Foundation 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS……………………………………………………………………………………………4 
1.0        PURPOSE OF STUDY AND BACKGROUND 
1.1 
Purpose of the study………………………………………………………………………6 
1.2 
Background………………………………………………………………………………..6 
1.3 
Supporting Data…………………………………………………………………………...8 
 
2.0 
STUDY DESIGN 
2.1 
Overview………………………………………………………………………………….9 
2.2 
Rationale for Study Design……………………………………………………………….9 
2.3 
Rationale for Dosage……………………………………………………………………..10 
2.4 
Rationale for Placebo Arm……………………………………………………………….10 
 
3.0 
CHARACTERISTICS OF RESEARCH POPULATION 
3.1 
Participant Characteristics……………………………………………………………….11 
 
a) Number of Participants 
 
b) Gender and Age of Participants 
 
c) Racial and Ethnic Origin 
 
d) Vulnerable Subjects 
3.2 
Inclusion and Exclusion Criteria…………………………………………………………11 
 
a) Inclusion Criteria 
 
b) Exclusion Criteria 
3.3  
Discussion of Study Population………………………………………………………….12 
 
4.0 
PARTICIPANT IDENTIFICATION, RECRUITMENT AND CONSENT 
4.1    
Method of Participant Identification and Recruitment…………………………………..13 
4.2 
Process of Consent……………………………………………………………………….13 
 
5.0 
METHODS AND STUDY PROCEDURES 
 
SCHEDULE OF ACTIVITIES…………………………………………………………………...15 
 
5.1 
Treatment Dosage and Administration…………………………………………………..16 
 
5.2 
Timing of Visits………………………………………………………………………….18 
5.3 
Efficacy Assessments…………………………………………………………………….20 
5.4        Safety Assessments………………………………………………………………………22 
5.5 
Assessment of Participant Compliance…………………………………………………..23 
5.6 
Dosage Assessment………………………………………………………………………24 
5.7  
Costs to the Participant…………………………………………………………………..24 
5.8 
Payment to the Participant……………………………………………………………….24 
5.9 
Return of Individual Research Results…………………………………………………..24 
5.10 
Pregnancy and Nursing…………………………………………………………………..24 
 
 
6.0   
CONCOMITANT AND DISALLOWED MEDICATIONS 
 
6.1 
Allowed Concomitant Medications……………………………………………………...24 
 
6.2 
Disallowed Medications………………………………………………………………….25 

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7.0 
PARTICIPANT WITHDRAWLS 
 
8.0 
STUDY DRUG ADMINISTRATION/ASSIGNMENT 
 
8.1 
Study Drug……………………………………………………………………………….26 
 
8.2 
Dosage of Study Drug……………………………………………………………………27 
 
8.3 
Participant Enrollment/Randomization…………………………………………………..27 
 
8.4 
Accountability of Investigational Supplies………………………………………………27 
 
8.5 
Participant Withdrawal of Study Drug…………………………………………………..28 
 
8.6 
Emergency Drug Disclosure……………………………………………………………..28 
 
9.0 
SAFETY AND REPORTABLE EVENTS 
 
9.1 
Adverse Event Definition………………………………………………………………..29 
 
9.2 
Serious Adverse Event…………………………………………………………………...29 
 
9.3 
Recording Adverse Events……………………………………………………………….29 
 
9.4 
Responsibilities for Reporting Serious Adverse Events…………………………………30 
 
9.5 
Assessment of Severity…………………………………………………………………..30 
 
9.6 
Assessment of Relationship……………………………………………………………...30 
 
10.0 
RISK/BENEFIT ASSESSMENT 
 
10.1 
Potential Risks…………………………………………………………………………...31 
 
10.2 
Protection Against Risks…………………………………………………………………32 
 
10.3 
Potential Benefits to Participants………………………………………………………...33 
 
10.4 
Alternatives to Participation……………………………………………………………..33 
 
11.0 
CONFIDENTIALITY OF DATA AND INFORMATION STORAGE 
 
12.0 
RESEARCH INFORMATION IN MEDICAL RECORDS 
 
13.0  
DATA ANALYSIS AND MONITORING 
 
13.1 
Sample Size Determination………………………………………………………………33 
 
13.2 
Planned Statistical Analysis……………………………………………………………...34 
 
13.3 
Data and Safety Monitoring……………………………………………………………...35 
 
14.0 
REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
FULL STUDY TITLE 
The Tolerability of Buspirone for Treatment of Anxiety in Parkinson’s 
Disease 
CLINICAL PHASE 
Phase II 
INVESTIGATORS/ STUDY 
GROUP 
Irene Richard, MD (PI), Ruth Schneider, MD (Co-PI) 
STUDY OBJECTIVE 
The primary objective of this study is to determine the tolerability of 
buspirone for the treatment of anxiety in PD.  
STUDY RATIONALE 
Anxiety is highly prevalent in Parkinson’s disease (PD) and negatively 
impacts quality of life yet it frequently remains untreated and there have 
been no clinical trials dedicated to evaluating the pharmacological 
treatment of anxiety in PD.  Buspirone, which primarily acts as a 5HT1A 
receptor partial agonist, is effective for the treatment of generalized 
anxiety disorder in the general and elderly population.  It is not known if it 
is effective for the treatment of anxiety in the PD population where there is 
a more heterogeneous phenomenology of anxiety.  Buspirone also may 
diminish levodopa-induced dyskinesias. However, concerns have been 
raised about its potential to worsen motor function.  A tolerability 
assessment is necessary prior to proceeding with a phase III efficacy trial.   
STUDY SITES 
University of Rochester  
STUDY PERIOD  
3 years 
STUDY POPULATION 
AND NUMBER OF 
SUBJECTS 
35 participants with idiopathic PD and clinically significant anxiety as 
defined by a score of ≥ 14 on the self-rated Parkinson Anxiety Scale. 
STUDY DESIGN 
This is a single-center, placebo-controlled, double-blind design with 
participants randomized with a 4:1 allocation ratio to flexible dosage 
buspirone (maximum dosage 30 mg twice daily) or placebo for 12 weeks.   
MAIN INCLUSION/ 
EXCLUSION CRITERIA 
  Inclusion Criteria: 
1. Diagnosis of idiopathic PD (UK PD Society Brain Bank  Diagnostic 
Criteria)  
2. Significant anxiety Parkinson Anxiety Scale (≥ 14) 
3. Able to provide written informed consent 
4. At least 18 years of age 
  
   Main Exclusion Criteria:  
1. Diagnosis of atypical or secondary  parkinsonism  
2. Concomitant treatment with an MAO inhibitor  
3. Significant renal or hepatic impairment  
4. Significant cognitive  impairment ( MOCA score < 23) 
5. Depression with suicidal or homicidal ideation and concern for patient 
safety based on clinical  determination by the investigator 
 
DOSAGE: ROUTE AND 
FORM 
Over-encapsulated buspirone tablets or matching placebo administered 
twice daily by mouth.  
DOSAGE: 
JUSTIFICATION 
Participants will initiate treatment with either buspirone 7.5 mg or placebo 
twice daily.  Dosage adjustments will be made at the discretion of the 
investigators at two-week intervals following pre-specified parameters 
until the optimal dosage has been obtained.  The optimal dosage is one 
that is associated with optimal anxiolytic benefit without intolerable 

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adverse events.  Investigators will be allowed to decrease or not escalate 
the dosage in the presence of adverse events.  The selected dosage 
range of 7.5 mg twice daily up to 30 mg twice daily is consistent with 
current prescribing guidelines.   
DURATION OF 
TREATMENT 
12 weeks 
PRIMARY OUTCOME 
MEASURE(S) 
The primary outcome measure is the proportion of participants who fail to 
complete the 12-week study on study drug. 
SECONDARY OUTCOME 
MEASURE(S) 
Safety and Tolerability: 
(1) Number and type of adverse events 
(2) Number and type of serious adverse events 
(3) Mean change in MDS-UPDRS motor from baseline to 12 weeks 
(4) Mean change in calculated levodopa-equivalent dose from 
baseline to 12 weeks 
Anxiety: 
(1) Mean change in Hamilton Anxiety Rating Scale (HAM-A) from 
baseline to 12 weeks 
(2) Proportion of responders (>50% reduction from baseline or 
reduction to ≤7 on HAM-A) at 12 weeks 
(3) Proportion “much improved” or “very much improved” on Clinical 
Global Impressions-Improvement (CGI-I) and Patient Global 
Impressions-Improvement (PGI-I) at 12 weeks 
(4) Mean change in Hospital Anxiety and Depression Scale (HADS) 
from baseline to 12 weeks 
Levodopa-Induced Dyskinesias: 
(1) Mean change in Unified Dyskinesia Rating Scale (UDysRS) from 
baseline to 12 weeks 
Parkinson Anxiety Scale: 
(1) Correlation of change with CGI-I and PGI-I 
 
SAFETY 
CONSIDERATIONS 
Buspirone is FDA-approved for treatment of generalized anxiety disorder.  
According to the package insert, in premarketing clinical efficacy trials, 
10% of 2200 participants discontinued treatment secondary to an adverse 
event and in pooled analysis of placebo-controlled clinical trials the most 
common adverse events included dizziness (12%), drowsiness (10%), 
nausea (8%), headache (6%), nervousness (5%), fatigue (4%), insomnia 
(3%), lightheadedness (3%), and dry mouth (3%).   
SAMPLE SIZE 
CONSIDERATIONS 
A sample size of 21 will provide 80% power to reject the null hypothesis of 
tolerability (observed intolerability rate of ≤20%) in favor of the alternative 
hypothesis of intolerability (observed intolerability rate of >20%) if the true 
intolerability rate is greater than 40%, using a binomial test and a one-
tailed significance level of 10%.  With the introduction of a placebo arm for 
blinding and relying on a 4:1 allocation ratio, the sample size increases to 
27.  The use of a futility design provides a higher probability of correctly 
failing to reject the null hypothesis of tolerability at the cost of a decreased 
chance of correctly rejecting the null hypothesis of tolerability. We are 
willing to accept a higher chance that we declare an intolerable drug 
tolerable as the expected intolerabilities (headache, nausea, drowsiness, 
dizziness, and worsening of PD motor function) are not expected to be 
severe, may be experienced by only a portion of subjects, and could be 
confirmed in larger studies.   
 

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1. PURPOSE OF THE STUDY AND BACKGROUND 
 
1.1. Purpose of the study 
 
Anxiety is common in patients with Parkinson’s disease (PD) and negatively impacts 
quality of life.  Despite this, anxiety is under-treated and there have been no clinical 
trials specifically examining the pharmacological treatment of anxiety in PD.  Buspirone 
may be effective for the treatment of anxiety in PD.  While it has the additional 
potential benefit of reducing levodopa-induced dyskinesias there have also been 
concerns that it may worsen PD motor function.  The primary objective of this study is 
to determine the tolerability of buspirone for the treatment of anxiety in Parkinson’s 
disease (PD). 
 
Primary Objective: 
To determine the tolerability of buspirone in PD as defined by the proportion of 
participants who complete the 12-week study on study drug. 
 
Secondary Objectives: 
a. To explore the preliminary efficacy of buspirone in reducing symptoms of anxiety. 
b. To explore the preliminary efficacy of buspirone in reducing levodopa-induced 
dyskinesias. 
c. To pilot the Parkinson Anxiety Scale (PAS) for assessing change in symptoms of 
anxiety over time. 
 
1.2. Background 
 
The prevalence of anxiety disorders in Parkinson’s disease (PD) is 25%-43%1,2,3,4,5 and 
anxiety as a symptom is reported by 56% of PD patients.6  Anxiety negatively impacts 
quality of life7,8 and may be a more important determinant than depression or apathy.9  
Yet anxiety disorders are untreated in up to 50% of patients with PD.10  The current 
state of treatment may reflect the heterogeneous phenomenology of anxiety in PD,1,3-5 
the lack to date of an appropriate scale to detect anxiety in PD,2,11,12 the absence of 
guidelines regarding the treatment of anxiety in PD or a combination of these factors.   
 
The National Institute of Neurological Disorders and Stroke (NINDS) 2014 PD 
Research Recommendations highlighted the treatment of non-motor symptoms as an 
area of importance.13  There is emerging interest in the treatment of anxiety 
specifically, including a recent pilot study examining the feasibility of cognitive 
behavioral therapy14.  However, there have been no clinical trials designed to evaluate 
the optimal pharmacological treatment of anxiety in PD.  With no evidence upon which 
to base treatment decisions for this common and disabling condition in patients with 
PD, clinicians most commonly prescribe selective serotonin reuptake inhibitors 
(SSRIs) and benzodiazepines.10  However, in the multicenter Study of Antidepressants 
in Parkinson’s Disease (SAD-PD) trial both paroxetine (an SSRI) and venlafaxine XR 
(a serotonin norepinephrine reuptake inhibitor or SNRI) were more effective than 
placebo for the treatment of depressive symptoms but neither demonstrated any effect 
on a secondary anxiety measure.15  In fact, higher baseline anxiety levels predicted 
poorer response to treatment of depressive symptoms.16  A second randomized 
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depression in PD also demonstrated no effect for paroxetine on a secondary anxiety 
measure.17  Although neither of these studies was powered to detect changes in 
anxiety, they highlight the need to further evaluate treatment approaches for anxiety in 
PD.  Benzodiazepine therapy is not ideal given a side effect profile including sedation, 
delirium, and balance impairment associated with an increased risk of falls.  
Benzodiazepines are also associated with high abuse potential and there is a possible 
increased risk of Alzheimer’s dementia associated with long-term use.18   
 
Buspirone is FDA approved for the treatment of generalized anxiety disorder.  It may 
be possible to reposition buspirone for the treatment of anxiety in PD however it has 
not yet been evaluated in this population, where the pathophysiology of anxiety might 
be different, and it is necessary to ensure that it does not worsen PD motor function.  
Buspirone is primarily a 5HT1A receptor partial agonist with weak dopamine D2 and 
5HT2 receptor activity.19 Buspirone is effective for the treatment of generalized anxiety 
disorder,20,21,22 is well-tolerated in the elderly population,23,24 and can be used as an 
adjunctive agent for the treatment of depression.25 Through its action on the 5HT1A 
receptor, buspirone may have the added benefit of diminishing levodopa-induced 
dyskinesias26,27,28 an effect corroborated by early clinical studies.29,30  This is a 
particularly compelling indication given the relationship between anxiety, motor 
fluctuations,31,32,33,34 and freezing of gait.35  However, this effect as not been 
conclusively demonstrated having only been shown in two very small trials and 
buspirone, through its effects on the dopaminergic system and weak affinity for D2 
receptors, could potentially be associated with worsening of PD motor function. The 
potential motor impact of buspirone in PD makes a preliminary tolerability study the 
first logical step prior to embarking on a larger efficacy trial. 
 
The underlying pathophysiology of anxiety in PD has not been fully elucidated and 
may differ from that of anxiety in the general population.  Anxiety symptoms in PD can 
respond to treatment with dopamine agonists36,37 and, among fluctuators, anxiety may 
improve acutely with levodopa infusions;38 however, in general, anxiety does not 
respond well to dopaminergic treatment39 supporting the notion that dopamine 
dysregulation is not the sole pathophysiologic mechanism.  Serotonergic dysfunction 
contributes to the pathophysiology of anxiety in the general population40 and 5HT1A 
receptors have been specifically implicated.41  5HT1A receptors modify serotonergic, 
glutaminergic, and dopaminergic transmission and in PD, 5HT1A receptor levels are 
altered.42  In rats with anxiety-like behavior induced by 6-hydroxydopamine lesions of 
the medial forebrain bundle, injection of a 5-HT1A receptor agonist, 8-OD-DPAT, into 
the prelimbic region or medial subdivision of the central nucleus of the amygdala has 
an anxiolytic effect.43,44  Thus, buspirone, which is primarily a 5HT1A receptor partial 
agonist, is a promising therapeutic for anxiety in PD.   
 
The phenomenology of anxiety in PD is heterogeneous.  Recent studies report 
variable prevalence rates for anxiety subtypes in PD: generalized anxiety disorder 3-
20.6%, agoraphobia without panic 1.6-15.5%, panic disorder 3.9-30%, social phobia 
7.9-13%, obsessive compulsive disorder 0.8-5.5%, and anxiety disorder not otherwise 
specified 11.4-25%.1,3-5 Commonly used anxiety scales, including the Beck Anxiety 
Inventory, Hamilton Anxiety Rating Scale, and Hospital Anxiety and Depression Scale 
were developed for use in the general population and do not have ideal psychometric 
properties for use in PD.2,11,45  A new scale, the Parkinson Anxiety Scale, was 
developed specifically for use in the PD population and has thus far demonstrated 

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validity and reliability46,47 but its sensitivity to change has not yet been demonstrated.  
This clinical trial will pilot the use of the Parkinson Anxiety Scale for detecting change 
over time and determine the feasibility of using it in larger phase III trials. 
 
      1.3   Supporting Data 
 
Pharmacokinetics: Buspirone is administered two to three times daily.  Buspirone is 
rapidly absorbed and metabolized via CYP3A4 to several metabolites, including 1-
pyrimidinylpiperazine (1-pp), which is an active metabolite.  The half-life is 
approximately 2-3 hours and time to peak concentration is 40-90 minutes.  It is 
excreted in urine (29-63%) and feces (18-38%).  There are no significant differences in 
AUC and C max between elderly and younger patients or between male and female 
subjects (label). 
 
General Population: Buspirone is FDA-approved for treatment of generalized anxiety 
disorder.  In premarketing clinical efficacy trials, 10% of 2200 participants discontinued 
treatment secondary to an adverse event.  In pooled analysis of placebo-controlled 
clinical trials of buspirone the most common adverse events included dizziness (12%), 
drowsiness (10%), nausea (8%), headache (6%), nervousness (5%), fatigue (4%), 
insomnia (3%), lightheadedness (3%), and dry mouth (3%).  Hypertensive crisis has 
been reported with concomitant MAO inhibitor use.  Possible serotonin syndrome has 
been reported with concomitant SSRI use.  Complete package insert information for 
buspirone can be found at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-
190_BuSpar_Prntlbl.pdf.48     
 
Parkinson’s Disease Population: There have been four small human studies of 
buspirone in PD.  None of the trials was designed to evaluate the efficacy of buspirone 
for the treatment of anxiety and none of the trials selected participants for the presence 
of anxiety at baseline.  In the two small trials that found no effect of buspirone on 
anxiety, baseline anxiety levels were low, suggesting a possible floor effect.29,49  Three 
of these studies suggest that, at dosages up to 60 mg per day, buspirone does not 
worsen PD motor function,29,49,50  however one study demonstrated worsening of PD 
motor function at lower dosages.30 
 
Table 1: Studies of buspirone in Parkinson’s disease. 
 
 Study 
 N 
 Design 
 Anxiety 
 Dyskinesias 
 Parkinsonism 
 Ludwig49 
 16   RCT; targeting 
 PD 
 No change at ≤60   
 mg/day 
 No change at  
 ≤60 mg/day 
 Worsened at 
 >60  mg/day 
 Hammerstad50  
 11 
 Open-label;  
 targeting PD 
 Not reported 
 Not reported 
 Worsened at  
 >60 mg/day  
 Bonifati29 
 10 
 RCT; targeting  
 dyskinesias 
 No change 
 Improved 
 No change 
 Kleedorfer30 
 5 
 Open-label;  
 targeting   
 dyskinesias 
 “heightened degree  
 of relaxation and  
 tranquility” 
 Improved 
 Worsened at  
 ≤60 mg/day 
 
Buspirone is FDA-approved for treatment of generalized anxiety disorder in the 
general population.  Given the heterogeneous phenomenology of anxiety in PD, this 
study will not be limited to those with generalized anxiety disorder.  As there is no 
intention to use the results of the proposed study to support a new indication, change 

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in labeling, or change in advertisement for buspirone, the proposed route of 
administration and dosage are consistent with current prescribing guidelines, and any 
special safety concerns relate only to potential worsening of PD motor function it is our 
determination that the proposed study is exempt from the investigational new drug 
requirements. 
 
2. STUDY DESIGN 
 
2.1. Overview 
 
This is a single-center, placebo-controlled, double-blind, futility study with participants 
with PD and anxiety randomized in a 4:1 allocation to flexible dosage buspirone or 
placebo for 12 weeks.  The initial dose will be 7.5 mg twice daily and investigators will 
increase the dosage as necessary and tolerated up to 30 mg twice daily to achieve the 
optimal dosage (the dosage with optimal balance of anxiolytic effect and adverse 
events).  Investigators will be encouraged to increase the dosage at two-week intervals 
until Hamilton Anxiety Scale (HAM-A) is ≤ 7 or there has been a 50% reduction in 
baseline score.  The investigator will be allowed to not escalate or decrease the 
dosage if the participant has significant adverse events.  Adverse events, severity of 
anxiety, presence of dyskinesias, and PD motor function will be assessed at baseline, 
week 2, 4, 8, and 12.  There will be interim telephone visits to assess efficacy and 
tolerability at week 6 and 10.  The primary outcome is the proportion of participants 
who fail to complete the 12-week study on study drug (any dosage).  Secondary 
analysis of efficacy will focus on the change in outcome variables from baseline to 12 
weeks. 
 
2.2. Rationale for Study Design 
 
The primary objective of this study is to determine the tolerability of buspirone in PD.  
The primary outcome is the proportion of participants who fail to complete the 12-week 
study on study drug.   We hypothesize that > 20% of participants will fail to complete 
the study on study drug.  As the primary tolerability concern with buspirone that is 
specific to the PD population is worsening of motor function, we considered selecting 
mean MDS-UPDRS motor scale change from baseline to 12 weeks as the primary 
outcome for tolerability.  This approach was rejected as it would not capture alternative 
reasons for intolerability (such as nausea, headache, or dizziness).  The 12-week 
duration should provide adequate time for response to treatment and to assess any 
effect on PD motor function.    
 
From the standpoint of sample size calculations and statistical analysis this is a single-
arm futility design; a placebo arm is introduced to allow for blinding and calibration.  
The use of a futility design over a traditional design allows for higher sensitivity at the 
cost of lower specificity.51  In other words, the futility design increases the probability of 
declaring a truly tolerable drug tolerable (correctly failing to reject the null hypothesis of 
tolerability) at the cost of a decreased probability of declaring a truly intolerable drug 
intolerable (correctly rejecting the null hypothesis of tolerability).  Given the importance 
of moving a therapeutic for anxiety through and as the expected intolerabilities 
(headache, nausea, drowsiness, dizziness, and worsening of PD motor function) are 
either not expected to be serious or expected to be reversible, and could be confirmed 
in larger studies, this is a favorable scenario. 

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The secondary exploratory objectives examining the efficacy of buspirone in reducing 
symptoms of anxiety and in reducing levodopa-induced dyskinesias were included to 
provide the opportunity to detect a signal of efficacy regarding potential therapeutic 
uses of buspirone in PD.   
 
This clinical trial will also pilot the use of the recently developed and validated 
Parkinson Anxiety Scale, which adequately captures the full phenomenological 
spectrum of anxiety in PD, for detecting change over time and determine the feasibility 
of using it in larger phase III trials.  We selected a cut-off of ≥ 14 on the Parkinson 
Anxiety Scale as necessary for study eligibility, consistent with the data from the initial 
validation study.46 We considered the use of a more traditional scale, such as the 
Hamilton Anxiety Scale or Hospital Anxiety and Depression Scale for use in the 
inclusion criteria, however concluded that these scales would not capture all of the 
subtypes of anxiety that are seen in PD and would result in the exclusion of 
appropriate participants.   
 
2.3. Rationale for Dosage 
 
A flexible dosage design was selected to reflect clinical practice, render more 
generalizable results, and remain consistent with general prescribing guidelines.  As 
such, this study assesses the tolerability of buspirone rather than the tolerability of a 
specific dosage of buspirone.  To minimize the risk for investigator bias influencing 
dosage adjustments we will employ specific parameters for dosage adjustment.  
Participants will receive 7.5 mg of buspirone or placebo twice daily for the first two 
weeks.  Increases can be made at two-week intervals if a dosage is without significant 
adverse events and optimal anxiolytic effect (defined as Hamilton Anxiety Scale score 
<50% of baseline score or ≤7) has not been attained.  These are traditional 
parameters used to define treatment efficacy in studies of anxiolytic medications.  Pre-
specified dosage levels of 7.5 mg twice daily, 10 mg twice daily, 15 mg twice daily 
(with 3 preceding days of 12.5 mg twice daily), 20 mg twice daily (with 3 preceding 
days of 17.5 mg twice daily), 25 mg twice daily (with 3 preceding days of 22.5 mg twice 
daily), and 30 mg twice daily (with 3 preceding days of 27.5 mg twice daily) will be 
imposed to minimize dosage variation and maintain consistency with prescribing 
guidelines.  This is detailed in section 5.1.2.  We anticipate that future phase III 
efficacy trials would employ a similar design.   
 
2.4    Rationale for Placebo Arm 
 
The introduction of a placebo arm enables the blinding of participants and investigators 
to treatment.  The introduction of some uncertainty regarding treatment assignment for 
both the participants and investigators will allow for more rigorous assessment of the 
tolerability of the study drug by reducing bias.  The use of a placebo arm will also allow 
for calibration, to verify assumptions about the background rate of intolerability.  The 
assumed intolerability rate of placebo is zero and the incorporation of a small placebo 
group allows for verification of this assumption.  The study will not be powered for 
direct between group comparisons.  A similar approach has been used in prior PD 
research studies; in these studies, a placebo group was introduced to verify historical 
data regarding the anticipated progression of PD (as measured by the Unified 
Parkinson’s Disease Rating Scale), which was used for sample size calculations.52,53  

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In both cases, the rate of progression in the placebo group did not align with historical 
data and the researchers were able to perform additional analyses based on an 
updated rate of progression. 
 
We recognize the potential for anxiety to not improve or worsen, particularly among 
those participants in the placebo arm, and that this may have a negative effect on their 
quality of life.  However, we believe that the benefits of including a placebo arm for 
blinding and to allow for calibration of baseline assumptions regarding intolerability 
outweigh the potential risks.  We will institute measures to ensure the safety of all 
participants.  Of note, participants will not be asked to discontinue any pre-existing 
anxiolytics or antidepressants (with the exception of MAO inhibitors which pose a 
potential safety concern) or discontinue psychotherapy to participate in the study.  
Participants will only be asked not to increase the dosage of pre-existing anxiolytics or 
antidepressants, start new anxiolytics or antidepressants, or initiate psychotherapy for 
the duration of the study.  Investigators will exclude from participation any patients 
where there is a concern for patient safety.   If a participant's anxiety symptoms 
worsen significantly during the course of the study or if he/she develops suicidal 
ideation, which is deemed severe enough to reflect a significant suicidal risk, we will 
terminate the participant from the study and we will immediately refer the patient to a 
mental health provider for treatment.  The investigator will determine the most 
appropriate referral, which may be referral to an outpatient mental health provider or 
referral to the Comprehensive Psychiatric Emergency Program.  Participants and their 
caregivers will be encouraged to contact the investigators at any time if there is 
concern about worsening anxiety or adverse experiences.   
 
3. CHARACTERISTICS OF THE RESEARCH POPULATION 
 
3.1. Subject Characteristics 
 
a) Number of Subjects:  300.  This number reflects the use of identified data during 
the screening process to identify potential participants.  The total anticipated 
number of enrolled participants is 35, which includes screen failures.   
 
b) Gender and Age of Subjects:  There will be no gender based enrollment 
restrictions.  Participants will need to be at least 18 years of age.  Based on the 
known demographics of PD, we anticipate that approximately 55-60% of the 
participants will be male and that the majority of participants will be over 50. 
 
c) Racial and Ethnic Origin: There will be no enrollment restrictions based upon 
race or ethnic origin.  Based on the known demographics of PD and our patient 
population, we anticipate that the majority of the participants will be Caucasian. 
 
d) Vulnerable Subjects:  PD is a disease that increases in prevalence with age and 
as such we expect a number of participants to be elderly.  Participants will be able 
to withdraw from the study at any time. 
 
3.2. Inclusion and Exclusion Criteria 
 
a) Inclusion Criteria:   
• Diagnosis of idiopathic PD by UK Parkinson’s Disease Society Brain Bank 

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Clinical Diagnostic Criteria 
• Significant anxiety as determined by the self-rated Parkinson Anxiety Scale 
(score ≥ 14) 
• Able to provide written informed consent 
• At least 18 years of age 
 
b) Exclusion Criteria:  
• Diagnosis of atypical or secondary parkinsonism 
• Concomitant treatment with an MAO inhibitor within the 14 days prior to 
screening visit 
• Significant renal or hepatic impairment 
• Significant cognitive impairment defined as MOCA score < 23 
• On-going depression with suicidal or homicidal ideation and concern for patient 
safety based on clinical determination by the investigator 
• Allergy or intolerance to study drug, matching placebo, or their formulations 
• History of prior exposure to study drug 
• Lactating or pregnant woman 
• Concomitant treatment with a disallowed medication (detailed in section 6.2) 
• Active drug or alcohol use or dependence that, in the opinion of the investigator, 
would interfere with adherence to study requirements 
• Concomitant treatment with an anxiolytic or antidepressant will be allowed 
however potential participants who had dosage changes in the 30 days prior to 
the screening visit will be excluded 
• Use of an investigational drug within 30 days prior to screening visit 
• Any medical or psychiatric comorbidity that, in the opinion of the investigator, 
would compromise study participation 
• Dysphagia defined as a score of ≥ 2 on MDS-UPDRS Item 2.3 Chewing and 
Swallowing 
 
During the Study: 
• The addition of new anti-parkinsonian medications or increase in dosage of 
existing anti-parkinsonian medications will be prohibited for the duration of the 
trial.  
• The addition of a new anxiolytic or antidepressant or increase in dosage of an 
existing anxiolytic or antidepressant will be prohibited for the duration of the 
trial. 
• Participants will not be allowed to initiate or discontinue psychotherapy following 
enrollment.  If they are participating in it at the time of enrollment, it should be 
continued for the duration of the study. 
 
3.3. Discussion of Study Population 
 
Participants will not be excluded on the basis of Hoehn and Yahr stage, pharmacologic 
treatment of Parkinson disease (with the exception of MAO inhibitors), or history of 
deep brain stimulation or stereotactic surgery.  Participants will not be excluded due to 
the presence of comorbid depression or other comorbid psychiatric disorders, unless, 
in the opinion of the investigator, their study participation would be compromised.  
While the exclusion of participants with depression would eliminate a potential 
confounding factor it would also limit recruitment as anxiety and depression are 

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common comorbid diagnoses.  Concomitant treatment with other anti-anxiety 
medications and/or antidepressants (with the exception of MAO inhibitors) will be 
allowed assuming stable dosages for 30 days prior to study entry.   Our criteria will 
allow for the most representative patient sample and improve the generalizability of the 
study results. 
 
4. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT 
 
4.1. Method Of Participant Identification And Recruitment 
 
We anticipate recruiting a total of 35 eligible participants at one site over a 24 month 
period.  We will use multiple methods to identify potential participants.  
  
(1) The primary investigator (Dr. Richard) and co-primary investigator (Dr. Schneider) 
will use i2b2 (Informatics for Integrating Biology and the Bedside), a software for 
running clinical database queries, to query our electronic medical record (EMR) and 
identify patients with an ICD-9 diagnosis of 332.0 (parkinsonism) or ICD-10 diagnosis 
G20 (Parkinson’s disease) and a diagnosis of an anxiety disorder who are seen by a 
URMC or URMC affiliated provider.  For each identified patient, the primary care 
provider or neurologist in charge of their care will be contacted and permission to 
contact the identified patient will be requested. 
 
(2)  We will design and distribute informational flyers to local patient advocacy groups 
and affiliated and non-affiliated neurology, primary care, and psychiatry offices.  Area 
providers will be sent informational letters and reference pocket cards.  We will 
conduct informational presentations for area providers and promote the study at 
regional symposiums and other events.  Additional efforts may be made to promote 
the study in the local media. 
 
(3)  The trial will be posted on appropriate clinical trial registries including Fox Trial 
Finder, clinicaltrials.gov and Research Match.   
 
(4) We will reach out to local patient advocacy groups to increase awareness and 
engage potential participants.   
 
A screening log will be maintained.  The screening log will document how potential   
participants learned about the trial, where they were referred from, reasons for 
ineligibility, and reasons for nonparticipation of eligible participants.  This information 
will be reviewed monthly to identify any problems and develop strategies to enhance 
recruitment. 
 
4.2. Process of Consent 
 
Interested participants will be contacted by a study coordinator to assess their 
willingness to participate.  Potential participants will be scheduled for a screening visit 
at which time eligibility will be assessed and written informed consent will be obtained.  
Written informed consent 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 Rochester IRB procedures.   
 

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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.  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 in a division office 
and consent acknowledgment will be electronically recorded in REDCap.  A copy of 
the consent form will be provided to the participant upon obtainment of consent.  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. 
 
 
 
5. METHODS AND STUDY PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEDULE OF ACTIVITIES 
 
Screening  
Baseline 
(within 0- 14 
days) 
Entry 
2 Week (+/- 
3 days) 
4 Week (+/- 
3 days) 
6 Week 
Phone (+/- 3 
days) 
8 Week (+/- 
3 days) 
10 Week 
Phone (+/- 3 
days) 
12 Week 
(+/- 3 days) 
Adverse 
Event Visit  
Premature 
Termina-tion 
Visit 
 Informed   
 Consent 
 X 
 
 
 
 
 
 
 
 
 
 
 Demographics 
 
 X 
 
 
 
 
 
 
 
 
 
 Neurological 
 Exam 
 X 
 
 
 
 
 
 
 
 
 X* 
 
 General  
 Medical Exam 
 X 
 
 
 
 
 
 
 
 
 X 
 
 Past Medical  
 History  
 X 
 
 
 
 
 
 
 
 
 
 
 Health Update 
 
 X 
 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Concomitant  
 Medications 
 X 
 X 
 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Labs 
X* 
 
 
 
 
 
 
 
  
 X* 
X* 
Urine 
Pregnancy 
Test 
X^ 
 
 
 
 
 
 
 
 
 
 
 UK Brain  
Bank 
 Criteria 
 X 
 
 
 
 
 
 
 
 
 
 
 NINDS CDE  
 PD Med 
History 
 
 X 
 
 
 
 
 
 
 
 
 
 MOCA 
 X 
 
 
 
 
 
 
 
 
 
 
 Adverse  
Events  
 
  
 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
UKU 
 
 
 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
MDS-UPDRS 
 
 X 
 
 
 
 
 
 
  
 
 
 MDS-UPDRS  
 motor 
 
  
 
 X 
 X 
 
 X 
 
 X 
 X 
 X 
MDS-UPDRS 
Item 2.3 
 X 
 
 
 
 
 
 
 
 
 
 
 Vital Signs 
 X 
 X 
 
 X 
 X 
 
 X 
 
 X 
 X 
 X 
 Unified  
 Dyskinesia  
 Rating Scale 
 
 X 
 
 X 
 X 
 
 X 
 
 X 
 
 X 
 Parkinson  
 Anxiety Scale 
 X 
  X 
 
  
 X 
 
 X 
 
 X 
 
 X 
 CGI- 
 Improvement   
 
 
 
 X 
 X 
 
 X 
 
 X 
 
 X 
 PGI- 
 Improvement  
 
 
 
 X 
 X 
 
 X 
 
 X  
 
 X 
 Hamilton  
 Anxiety Rating   
 Scale 
 
 X 
 
 X 
 X 
 X 
 X 
 X 
 X 
 
 X 
 Hospital  
 Anxiety and 
 Depression  
 Scale 
 
 X 
 
 X 
 X 
 
 X 
 
 X 
 
 X 
 Dosage  
 Assessment 
 
 
 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
  
 Adherence 
 Assessment 
 
 
 
 X 
 X 
 
 X 
 
 X 
 X 
 X 
*If required as determined by investigator 
 
 
 
^For women of child-bearing potential 

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5.1. Treatment Dosage and Administration 
 
5.1.1. Overview 
Participants will initially receive buspirone or placebo 7.5 mg twice daily 
administered orally.  Investigators will evaluate the participants at two-week 
intervals and make dosage adjustments as necessary and tolerated up to a 
maximum of 30 mg twice daily to achieve an optimal dosage that balances 
efficacy with tolerability.  Treatment duration is 12 weeks. 
 
5.1.2. Dosage Adjustments 
Study investigators and study team members, with the exception of the study 
team member managing drug dispensation, will be blinded to treatment 
assignment.  To minimize the risk for investigator bias influencing dosage 
adjustments we will employ specific parameters for dosage adjustment.  If a 
dosage is tolerable, the investigator will increase the dosage if optimal anxiolytic 
effect (defined as Hamilton Anxiety Scale score <50% of baseline score or ≤7) 
has not been attained.  Participants will not be blinded to dosage adjustments but 
will remain blinded to treatment assignment.  Pre-specified dosage levels of 7.5 
mg twice daily, 10 mg twice daily, 15 mg twice daily (with 3 preceding days of 
12.5 mg twice daily), 20 mg twice daily (with 3 preceding days of 17.5 mg twice 
daily), 25 mg twice daily (with 3 preceding days of 22.5 mg twice daily), and 30 
mg twice daily (with 3 preceding days of 27.5 mg twice daily) will be imposed as 
detailed in the following table.  The investigator will be allowed to decrease the 
dosage or not escalate the dosage if there are adverse events. 
 
 
 
 
REGIMEN DESCRIPTION 
 
Agent 
 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Buspirone 
Take consistently 
either with or 
without food.   
7.5 mg twice 
daily 
Oral 
Week 1-2 
Placebo 
Take consistently 
either with or 
without food.  
7.5 mg twice 
daily 
Oral 
Week 1-2 
 
 
 
 
 
 
 
 
 
 
 
 

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DOSAGE ADJUSTMENTS 
 
Agent 
 
Precautions 
 
Prior Dose 
 
New Dose 
 
Route 
 
Schedule 
Buspirone 
Take consistently 
either 
with 
or 
without food.   
7.5 
mg 
twice daily 
10 
mg 
twice daily 
Oral 
Week 1-2 
 
 
10 mg twice 
daily 
15 
mg 
twice daily 
Oral 
Day 1-3: 12.5 mg 
twice daily 
 
Day 4-14: 15 mg 
twice daily 
 
 
15 mg twice 
daily 
20 
mg 
twice daily 
Oral 
Day 1-3: 17.5 mg 
twice daily 
 
Day 4-14: 20 mg 
twice daily 
 
 
20 mg twice 
daily 
25 
mg 
twice daily 
Oral 
Day 1-3: 22.5 mg 
twice daily  
 
Day 4-14: 25 mg 
twice daily 
 
 
25 mg twice 
daily 
30 
mg 
twice daily 
Oral  
Day 1-3: 27.5 mg 
twice daily 
 
Day 4-14: 30 mg 
twice daily 
Placebo 
Take consistently 
either 
with 
or 
without 
food.  
Avoid grapefruit. 
7.5 
mg 
twice daily 
10 
mg 
twice daily 
Oral 
Week 1-2 
 
 
10 mg twice 
daily 
15 
mg 
twice daily 
Oral 
Day 1-3: 12.5 mg 
twice daily  
 
Day 4-14: 15 mg 
twice daily 
 
 
15 mg twice 
daily 
20 
mg 
twice daily 
Oral 
Day 1-3: 17.5 mg 
twice daily  
 
Day 4-14: 20 mg 
twice daily 
 
 
20 mg twice 
daily 
25 
mg 
twice daily 
Oral 
Day 1-3: 22.5 mg 
twice daily  
 
Day 4-14: 25 mg 
twice daily 
 
 
25 mg twice 
daily 
30 
mg 
twice daily 
Oral  
Day 1-3: 27.5 mg 
twice daily 
 
Day 4-14: 30 mg 
twice daily 
 
 
 
 

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5.1.3. Study Drug/Placebo 
The absorption of buspirone may be decreased by taking it will food and 
participants will be instructed to take the study drug either consistently with food 
or consistently without food.   
 
5.2   Timing of Visits 
 
5.2.1 Screening Visit 
The screening visit will occur within 0-14 days of the baseline visit.  Prior to completing 
any study activities, written informed consent will be obtained.  Participants will be 
assigned a confidential participant identification number. The study coordinator and 
investigator will assess potential participants for study eligibility.  All of the inclusion 
criteria and none of the exclusion criteria must be met.  If a participant is being 
withdrawn from a medication to qualify for the study, the consent form must be signed 
prior to the initiation of the withdrawal. 
 
Evaluations: 
• Informed Consent 
• Neurological Examination 
• General Medical Examination 
• Past Medical History 
• Concomitant Medications 
• Labs (if required as determined by investigator) 
• Verification of Parkinson’s disease diagnosis (UK Brain Bank Criteria) 
• MOCA 
• Vital Signs 
• Parkinson Anxiety Scale 
• MDS-UPDRS Item 2.3 
• Urine pregnancy test for women of child-bearing potential 
 
 
5.2.2 Baseline Visit 
The baseline visit will occur within 0-14 days of the screening visit.  If laboratory 
studies are obtained at the screening visit, results must be reviewed prior to the 
baseline visit.  Participants will be randomized to one of two treatment groups.  
Participants will be randomized to group according to a computer-generated 
randomization scheme.  Based on this randomization, study personnel will be informed 
which drug bottles to supply the participant.  The first dose of study drug or placebo 
should be taken the following morning. 
 
Evaluations: 
• Demographics 
• Health Update 
• Concomitant Medications 
• NINDS Common Data Elements PD Medical History 
• MDS-UPDRS 
• Vital Signs 
• Unified Dyskinesia Rating Scale 
• Parkinson Anxiety Scale 
• Hamilton Anxiety Scale 

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• Hospital Anxiety and Depression Scale 
 
 
 
5.2.3 Visit 01 (Day 14 +/- 3 days), Visit 02 (Day 28 +/- 3 days), Visit 03 (Day 56 +/- 3  
 
 
days), and Visit 04 (Day 84 +/- 3 days) 
 Visit 01, Visit 02, Visit 03, and Visit 04 should occur within 3 days of the target date.    
   Previously dispensed study drug bottles will be collected and new study drug bottles   
   dispensed at each visit. 
 
 
Evaluations: 
• Health Update 
• Concomitant Medications 
• Adverse Events 
• UKU Side Effect Rating Scale 
• MDS-UPDRS Motor Component 
• Vital Signs 
• Unified Dyskinesia Rating Scale 
• Parkinson Anxiety Scale (except at Visit 01) 
• CGI-Improvement 
• PGI-Improvement 
• Hamilton Anxiety Rating Scale 
• Hospital Anxiety and Depression Scale 
• Dosage Assessment 
• Adherence Assessment 
 
 
 
5.2.4 Telephone Visit T01 (Day 42 +/- 3 days) and Telephone Visit T02 (Day 70 +/- 3  
 
days) 
Visit 03 and Visit 05 will occur via telephone and should occur within 3 days of the 
target date.  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 so 
long as they occur within the specified target period.  Participants will be required to 
return previously dispensed study drug bottles and pick up new study drug bottles 
following each telephone visit within the same designated timeframe (Day 42 +/- 3 
days or Day 70 +/- 3 days). 
 
Evaluations: 
• Health Update 
• Concomitant Medications 
• Adverse Events 
• UKU Side Effect Rating Scale 
• Hamilton Anxiety Rating Scale 
• Dosage Assessment 
 
 
 
5.2.5 Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the 
participant’s request or as deemed necessary by the investigator.  The date and 
reason for the unscheduled visit will be recorded. 
 
Evaluations: 
• Neurological Exam (if deemed necessary by investigator) 

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• General Medical Exam 
• Health Update 
• Concomitant Medications 
• Laboratory Studies (if deemed necessary by investigator) 
• Adverse Events 
• UKU Side Effect Rating Scale 
• MDS-UPDRS Motor Component 
• Vital Signs 
• Dosage Assessment 
• Adherence Assessment 
 
 
 
5.2.6 Premature Termination Visit 
Participants may withdraw from the study at any time.  In the event of premature study 
withdrawal (either participant or investigator initiated), a premature termination 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.  The study drug may be discontinued without a taper. 
 
 
Evaluations: 
• Health Update 
• Concomitant Medications 
• Laboratory Studies (if deemed necessary by investigator) 
• Adverse Events 
• UKU Side Effect Rating Scale 
• MDS-UPDRS Motor Component 
• Vital Signs 
• Unified Dyskinesia Rating Scale 
• Parkinson Anxiety Scale 
• CGI-Improvement 
• PGI-Improvement 
• Hamilton Anxiety Rating Scale 
• Hospital Anxiety and Depression Scale 
• Dosage Assessment 
• Adherence Assessment 
 
5.3 
Efficacy Assessments 
 
5.3.1 Parkinson Anxiety Scale (PAS) 
The heterogeneous appearance of anxiety in Parkinson’s disease presents difficulties 
in diagnosing and monitoring anxiety.  The PAS was developed specifically for use in 
the PD population and has demonstrated validity.46,47  Commonly used anxiety scales, 
such as the Hamilton Anxiety Rating Scale and Hospital Anxiety and Depression 
Scale, do not have ideal psychometric properties for use in PD.2,11,45  The self-rated 
PAS was selected as a screening tool because it was felt to best capture the full 
phenomenological spectrum of anxiety in PD.  A score of ≥ 14 will be required in order 
to be eligible to participate in this study.  A cut-off score of ≥ 14 was selected in 
accordance with the original study of this scale by Leentjens et al.46 The self-rated PAS 
will be completed at screening, baseline, and each subsequent in-person study visit.  It 

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was not selected as an outcome measure for the secondary anxiety endpoint because 
its ability to detect changed over time has not yet been validated.  This trial will pilot 
the use of the PAS for detecting change over time by correlating change with the 
Clinical Global Impression-Improvement and Patient Global Impression-Improvement 
scales.  Participants will be trained to complete this scale by the study coordinator at 
the screening visit and the study coordinator will review the scale for completion. 
 
5.3.2 Clinical Global Impression-Improvement (CGI-I) 
The widely-used CGI-I was selected for the ability to obtain clinician impressions of 
improvement in overall functioning.  The CGI-I will be administered by an investigator 
at the 2 week, 4 week, 8 week, and 12 week visits.  Secondary outcome measures will 
include the proportion “much improved” or “very much improved” on CGI-I at 12 
weeks.   
 
5.3.3 Patient Global Impression-Improvement (PGI-I) 
The PGI-I was selected for the ability to obtain patient impressions of improvement in 
overall functioning.  The PGI-I will be completed at the 2 week, 4 week, 8 week, and 
12 week visits.  Secondary outcome measures will include the proportion “much 
improved” or “very much improved” on PGI-I at 12 weeks.  Participants will be trained 
to complete this scale by the study coordinator at the screening visit and the study 
coordinator will review the scale for completion. 
 
5.3.4 Hamilton Anxiety Rating Scale (HAM-A) 
Despite concerns about construct validity and predictive validity, the 14-item HAM-A 
was selected because it is a widely used clinician-rated measure and has 
demonstrated sensitivity to change.  The HAM-A will be administered by an 
investigator at baseline and each subsequent telephone and in-person study visit.  
There is precedent for administering the HAM-A by telephone and it was done in a 
study of telephone-based cognitive behavioral therapy for depression in PD.54  
Secondary outcome measures will include the mean change in HAM-A from baseline 
to 12 weeks and proportion of responders (>50% reduction from baseline or reduction 
to ≤ 7 in HAM-A).   
 
5.3.5 Hospital Anxiety and Depression Scale (HADS) 
Although there are some concerns regarding validity in the PD population, the HADS 
was selected because it is a self-rated measure with anxiety and depression subscales 
and multiple studies have shown acceptable psychometric properties in the PD 
population.55,56  This 14-item self-rated scale does not include somatic symptom 
questions, which could potentially overlap with PD symptoms.  It will be completed at 
baseline and each subsequent in-person study visit.  Secondary outcome measures 
will include mean change in HADS from baseline to 12 weeks.  Participants will be 
trained to complete this scale by the study coordinator at the screening visit and the 
study coordinator will review the scale for completion. 
 
5.3.6 Unified Dyskinesia Rating Scale (UDysRS) 
The UDysRS was selected as it is a comprehensive, PD-specific tool that incorporates 
both historical and objective data.  It has been shown to be superior to multiple other 
dyskinesia rating scales.57  It will be administered by an investigator at baseline and 
each subsequent in-person study visit.  Investigators will have completed the 
certification course to ensure adequate inter-rater reliability. In order to minimize 

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differences in scores attributable to the timing of Parkinson’s disease medications, 
investigators will always attempt to administer the UDysRS during the ON state 
(generally about 1 hour after levodopa administration).  Secondary outcome measures 
will include mean change in UDysRS from baseline to 12 weeks. 
 
5.4 
Safety Assessments 
 
5.4.1 Medical Assessment 
A general medical examination will be performed by an investigator at the screening 
visit.  The need for liver function tests, BUN and creatinine to determine the presence 
of significant renal or liver impairment at screening or to evaluate an adverse event will 
be left to the discretion of the investigator.  The investigator may decide such testing is 
indicated based on the reporting of a history of certain medical conditions or surgeries, 
the presence of symptoms that may indicate renal or liver impairment, or examination 
findings that are concerning for renal or liver impairment.  A serum pregnancy test will 
be obtained at screening for all women of child-bearing potential.  All blood and urine 
tests will be obtained on-site and sent to URMC Labs for processing.  A complete list 
of concomitant medications will be obtained at screening, baseline, and all subsequent 
telephone and in-person study visits by a study coordinator.  A medical health update 
will be obtained by a study coordinator at baseline and all subsequent telephone and 
in-person study visits.  
 
5.4.2 Confirmation of Diagnosis of Parkinson’s Disease 
The diagnosis of PD will be confirmed by an investigator following a complete 
neurological examination using the UK Parkinson’s Disease Society Brain Bank 
Clinical Diagnostic Criteria at the screening visit.  The NINDS Common Data Elements 
Parkinson’s Disease Medical History form will be completed by an investigator to 
better characterize the participants Parkinson’s disease at the baseline visit.   
 
5.4.3 Montreal Cognitive Assessment (MOCA) 
The MOCA is a reliable and valid instrument in Parkinson’s disease58 and is felt to be a 
better screening instrument in Parkinson’s disease than the commonly used Mini-
Mental State Exam (MMSE).59  It will be administered by an investigator at the 
screening visit and significant cognitive impairment will be defined as a score < 23. 
 
5.4.5 Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) 
The MDS-UPDRS has been previously validated,60 is increasingly being used in 
Parkinson’s disease clinical trials, and is preferable over the UPDRS due to its ability 
to more finely discriminate degree of impairment. The minimally clinically important 
difference for improvement (-3.25) and worsening (4.63) on the MDS-UPDRS Motor 
was recently established.61  Investigators will be required to provide verification of their 
completion of the MDS-UPDRS certification course to ensure adequate inter-rater 
reliability.  In order to minimize differences in scores attributable to the timing of 
Parkinson’s disease medications, for participants who are on levodopa investigators 
will always attempt to administer the MDS-UPDRS Motor during the ON state 
(generally about 1 hour after levodopa administration).  MDS-UPDRS Item 2.3 
Chewing and Swallowing will be completed by the participant at the screening visit to 
screen for dysphagia that may result in difficulty swallowing the study drug and would 
preclude safe participation in the study.  A score of ≥ 2 (“I need to have my pills cut or 

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my food specially prepared because of chewing or swallowing problems, but I have not 
choked over the past week”) will exclude the participant from the study.  The full MDS-
UPDRS, including Part 1: Non-Motor Aspects of Experiences of Daily Living, Part II: 
Motor Aspects of Experiences of Daily Living, Part III: Motor Examination, and Part IV: 
Motor Complications, will be administered by an investigator at the baseline visit and 
the participant will complete those aspects of the MDS-UPDRS covered in the patient 
questionnaire (items 1.7-1.13 and 2.1-2.13).  The MDS-UPDRS Motor will be 
administered by an investigator at each subsequent in-person study visit. 
 
5.4.6 Vital Signs 
Pulse, temperature, weight, and blood pressure will be obtained at every in-person 
study visit. 
 
5.4.7 Adverse Events 
Soliciting of adverse events will be non-specific and participants will be asked the 
question, “Do you feel different in any way since starting the new treatment?” All 
adverse events occurring after the baseline visit will be reported.  All subsequent 
adverse events will be reported regardless of relationship to drug. 
 
 
At each in-person and telephone visit, a study coordinator will solicit adverse events.  
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 drug.  Details of change to the dosing schedule, any corrective 
treatment, or prescription of a concomitant medication, must be recorded on the 
appropriate pages of the case report form.  We will use the UKU Side Effects Rating 
Scale, developed by the Committee on Clinical Investigations (Udvalg for kliniske 
undersogelser, UKU), which is a standing committee under the Scandinavian Society 
of Psychopharmacology.62  Items in the UKU are sub-grouped into psychic, 
neurological, autonomic, and other categories.  The cardinal PD symptoms of tremor, 
rigidity, and hypokinesia are included. 
 
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, 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 documentation and classification of adverse events is further 
reviewed in section 9. 
 
5.5 Assessment of Participant Compliance 
 
In order to determine adherence, participants will be asked to complete an adherence 
questionnaire in conjunction with the study coordinator and will be instructed to bring 
previously dispensed study drug bottles to each in-person visit and following telephone 
visits for pill counts.  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 

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form.  Any discrepancies will be resolved and the data form will be updated as 
necessary. 
 
5.6 Dosage Assessment 
 
At each visit, the investigator will consider the need for dosage adjustment.  If a 
dosage is tolerable, the investigator will increase the dosage if optimal anxiolytic effect 
(defined as Hamilton Anxiety Scale score <50% of baseline score or ≤7) has not been 
attained.  This is further detailed in section 5.1.2.  
 
5.7 Costs to the Participant 
 
Neither the participant not the participant’s insurance will incur any costs as a result of 
participation in this study.   
 
5.8    Payment for Participation 
 
Participants will not be paid.  Participants will be reimbursed at a rate of $0.54/mile for 
travel by car.  Participants will be reimbursed up to $50 per study visit for travel 
expenses.   
 
5.9 Return of Individual Research Results 
 
Research results will not be provided to the participant.  The exception will be results 
of laboratory studies, which may be obtained 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. 
 
5.10 Pregnancy and Nursing 
 
Female participants of childbearing potential will be advised to use adequate birth  
control as there is insufficient date regarding the effects of buspirone 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 tapered 
immediately.  The participant may continue in the study off of study drug.  All attempts 
will be made to follow the participant until delivery.   
 
 
6.0 
CONCOMITANT AND DISALLOWED MEDICATIONS 
 
 6.1 Allowed Concomitant Medications 
 
Enrolling participants may be on PD medications, with the exception of monoamine 
oxidase inhibitors.  The dosage must be stable for 30 days prior to the baseline visit.  

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No new PD medications may be initiated for the duration of the study and no increases 
in the dosages of current PD medications will be allowed.   
 
Enrolling participants may be on antidepressants (with the exception of monoamine 
oxidase inhibitors), antipsychotics, and/or anxiolytics.  The dosage must be stable for 
30 days prior to the baseline visit and for the duration of the study.  The initiation of 
one of these medications will be prohibited for the duration of the study. 
 
Strong CYP3A4 inhibitors (atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat 
and cobicistat containing formulations, darunavir, idelalisib, indinavir, itraconazole, 
ketoconazole, 
lopinavir, 
nefazodone, 
nelfinavir, 
ombitasvir-paritaprevir-ritonavir, 
ombitasvir-paritaprevir-ritonavir plus dasabuvir, posaconazole, ritonavir and ritonavir 
containing formulations, saquinavir, telaprevir, telithromycin, and voriconazole) will be 
allowed.  Participants will be monitored for potential adverse events related to an 
increase in the serum study drug concentration. 
 
Strong CYP3A4 Inducers (carbamazepine, enzalutamide, fosphenytoin, lumacaftor, 
mitotaine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and rifapentine) will 
be allowed.   
 
Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) and interacting 
macrolide antibiotics (erythromycin, clarithromycin, and telithromycin) will be allowed.  
Participants will be monitored for potential adverse events related to an increase in the 
serum study drug concentration. 
 
6.2 Disallowed Medications and Supplements 
 
 
The following medications will not be allowed during the study: 
 
• Selective and non-selective MAO inhibitors including those whose primary 
mechanism of action is not monoamine oxidase inhibition: phenelzine, 
rasagiline, selegiline, procarbazine, isocarboxazid, tedizolid, tranylcypromine, 
syrian rue, linezolid, methylene blue, moclobemide 
• Initiation of any antidepressants, antipsychotics, or anxiolytics.   
• Azelastine 
• Conivaptan 
• Dapoxetine 
• Fusidic Acid 
• Idelasib 
• Orphenadrine 
• Paraldehyde 
• Thalidomide 
• Grapefruit juice, gingko biloba, St. John’s wort, and ginseng (which interfere with 
study drug metabolism). 
• Initiation of any new PD medications and increases in the dosage of existing PD 
medications will be prohibited. 
• Participants will also be prohibited from beginning any form of psychotherapy 
following study entry. 
 

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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. 
 
7.0 
PARTICIPANT 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: 
 
(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 
(6) Worsening of anxiety that in the investigator’s judgment requires prompt treatment with 
an alternative therapy 
 
In the event of a premature study withdrawal, a premature termination visit should occur.  
Evaluations are detailed in section 5.2.6.  Participants withdrawn from the study will not be 
replaced.  
 
8.0 
STUDY DRUG ADMINISTRATION/ASSIGNMENT 
 
8.1 Study Drug 
 
 
It is the investigator’s determination that this study drug is IND exempt. 
 
• Buspirone is lawfully marketed in the United States and is FDA-approved for the 
treatment of generalized anxiety disorder in the general population. 
• There is no intention to use the results of the proposed study to support a new   
indication or change in labeling for buspirone. 
• There is no intention to use the results of the proposed study to support a change in 
advertisement for buspirone. 
• The proposed route of administration (oral) and dosage (up to 30 mg twice daily) are 
consistent with current prescribing guidelines.   There have been prior human studies of 
buspirone in the Parkinson disease population. One very small study30 indicated that use 
of buspirone dosages consistent with current prescribing guidelines might be associated 
with worsening of PD motor function however three studies showed no worsening of PD 
motor function at the same dosages. The proposed study is designed to determine the 
tolerability of buspirone in this population. Adverse events will be closely monitored. 
Buspirone is generally well tolerated and there is no reason to believe that using the 
medication for the treatment of anxiety in the PD population would significantly increase 
the risks associated with use of the drug. 
• The study will be conducted only after approval by my institutional IRB and participants 
will be required to provide informed consent. 
 
The buspirone label is included in RSRB application section 50.1 and can be found at 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-190_BuSpar_Prntlbl.pdf.  
 

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The Investigational Drug Service at the University of Rochester will manage the over-
encapsulation, packaging, and distribution of the study drug and placebo in 
conjunction with an un-blinded study team member.  5 mg tablets of the study drug will 
be purchased in bulk from Teva Pharmaceutical.  The study drug will be over-
encapsulated and repackaged into labeled bottles.  In order to account for the 
necessary titration step with dosage increases (as described in section 5.1.2) the 
Investigational Drug Service will dispense bottles containing 6 capsules (to cover the 
3-day titration period) and 34 capsules (to cover the maintenance period).  In the event 
of dosage escalation beyond 7.5 mg study drug/placebo, participants will be provided 
with two bottles, one to cover the titration period and one to cover the maintenance 
period, at each dispensation and carefully instructed as to which bottle to begin with.  
Double panel medication labels will be provided by the Investigational Drug Service 
and labeling will include the study number, dosage, 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 
unblinded team member will remove the outer panel, which will specify whether the 
bottle contains study drug or placebo, to reveal the inner panel which will not include 
this specification.  
 
The drug will be stored at the site in a locked storage area with controlled temperature 
(59°- 86° F). 
 
At each in-person visit and following each telephone visit, participants will receive a 20 
day supply of study drug, which will ensure that participants have an adequate supply 
of study drug until their next visit.   
 
8.2 Dosage of Study Drug 
 
The study drug will be administered orally.  Participants will initially receive buspirone 
7.5 mg or matching placebo twice daily.  Investigators will evaluate the participants at 
two-week intervals and make dosage adjustments as necessary and tolerated up to a 
maximum of 30 mg twice daily to achieve an optimal dosage that balances efficacy 
with tolerability.  The investigator will be allowed to decrease the dosage or not 
escalate the dosage if there are adverse events.  The titration schedule and 
parameters for dosage adjustment are detailed in section 5.1.   
 
In the event of study drug discontinuation due to treatment with a disallowed 
medication, the study drug may be re-started following discontinuation of the 
disallowed medication and the same titration schedule and parameters for dosage 
adjustment should be followed (as specified in section 5.1.2). 
 
8.3 Participant Enrollment/Randomization 
 
We will use computer-generated randomization with participants randomized in a 4:1 
ratio to study drug or placebo.  Randomization will be managed by the statistician. 
 
8.4 Accountability of Investigational Supplies 
 
The Investigational Drug Service and on-site personnel will share responsibility for 
control of the study drug.  The Investigational Drug Service will be responsible for 

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dispensing labeled supplies of study drug to the study site.  The study coordinator will 
be responsible for acknowledging the receipt of study drug within 48 hours.  The study 
coordinator and Investigational Drug Service will maintain accurate records of all 
supplies dispensed/received.  Prior to dispensation to the participant, an un-blinded 
study team member will remove the outer panel of the double panel label on the drug 
bottle(s) and place this on the Drug Dispensing/Return Log.  The un-blinded study 
team member will be a study coordinator who will not have any role in data collection.  
All study drug supplies issued to, used by, and returned by each participant must be 
recorded on the Drug Dispensing/Return Log.  Participants will return all unused study 
drug, including empty bottles.  After reconciliation, all remaining study supplies may be 
destroyed as per institutional policy. 
 
The Investigational Drug Service and study coordinators will communicate regularly 
regarding study drug supply.   
 
8.5 Participant Withdrawal of Study Drug 
 
Participants who discontinue study drug and do not withdraw their consent, will 
continue to be followed in the study.   
 
8.6 Emergency Drug Disclosure 
 
The study team will be provided with individually sealed envelopes for each participant 
containing the treatment assignment.  All sealed envelopes will be returned to the 
statistician at the conclusion of the study and will be inspected to ensure that they 
have not been opened.  A participant’s envelope should be opened only in the event of 
a medical emergency.  Treatment assignment may be revealed if the investigator feels 
that study drug discontinuation is insufficient and knowledge about treatment 
assignment and/or dosage is required to ensure the safety of the participant.  If a drug 
disclosure is made, a record must be made by the investigator detailing the purpose, 
date, and personnel involved.  The participant will be withdrawn from further exposure 
to study medication.  In accordance with the intention-to-treat principle, these 
participants will be encouraged to remain in the study and every attempt will be made 
to continue to follow them and obtain data. 
 
9 SAFETY AND REPORTABLE EVENTS 
 
Buspirone is FDA-approved for the treatment of generalized anxiety disorder with a well-
established side effect profile, with common adverse events (>5%) including dizziness, 
drowsiness, nausea, and headache.  Package insert information for buspirone can be 
found at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-190_BuSpar_Prntlbl.pdf 
and is also included in RSRB application section 50.1.  There is some data to suggest 
that buspirone may cause worsening of PD motor function and this will be monitored 
with the use of the MDS-UPDRS motor scale.  Hypertensive crisis has been reported 
and concomitant MAOI use will be prohibited.  There have been case reports of possible 
serotonin syndrome in patients receiving buspirone and fluoxetine,63 sertraline,64 
citalopram,65 and fluvoxamine.66  However, buspirone is commonly co-prescribed with 
SSRIs and in a study examining buproprion versus buspirone for augmentation of 
citalopram for treatment of depression, 286 participants were randomized to the 
buspirone-citalopram arm and there were no reports of serotonin syndrome.25  All 

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participants will be monitored closely. 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 dosage or 
to discontinue the study drug.  Participants will be able to withdraw from the study at any 
time. 
 
9.1 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. 
 
9.2 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. 
 
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   
 
9.3 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 

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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.  
 
9.4 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 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.   
 
 
9.5   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 
 
       9.6    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 

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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 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). 
 
 
10 RISK/BENEFIT ASSESSMENT 
 
10.1  Potential Risks 
 
Potential risks of participating in the study include side effects of therapy.  The most 
common side effects of buspirone include dizziness, drowsiness, headaches, nausea, 
and nervousness.  10% of those who participated in premarketing clinical efficacy trials 
for BuSpar stopped treatment as a result of an adverse event (label).  In placebo-
controlled clinical trials the most common adverse events were: dizziness (12%), 
drowsiness (10%), nausea (8%), headache (6%), nervousness (5%), fatigue (4%), 
insomnia (3%), lightheadedness (3%), dry mouth (3%), weakness (2%), numbness 
(2%), abdominal/gastric distress (2%), diarrhea (2%), blurred vision (2%), depression 
(2%), confusion (2%), anger/hostility (2%), excitement (2%), and decreased 
concentration (2%) (label). Some studies have shown worsening of PD motor function 
with buspirone treatment. However, in the two largest studies this occurred only with 
dosages higher than 60 mg/day,49.50 which will not be used in this study, and it is only 
in a small (n=5) open-label study where worsening of PD motor function was reported 
with lower dosages.30  There are case reports of possible serotonin syndrome 
occurring with concomitant SSRI use61-64, however, in clinical practice buspirone and 
SSRIs are commonly co-prescribed  All participants will be monitored closely.  The 
participant’s anxiety may not improve or may worsen during the course of the study.  
Participants will be encouraged to contact the investigators at any time if there is 
concern about worsening anxiety or adverse events. 
 

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Participants will also be forgoing the initiation of other potential treatment options, 
including medications and non-pharmacological therapy, for the duration of the trial.   
Although there is currently insufficient evidence to guide the choice of therapy in the 
treatment of anxiety in Parkinson’s disease, there is evidence to support the use of a 
variety of different anxiolytics as well as non-pharmacological therapy options in the 
general population, and these are often offered as treatment options in clinical 
practice.  Participants may experience a lack of improvement or worsening of anxiety 
during the trial. 
 
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.  Breach of confidentiality is a potential risk.  If a breach of 
confidentiality occurs, the participant(s) will be immediately notified and appropriate 
steps will be taken to minimize the risk of a future breach of confidentiality occurring. 
 
10.2 Protection Against Risks 
 
To minimize the risk of side effects, we will follow the recommended titration schedule 
for buspirone.  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/placebo dosage or to discontinue 
the study drug/placebo.  Participants will be able to withdraw from the study at any 
time. 
 
Participants in either the study drug or placebo arm may experience worsening of their 
anxiety.  If a participant develops suicidal ideation, which is deemed severe enough by 
an investigator to reflect a significant suicidal risk, we will terminate the participant from 
the study and we will immediately refer the patient to a mental health provider for 
treatment.  The investigator will determine the most appropriate referral, which may be 
referral to an outpatient mental health provider or referral to the Comprehensive 
Psychiatric Emergency Program.  Participants and their caregivers will be encouraged 
to contact the investigators at any time if there is concern about worsening anxiety.  As 
detailed in section 5.1, investigators will re-evaluate the dosage every two weeks and 
make dosage adjustments as necessary and tolerated up to a maximum of 30 mg 
twice daily to achieve an optimal dosage that balances efficacy with tolerability.  If, in 
the opinion of either the participant or the investigator, the level of anxiety is resulting 
in a degree of emotional distress or impairment considered to be unacceptable, the 
participant’s participation in the study will be terminated and the subject will be referred 
immediately to a mental health provider for treatment. 
 
Un-blinding of treatment assignment can occur if it is medically required to reveal a 
participant’s actual treatment.  This should only occur in consultation with the principal 
investigator unless there is a medical emergency and the principal investigator cannot 
be immediately reached.  There are very few reasons (eg. medication overdose) that 
medically require such un-blinding and worsening of baseline anxiety would not in and 
of itself be considered sufficient cause for un-blinding. 
 
To minimize the risks of breach of confidentiality, study data will be collected using the 
University of Rochester’s REDCap (Research Electronic Data Capture) system, 
designed specifically for use in research, which restricts access to study data.  

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REDCap servers are housed in a local data center at the University of Rochester and 
all web-based information transmission is encrypted.  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.  All study documents will be reviewed for consistency 
and completeness when entered into the REDCap database.  Each eligible participant 
will be assigned a unique subject identifier.  Data will be collected in a de-identified 
manner.  The log linking subject identifiers to identifying participant information will be 
destroyed once study data have been fully verified by study investigators.  Any paper 
documents will be stored in locked filing cabinets.  The screening log will be destroyed 
once study recruitment has been completed and study data have been fully verified by 
study investigators.  
 
All study personnel will be appropriately trained in the administration of study 
assessments. 
 
10.3 Potential Benefits to Subjects 
 
Participants may experience an improvement in anxiety as a result of participation in 
this study, however, buspirone is readily available and may be prescribed in the 
context of routine clinical care. 
 
10.4 Alternatives to Participation 
 
Patients who decline to participate in the study will receive routine clinical care. 
 
11 CONFIDENTIALITY OF DATA AND INFORMATION STORAGE  
 
Each participant will be assigned a unique subject identifier.  Study data will be collected 
using the University of Rochester’s REDCap system, designed specifically for use in 
research, which restricts access to study data to individuals granted access.  All records 
pertaining to the study will be kept in a secure location with limited access and destroyed 
according to institutional guidelines.   
 
Clinical information will not be released without written permission of the participant, except 
as necessary for monitoring by the IRB, OHSP, the sponsor, or the sponsor’s designees.  
An intentional breach of confidentiality may occur if the investigator feels that the participant 
represents a risk to him or herself or others as is standard medical practice. 
 
12 RESEARCH INFORMATION IN MEDICAL RECORDS 
 
Information concerning participation in this study will be included in the participant’s medical 
record. 
 
13 DATA ANALYSIS AND MONITORING 
 
13.1  Sample Size Determination 
 
The primary outcome for tolerability is the proportion of participants who fail to 
complete the 12-week study on study drug (intolerability).  This study uses a single-

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arm futility design to determine the tolerability of buspirone by comparing the observed 
intolerability rate 
E) against an intolerability rate that would be unacceptably high 
O).  20% represents a reasonable value for unacceptably high intolerability 
O).  
Our null hypothesis is that buspirone is tolerable and 
E ≤ 
O.  Our alternative 
hypothesis is that buspirone is intolerable and that 
E > 
O.  A sample size of 21 will 
provide 80% power to reject the null hypothesis of tolerability (observed intolerability 
≤20%) in favor of the alternative hypothesis of intolerability (observed intolerability 
>20%) if the true intolerability is greater than 40%, using a binomial test and a one-
tailed significance level of 10% significance.  With the introduction of a placebo arm for 
blinding and relying on a 4:1 allocation ratio, the desired sample size increases to 27.  
We are willing to accept a higher chance that we declare an intolerable drug tolerable 
as the expected intolerabilities (headache, nausea, drowsiness, dizziness, and 
temporary worsening of PD motor function) are not expected to be serious and could 
be confirmed in larger studies.  We are more concerned about declaring a truly 
tolerable drug intolerable and not moving forward with larger studies. 
 
13.2 Planned Statistical Analysis 
 
The primary outcome for tolerability is the proportion of participants who fail to 
complete the 12-week study on study drug, as described in Sample Size and 
Accrual. The number of participants who fail to complete the study on study drug will 
be determined and if 7 or more participants fail to tolerate the study drug, the null 
hypothesis will be rejected.  Participants who do not complete the study on study drug 
for any reason will be considered as experiencing intolerability for purposes of the 
primary analysis.   
 
As a secondary analysis we will calculate the number of participants who fail to 
complete the study on study drug due to adverse events; separating them from those 
who fail to complete the study on study drug for alternative reasons.  We will also 
calculate the number of participants who required dosage reductions during the study 
and use descriptive statistics to describe the average study drug dosage and dosage 
reductions. 
 
Safety analyses will include tabulating adverse events by treatment group and severity 
and codifying the relationship to study drug.  Serious adverse events attributable to 
buspirone treatment will be described in detail.  Adverse event incidence will be 
summarized along with the corresponding 95% two-sided confidence interval.  The 
mean change in MDS-UPDRS motor score and from baseline to 12 weeks will be 
calculated.  We will use descriptive statistics to characterize the range and variability of 
study drug dosages.   
 
Secondary outcomes related to anxiety will include the mean change in HAM-A score 
from baseline to 12 weeks, mean change in HADS score from baseline to 12 weeks 
and the proportion of participants “much improved” or “very much improved” on CGI-I, 
proportion “much improved” or “very much improved” on PGI-I, and proportion of 
responders (>50% reduction from baseline or reduction to ≤7 in HAM-A) at 12 weeks.  
The secondary outcome regarding levodopa-induced dyskinesias will be the mean 
change in UDysRS score from baseline to 12 weeks.  Similar analyses will be done for 
all outcomes at 2 weeks, 4 weeks, and 8 weeks.  For participants lost to follow up, the 

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last observation carried forward will be used. We will also correlate mean change in 
the Parkinson Anxiety Scale scores with mean change in the CGI-I and PGI-I scores. 
 
13.3 Data and Safety Monitoring 
 
The principle investigator will be responsible for the overall conduct of this small, 
phase 2, single-center tolerability study.  A neurologist, who is not involved in the 
conduct of the study, will be appointed to independently monitor the safety of study 
participants and validity and integrity of the data.  If a serious adverse event occurs, a 
detailed report will be sent to the independent monitor.  The independent monitor will 
periodically review the study; including appropriateness of participant inclusion, 
protocol adherence, adverse events, and completion of data forms.  Following study 
initiation, a comprehensive review will occur following enrollment of the first 5 
participants and then every six months or more frequently if deemed necessary by the 
independent monitor.  Adverse events will be reviewed by the independent monitor 
every 3 months.  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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14 REFERENCES 
                                                     
 
 
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study of the Hamilton anxiety rating scale, the Beck anxiety inventory, and the hospital anxiety and 
depression scale.  Movement Disorders.  2011; 26: 407-415. 
3 Leentjens, AFG, Dujardin K, Marsh L, et al.  Symptomatology and markers of anxiety disorders in 
Parkinson’s disease: a cross-sectional study.  Movement Disorders.  2011;26: 484-492. 
4 Nuti A, Ceravolo R, Piccinni A, et al.  Psychiatric comorbidity in a population of Parkinson’s disease 
patients.  European Journal of Neurology.  2004;11: 315-320. 
5 Pontone GM, Williams JR, Anderson KE, et al.  Prevalence of anxiety disorders and anxiety subtypes in 
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6 Barone P, Antonini A, Colosimo C, et al.  The Priamo study: a multicenter assessment of nonmotor 
symptoms and their impact on quality of life in Parkinson’s disease.  Movement Disorders.  2009;24: 
1641-1649. 
7 Rahman S, Griffin HJ, Quinn NP, et al.  Quality of life in Parkinson’s disease: the relative importance of 
the symptoms.  Movement Disorders.  2008;23: 1428-1434. 
8 Duncan GW, Khoo TK, Yarnall AJ, et al.  Health-related quality of life in early Parkinson’s disease: the 
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