Conditions: Parkinsons Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The purpose of this study is to see if the study drug, Mirabegron, is safe and effective in treating symptoms of Overactive Bladder in people with Parkinson's Disease.

Detailed description:
This study is a randomized 1:1 placebo-controlled 10-week study of Mirabegron as add-on therapy to an educational intervention of behavioral modification including pelvic floor exercise (PFE) in a cohort of 40 Parkinson's subjects over the age of 30 with overactive bladder (OAB). Active drug will be Mirabegron 25 mg daily with up-titration to 50 mg daily after 5 weeks. Subjects will be enrolled based on response to an overactive bladder questionnaire at visit 2.

Enrolled subjects will have 4 study visits to the clinic as well as 2 phone visits.

Enrolled subjects will be asked to record urinary symptoms and pelvic floor exercises in a diary at 3 separate time points for a 72 hour period.

Arms:
arm 1: 1:1 randomization to receive Mirabegron 25 mg daily or placebo at visit 2. At visit 3 all subjects who have tolerated Mirabegron 25 mg daily (no adverse events on this dose) will be up-titrated to Mirabegron 50 mg daily. This will be dispensed as two 25mg tablets or, for those in the placebo arm, two placebo tablets. arm 2: 1:1 randomization to receive Mirabegron 25 mg daily or placebo at visit 2. At visit 3 all subjects who have tolerated Mirabegron 25 md daily (no adverse events on this dose) will be up-titrated to Mirabegron 50 mg daily. This will be dispensed as two 25mg tablets or , for those in the placebo arm, two placebo tablets.

Interventions: intervention 1: Mirabegron intervention 2: Placebo
Intervention descriptions: intervention 1: 25 mg po daily for 32-40 days. Following up-titration to 50 mg po daily. This is pending no adverse events on the 25 mg dose. intervention 2: Placebo 25 mg po daily. Following up-titration to 50 mg po daily. This is pending no adverse events on the 25 mg dose.

Protocol document:
Prot_000.pdf: 
Confidential**  Daniel J. Burdick, MD 
 
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Protocol DBPA-2013-01; Mirabegron and PFE for OAB in PD; 
version: 2.0 April 23 2014 
 
 
Page 1 
A Pilot Study of Mirabegron and Behavioral Modification 
including Pelvic Floor Exercise for Overactive Bladder in 
Parkinson Disease (MAESTRO) 
Co-Principal 
Investigators 
Daniel J. Burdick, MD 
Pinky Agarwal, MD 
 
Sub-Investigators 
Ted Brown, MD, MPH 
Alida Griffith, MD 
 
Affiliation  
Booth Gardner Parkinson’s Care Center & MS Center at Evergreen 
EvergreenHealth Neuroscience Institute 
EvergreenHealth, Kirkland, WA  
Phase  
IV 
 
Protocol No. 
DBPA-2013-01 
 
Contact 
Daniel J. Burdick, MD 
Booth Gardner Parkinson’s Care Center 
12039 NE 128th St, Ste 300 
Kirkland, WA 98034 
Ph: 425-899-3108 
Fax: 425-899-3114 
djburdick@evergreenhealth.com 
 
 
 
 


Confidential**  Daniel J. Burdick, MD 
 
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2. 
SYNOPSIS 
 
STUDY DRUG:  
 
Mirabegron 25-50 mg daily 
STUDY TITLE:  
 
A pilot study of Mirabegron and behavioral modification including pelvic 
floor exercise for overactive bladder in Parkinson Disease (PD) 
STUDY OVERVIEW: 
This study is a randomized 1:1 placebo-controlled 10-week study of 
mirabegron as add-on therapy to an educational intervention of behavioral 
modification including pelvic floor exercise (PFE) in a cohort of 40 PD 
subjects over the age of 30 with overactive bladder (OAB).    Active drug 
will be mirabegron 25 mg daily with up-titration to 50 mg daily after 5 
weeks.  Subjects will be enrolled based on response to an overactive 
bladder questionnaire at baseline –visit 2. Voiding diaries (72-hr) will be 
utilized following the screening visit and phone visits 1 and 2. In the 
diaries, subjects will record the time of each micturition and/or urgency 
episode, urine volume with each void, any episode of incontinence, and the 
severity of urgency (according to the scale used in the Overactive Bladder 
Symptom Composite Score, OAB-SCS): 1 = no urgency (normal voiding); 
2 = mild (could postpone voiding for as long as necessary without fear of 
incontinence); 3 = moderate (could postpone voiding for a short while 
without fear of leakage); 4= severe (could not postpone, had to rush to the 
toilet); 5= urgency incontinence (could not make it to the toilet without 
some leakage).    
 
Diaries will also record pelvic floor exercises. Primary outcome will be 
change in mean daily OAB-SCS (summation of all urgency scores 
recorded at all voids throughout the 72hr diary recording averaged over 3 
days), visit 4 vs. baseline.  
 
STUDY HYPOTHESIS: 
 
 
Treatment with Mirabegron will improve urinary urgency control beyond 
that achieved with pelvic floor exercises alone. 
STUDY SUBJECTS: 
 
40 subjects with Parkinson disease and OAB complaints.   
DESIGN:  
Multiple-dose, randomized, placebo-controlled prospective, single-site, 
investigator-initiated trial. 
DURATION OF STUDY: 
 
10 weeks (active treatment) 
TREATMENT REGIMEN: 
 
Group A will receive Mirabegron 25mg daily; at visit 3, those who up-
titrate will receive two 25mg tablets 
Group B will receive placebo; at visit 3, those who up-titrate will receive 
two placebo tablets 
Group A and B will receive the same baseline education in pelvic floor 
exercise based on viewing of an instructional PowerPoint presentation plus 
take-home printed material. 


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TREATMENT PERIOD: 
 
Treatment Period: 
• Screening =  Screening to baseline (1-2 weeks) 
• Active period = Baseline to final visit (10-12 weeks) 
Number of Visits: 4 (screening, randomization, visit 3 (titration) and visit 4 
(final) 
Two phone visits. Phone visit 1 at 7-14 days post visit 1. Phone visit 2 at 
70-74 days post visit 2 
 
 
INCLUSION AND EXCLUSION 
CRITERIA: 
Inclusion Criteria 
• Diagnosis of PD by UK brain bank criteria 
• Age > 30 years old 
• No change in PD medications during the 4 weeks preceding 
screening, with no dose changes during the study, except that PRN 
(as needed) doses of carbidopa/levodopa will be allowed to address 
periodic worsening of parkinsonian symptoms.  
• Patient willing and able to complete micturition diary 
• Urinary urgency (≥ 8 entries of bladder urgency score > 2) in 72hr 
voiding diary during screening period 
• Micturition frequency ≥ 8 / 24hr or incontinence ≥ 2 episodes in 
72hr voiding diary during screening period 
• Use of other medication that could influence bladder function, other 
than those specifically prohibited (see below), will be permitted as 
long as the dose is stable for 4 weeks preceding screening, with no 
dose changes during the study. 
• Patient expects to have valid health insurance for the duration of 
the study period 
 
Exclusion Criteria 
• Women who are breast-feeding, pregnant or have potential to 
become pregnant during the course of the study (fertile and 
unwilling/unable to use effective contraceptive measures). 
• Cognitive deficits that in the opinion of the investigator would 
interfere with the subject’s ability to give informed consent or 
perform study testing. 
• Screening blood pressure > 165 systolic or 100 diastolic 
• Heart rate > 100 
• History of allergy to Mirabegron.   
• Screening post-void residual > 200ml 
• Evidence of urinary tract infection at screening 
• History of chronic inflammation such as interstitial cystitis, bladder 
stones, previous pelvic radiation therapy, or previous or current 
malignant disease of the pelvic organs 
• Intravesical botulinum toxin treatment within the previous six 


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months of screening. 
• Presence of Interstim device 
• Use of indwelling catheter or self-catheterization 
• Concurrent use of thioridizine, flecainide, propafenone, or Digoxin 
• Concurrent use of warfarin (Coumadin) 
• Use of one of the anti-cholinergic bladder medications specified 
below within 14 days of the screening visit. Subjects who have 
used one of these medications in the past but discontinued it at least 
14 days prior to the screening visit can be enrolled. 
• Screening estimated glomerular filtration rate (eGFR) < 60, AST  
or ALT > 2x upper limit of normal 
• Any other serious and/or unstable medical condition 
• Participation in other drug studies or use of other investigational 
drugs within 30 days prior to Screening Visit. 
 
PROHIBITED MEDICATIONS: 
Warfarin (Coumadin) 
Thioridizine 
Flecainide 
Propafenone 
Digoxin 
Intravesical botulinum toxin 
Anticholinergic bladder agents 
    Darifenacin (Enablex) 
    Fesoteridine (Toviaz) 
    Flavoxate (Urispas) 
    Oxybutynin (Ditropan, Ditropan XL, Oxtyrol, Uromax, Apo-     
    Oxybutynin, Riva-Oxybutynin, Cystrin) 
    Solifenacin (Vesicare) 
    Tolterodine (Detrol, Detrol LA, Detrusitol, Unidet) 
    Trospium (Sanctura, Sanctura XR) 
 
LOCATION: 
 
 
 
Booth Gardner Parkinson’s Care Center 
EvergreenHealth 
Suite 300 
12039 Northeast 128th Street 
Kirkland, Washington 98034, United States 
 
Ph: 425-899-3123 Fax: 425-899-3114 
 
NO. OF SUBJECTS: 
 
N= 40.  This will include 20 subjects taking Mirabegron and 20 subjects 
taking placebo.   
 


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EFFICACY 
(Outcome measures): 
 
Primary Outcome Measure 
Change in mean daily OAB-SCS, visit 4 vs. baseline. 
 
Secondary Outcome Measures based on voiding diary 
• Change in mean daily OAB-SCS, Visit 3 vs. baseline 
• Mean number of micturitions per 24 hours, Visit 3 and Visit 4 vs. 
baseline 
• Mean number of incontinence episodes per 24 hours, Visit 3 and 
Visit 4  vs. baseline 
• Mean volume voided per micturition, Visit 3  and  Visit 4 vs. 
baseline 
 
Secondary Outcome Measures based on clinic visits 
• Overactive Bladder questionnaire symptom severity scale (OAB-q), 
Visit 3 and Visit 4 vs. baseline 
• Non-Motor Symptoms Scale (NMSS), which includes questions 
about cognition, psychosis, and constipation, in addition to urinary 
symptoms; Visit 3 and Visit 4 vs. baseline. 
• Patient Perception of Bladder Condition at Visit 3 and Visit 4 vs. 
baseline 
• Subject’s Global Impression of Change at Visit 3 and Visit 4 vs. 
baseline 
STATISTICAL METHODS: 
Demographics and baseline disease characteristics, including age, gender, 
duration of disease, modified Hoehn and Yahr stage, MDS-UPDRS motor 
(part 3) subscore, PD medications including levodopa-equivalent daily 
dose (LEDD), and other medications for OAB will be compared between 
study groups. 
 
LEDD will be calculated according to standardized formulae (Tomlinson 
2010). 
 
Analysis of primary and secondary outcome measures will include: 
• Summary statistics (n, mean, standard deviation, median, 
minimum and maximum) at baseline, visit 3 and visit 4 by 
treatment.  
• Summary of % change from baseline to visit 3 and 4. 
• Significance testing 
 
The primary time points for all comparative measures will be Baseline 
Visit (Visit 2), Titration Visit (Visit 3) and Final Visit (Visit 4). Outcome 
measures will be compared between groups using analysis of covariance 
(ANCOVA) or other method as deemed appropriate by the consulting 
statistician. Demonstration of superiority will depend on achieving 
statistical significance for the primary endpoint. Level of significance will 
be defined as p = 0.05. All statistical tests will be two-sided. Statistical 


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assistance will be provided by a statistician consultant whose company is 
contracted with EvergreenHealth and whose services we have used on 
recent studies in PD. 
 
This is an exploratory study.  Therefore, a small sample size is appropriate.  
Any treatment effect could be used to power a future larger study.  
 
SAFETY: 
 
Female subjects will undergo urine pregnancy testing if they are deemed to 
have any risk of being pregnant or becoming pregnant during the study.  
Baseline assessment of CBC, CMP, urinalysis, urine culture, and post-void 
residual will be conducted to address exclusion criteria. 
 
Adverse Event Monitoring:  
• This will be assessed at phone visits, visit 3 and 4 and continuously 
through phone contact and unscheduled visits as needed (see 
below) 
• Additionally, post-void residual will be assessed at screening, visit 
3, and visit 4 to screen for urinary retention as an adverse event. 
 
Subjects will be monitored for adverse events throughout the trial. The 
occurrence of adverse events will be ascertained by observation, telephone 
monitoring if subjects call in, and by questioning by the investigator. 
Safety assessments will consist of monitoring and recording all adverse 
events, including serious adverse events. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting 
study drug (or therapy). Medical conditions/diseases present before starting 
study treatment are only considered adverse events if they worsen after 
starting study treatment.  
 
Adverse events include adverse drug reactions, illness with onset during 
the study, exacerbations of pre-existing conditions or clinically significant 
changes in physical examination or significantly abnormal objective test 
findings.  All adverse events will be recorded and graded as mild, moderate 
or severe by the principal investigator in accordance with general 
guidelines of clinical research.   
 
A serious adverse event is an undesirable sign, symptom or medical 
condition which: 1. is fatal or life-threatening, 2. requires or prolongs 
hospitalization, 3. results in persistent or significant disability/incapacity, 
4. constitutes a congenital anomaly or a birth defect, 5. is medically 
significant, in that it may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed above. If any 
serious adverse events occur, the treatment status of the subject(s) may be 
revealed, as clinically indicated.  Subjects who discontinue medication use 


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will be followed for adverse events until reaching the termination of 
adverse events.  The frequency of adverse events (AE) will be under 
continuous scrutiny during the observation with comparison to AE rates 
that have been recorded in published PD drug trials.   
 
SCHEDULE OF EVENTS: 
Refer to the Schedule of Events for timing of procedures 
STUDY TIMELINE: 
Start-up 2 months, period of enrollment 24 months, data analysis and final 
report 3 months 
 
 


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3. 
TABLE OF CONTENTS 
 
1. TITLE PAGE 
 
 
 
 
 
 
 
 
 
  1 
 
2. SYNOPSIS  
 
 
 
 
 
 
 
 
 
  2 
 
3. TABLE OF CONTENTS  
 
 
 
 
 
 
 
  8 
 
4. LIST OF ABBREVIATIONS 
 
 
 
 
 
 
 
10 
 
5. INTRODUCTION (BACKGROUND AND RATIONALE) 
 
 
 
11 
 
5.1 OAB Symptoms in PD 
 
 
 
 
 
 
 
11 
 
5.2 Pelvic Floor Exercises (PFE) in PD 
 
 
 
 
 
11 
 
5.3 Mirabegron for OAB 
 
 
 
 
 
 
 
12 
 
6. STUDY OBJECTIVES 
 
 
 
 
 
 
 
 
12 
 
6.1 Primary Objective  
 
 
 
 
 
 
 
12 
 
6.2 Secondary Objectives 
 
 
 
 
 
 
 
12 
 
7. INVESTIGATIONAL PLAN 
 
 
 
 
 
 
 
13 
 
7.1 Overall Study Design 
 
 
 
 
 
 
 
13 
 
7.2 Enrollment 
 
 
 
 
 
 
 
 
14 
 
7.3 Screening (Visit 1) 
 
 
 
 
 
 
 
14 
 
7.4 Baseline (Visit 2) Treatment Initiation   
 
 
 
 
14
 
 
 
 
 
 
7.4.1 Confirmation of Eligibility 
 
 
 
 
 
14 
 
 
7.4.2 Baseline Assessments  
 
 
 
 
 
15 
 
 
7.4.3 Phone Visit 1 
 
 
 
 
 
 
 
15 
 
7.5 Treatment Initiation 
 
 
 
 
 
 
 
15 
 
 
7.5.1 Visit 3 (Titration)  
 
 
 
 
 
 
15
 
 
 
 
 
7.5.2 Phone Visit 2 
 
 
 
 
 
 
 
15 
 
7.6 Final Assessment (Visit 4) 
 
 
 
 
 
 
16 
 
7.7 Unscheduled Visits 
 
 
 
 
 
 
 
16 
 
8. STUDY POPULATION 
 
 
 
 
 
 
 
 
16 
 
8.1 Inclusion Criteria  
 
 
 
 
 
 
 
16 
 
8.2 Exclusion Criteria  
 
 
 
 
 
 
 
16 
 
8.3 Removal of Patients from Study  
 
 
 
 
 
17 
 
8.4 Screen Failures / Rescreening 
 
 
 
 
 
 
18 
 
9. TREATMENTS 
 
 
 
 
 
 
 
 
 
18 
 
9.1 Pelvic Floor Exercise (PFE) Educational Material 
 
 
 
18 
 
9.2 Investigational Drug 
 
 
 
 
 
 
 
18 
 
9.3 Randomization and Blinding 
 
 
 
 
 
 
19 


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9.4 Concomitant Therapy 
 
 
 
 
 
 
 
19 
 
9.5 Treatment Compliance 
 
 
 
 
 
 
 
19 
 
10. DESCRIPTION OF ASSESSMENTS 
 
 
 
 
 
 
20 
 
10.1 Safety Monitoring 
 
 
 
 
 
 
 
20 
 
 
10.1.1 Physical Examination  
 
 
 
 
 
20 
 
 
10.1.2 Vital Signs 
 
 
 
 
 
 
 
20 
 
 
10.1.3 Laboratory Evaluations 
 
 
 
 
 
20 
 
 
10.1.4 Pregnancy Status 
 
 
 
 
 
 
20 
 
 
10.1.5 Post-Void Residual 
 
 
 
 
 
 
20 
 
 
10.1.6 Adverse Events 
 
 
 
 
 
 
20 
 
 
10.1.7 Serious Adverse Events 
 
 
 
 
 
22 
 
 
 
10.1.7.1 Serious Adverse Events Reporting  
 
 
22 
 
10.2 Efficacy Assessments 
 
 
 
 
 
 
 
22 
 
 
10.2.1 OAB-SCS 
 
 
 
 
 
 
 
22 
 
 
10.2.2 Voiding Diary  
 
 
 
 
 
 
23 
 
 
10.2.3 OAB-q  
 
 
 
 
 
 
 
23 
 
 
10.2.4 NMSS  
 
 
 
 
 
 
 
23 
 
 
10.2.5 PPBC  
 
 
 
 
 
 
 
24 
 
 
10.2.6 SGI-C  
 
 
 
 
 
 
 
24 
 
11. DATA MANAGEMENT AND STATISTICAL ANALYSIS 
 
 
 
24 
 
11.1 Sample Size Considerations 
 
 
 
 
 
 
24 
 
11.2 Study Population 
 
 
 
 
 
 
 
24 
 
11.3 Baseline and Demographic Characteristics 
 
 
 
 
24 
 
11.4 Safety Analysis  
 
 
 
 
 
 
 
25 
 
11.5 Efficacy Analysis 
 
 
 
 
 
 
 
25 
 
12. STUDY MANAGEMENT 
 
 
 
 
 
 
 
25 
 
12.1 Ethics and Good Clinical Practice 
 
 
 
 
 
25 
 
12.2 Informed Consent 
 
 
 
 
 
 
 
25 
 
13. REFERENCES 
 
 
 
 
 
 
 
 
 
26 
 
14. APPENDICES 
 
 
 
 
 
 
 
 
 
28 
 
 


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4. 
LIST OF ABBREVIATIONS 
AE 
 
 
adverse event 
ALT 
 
 
alanine aminotransferase 
ANCOVA 
 
analysis of covariance 
AST 
 
 
aspartate aminotransferase 
BP 
 
 
blood pressure 
CBC  
 
complete blood count 
CMP  
 
complete metabolic panel 
eGFR  
 
estimated glomerular filtration rate 
FDA  
 
United States Food & Drug Administration 
GCP  
 
good clinical practice 
HEENT 
 
head, eyes, ears, nose, & throat 
hCG 
 
 
human chorionic gonadotropin 
HR 
 
 
heart rate 
HY 
 
 
Hoehn & Yahr 
ICF 
 
 
informed consent form 
ICH 
 
 
International Conference on Harmonisation 
IRB 
 
 
institutional review board 
LEDD  
 
levodopa-equivalent daily dose 
LUTS  
 
lower urinary tract symptoms 
MDS  
 
Movement Disorder Society 
MDS-UPDRS  
MDS’ Unified Parkinson Disease Rating Scale 
NMSS  
 
non-motor symptom assessment scale for PD 
OAB  
 
overactive bladder 
OAB-q 
 
OAB questionnaire symptom severity scale 
OAB-SCS 
 
OAB symptom composite score 
PD 
 
 
Parkinson disease 
PFE 
 
 
pelvic floor exercise 
PPBC  
 
patient perception of bladder condition 
PVR  
 
post-void residual 
RR 
 
 
respiratory rate 


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SAE 
 
 
serious AE 
SGI-C  
 
subject’s global impression of change 
U/A 
 
 
urinalysis 
UK 
 
 
United Kingdom 
 
5. 
INTRODUCTION (BACKGROUND AND RATIONALE) 
 
5.1 OAB Symptoms in PD 
 
Parkinson disease (PD) is the second most common neurodegenerative disease, behind only 
Alzheimer disease. Prevalence is estimated to be 0.3% of the general population and 1-2% of 
the population over the age of 60 (de Lau 2006, Kowal 2013). In 2005, 4 million people 
worldwide had PD, and that number is expected to more than double by 2030, to 8.7 million 
(Dorsey 2007). Estimates of prevalence in the United States vary from 340,000 (Dorsey 2007) 
to 630,000 (Kowal 2013). Prevalence in the US is expected to nearly double by 2030, with 
estimates ranging from 610,000 (Dorsey 2007) to 1.06 million (Kowal 2013) by 2030, and an 
estimate of 1.34 million by 2050 (Kowal 2013).  
 
Urinary symptoms are common in PD. Prevalence estimates of lower urinary tract symptoms 
(LUTS) in PD range from 27% to 88% depending on severity threshold, screening tool, and 
sampling methods (Araki 2000b, Sammour 2009, Winge 2006, Winge 2012). LUTS include 
nocturia, urgency, frequency, and incontinence. LUTS increase morbidity (Balash 2005) and 
decrease quality of life (Araki 2000a, Sammour 2009) in PD. 
 
Aside from the current study drug (Mirabegron), other FDA-approved oral medications for 
OAB have an anticholinergic mechanism of action. Patients with PD are especially sensitive 
to cognitive side effects of anticholinergic medications because they, by nature of their 
disease, have a significant cholinergic deficit. In addition, because of autonomic involvement 
in PD, these patients have a high rate of constipation, another symptom that may be 
significantly worsened by anticholinergic medications.  
 
5.2 Pelvic Floor Exercises (PFE) in PD 
 
There is limited research of PFE in PD. These are simple interventions that can be easily 
applied in a clinical setting (such as an educational video/handout).  One uncontrolled pilot 
study in 20 patients with PD showed a significant improvement in episodes of urinary 
incontinence from baseline to follow-up after an 8-week, 5-visit course of PFE-based 
behavioral therapy (Vaughn 2011).  
 
This design will demonstrate the effects of PFE on OAB in PD through the placebo arm of the 
study.  Because PFE are possibly effective with virtually no risk, they are the preferred first-
line intervention, but their efficacy has not been rigorously demonstrated. In addition, 


Confidential**  Daniel J. Burdick, MD 
 
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including PFE in the protocol eliminates a possible confounder, as some, but likely not all, 
patients may have received training in PFE and be practicing them on their own.   
 
5.3 Mirabegron for OAB 
 
Adding mirabegron may yield greater results than PFE alone. Mirabegron is an FDA-
approved treatment for OAB that has not been studied in Parkinson disease (PD). Importantly, 
mirabegron has a novel mechanism of action, activating Beta-3 adrenergic receptors in 
detrusor muscles (Chapple 2012). It is therefore expected to avoid anticholinergic side effects 
such as confusion, hallucinations, and constipation, to which PD patients are especially 
susceptible.  
 
In phase 3 clinical trials, mirabegron demonstrated efficacy in treating OAB symptoms in a 
general adult population. In a sample of 1978 patients, mirabegron 50 mg daily and 100 mg 
daily produced statistically significant improvements over placebo in the number of 
incontinence episodes per 24 hours and number of micturitions per 24 hours (Khullar 2013). 
Incidence of adverse events (AEs) in the groups receiving mirabegron was not significantly 
different from AEs in a group receiving tolterodine ER 4 mg daily (Khullar 2013). This 
substantiated an earlier study (Chapple 2012) that found equivalent treatment effects and AE 
profile when comparing mirabegron 50 mg and 100 mg to tolterodine ER 4 mg in a sample of 
2444 patients. This study was not placebo-controlled. Mirabegron efficacy was similarly 
demonstrated in a sample of 1329 patients (Nitti 2013), wherein mirabegron 50 mg and 100 
mg showed statistically significant improvement over placebo in incontinence episodes and 
micturitions per 24 hours. 
 
The standard starting dose of mirabegron is 25 mg daily (Prescribing Information, Astellas 
Pharma, Inc.). A higher dose of 50 mg daily is also approved for use, and titration to this dose 
will be allowed at the mid-point of the trial (after 5 weeks), as it is likely that some patients 
will respond better to the higher dosage.  
 
6. 
STUDY OBJECTIVES 
 
6.1 Primary Objective 
 
• To compare the effects of mirabegron to the effects of placebo on the change from 
baseline to Visit 4 in mean daily OAB-SCS, the summation of all OAB-SCS urgency 
scores recorded at all voids throughout a 72-hour diary recording averaged over 3 
days. 
 
6.2 Secondary Objectives 
 
Objectives based on micturition diary: 
• To compare the effects of mirabegron to the effects of placebo on the change from 
baseline to Visit 3 in mean daily OAB-SCS 


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• To compare the effects of mirabegron to the effects of placebo on the change from 
baseline to visit 3 and to visit 4 in mean number of micturitions per 24 hours 
• To compare the effects of mirabegron to the effects of placebo on the change from 
baseline to visit 3 and to visit 4 in mean number of incontinence episodes per 24 hours 
• To compare the effects of mirabegron to the effects of placebo on the change from 
baseline to visit 3 and to visit 4 in mean volume voided per micturition. 
 
Objectives based on clinic visits: 
• To compare the effects of mirabegron to the effects of placebo on the change from 
baseline to visit 3 and to visit 4 in Overactive Bladder questionnaire symptom severity 
scale (OAB-q) score 
• To compare the effects of mirabegron to the effects of placebo on the change from 
baseline to visit 3 and to visit 4 in Non-Motor Symptoms Scale (NMSS) score, which 
includes questions about cognition, psychosis, and constipation, in addition to urinary 
symptoms. 
• To compare the effects of mirabegron to the effects of placebo on the change from 
baseline to visit 3 and to visit 4 in Patient Perception of Bladder Condition (PPBC). 
• To compare the effects of mirabegron to the effects of placebo on the change from  
visit 3 and to visit 4 in Subject’s Global Impression of Change (SGI-C). 
 
7. 
INVESTIGATIONAL PLAN 
 
7.1 Overall Study Design 
 
This study is a randomized, double-blind, placebo-controlled 10-week study of mirabegron as 
add-on therapy to an educational intervention of behavioral modification including pelvic 
floor exercise (PFE) in a cohort of 40 PD subjects over the age of 30 with overactive bladder 
(OAB). Active drug will be mirabegron 25mg daily with optional up-titration to 50mg daily at 
visit 3. . Subjects will be enrolled based on response to an overactive bladder questionnaire at 
baseline –visit 2.  Voiding diaries (72-hr) will be utilized following screening visit, Phone 
visit 1, and phone visit 2. In the diaries, subjects will record the time of each micturition 
and/or urgency episode, urine volume with each void, any episode of incontinence, and the 
severity of urgency as measured by the Overactive Bladder Symptom Composite Score 
(OAB-SCS): 1 = no urgency (normal voiding); 2 = mild (could postpone voiding for as long 
as necessary without fear of incontinence); 3 = moderate (could postpone voiding for a short 
while without fear of leakage); 4= severe (could not postpone, had to rush to the toilet); 5= 
urgency incontinence (could not make it to the toilet without some leakage).    
 
Diaries will also record pelvic floor exercises. The primary outcome measure will be mean 
daily OAB-SCS (summation of all urgency scores recorded at all voids throughout the 72hr 
diary recording averaged over 3 days), visit 4 vs. visit 2-baseline. This measure accounts for 
both the frequency and the urgency components of OAB.  
 
The study is composed of 4 clinic visits and 2 phone visits over the course of 11-12 weeks. 


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7.2 Enrollment 
Subjects who may qualify for this study will be identified in the context of clinical care at the 
EvergreenHealth Neuroscience Institute. Such eligible patients may receive a copy of the 
informed consent form (ICF) at the time of their clinic visit. Recruitment may also occur 
through local promotional opportunities, referrals from other area neurologists, urologists, 
EvergreenHealth Pelvic Health Rehab, and the Washington State Parkinson Disease Registry. 
Patients may contact the EvergreenHealth Neuroscience Institute without clinic visitation after 
reading a notice about the study on the Institute’s website or other online postings. Subjects 
who are not established patients at EvergreenHealth will be offered the chance to undergo a 
telephone screening using an institutional review board (IRB) approved telephone screening 
text.  Subjects will be requested to send pertinent outside medical records for chart review by 
the principal investigator and be scheduled for a screening visit. 
 
7.3 Screening (Visit 1) 
 
Visit 1 is the screening visit. At this clinic visit, patients will provide written, informed 
consent and be assessed for eligibility (excluding those eligibility criteria requiring 
completion of the voiding diary). A history of the patient’s PD symptoms and LUTS will be 
taken, and the patient’s past medical history will be reviewed. Diagnosis of PD will be 
confirmed based on UK PD Society Brain Bank criteria (Hughes 1992). Current medication 
list will be reviewed, and a levodopa-equivalent daily dose will be calculated based on the 
patient’s current PD medication list and on published conversion factors (Tomlinson 2010). 
Eligible subjects will have a stable PD medication regimen for 4 weeks prior to the screening 
visit and remain on a stable regimen for the duration of the study. Eligible patients will also 
not be concomitantly taking any of the prohibited medications, including none of the 
prohibited bladder medications for at least 14 days prior to the screening visit. The patient’s 
history of medication allergies will be reviewed. 
 
Physical examination will be performed, both a general medical examination including vital 
signs and a neurological examination. Neurological exam will include MDS-UPDRS part 3 
evaluation and modified Hoehn and Yahr (HY) staging of PD (Goetz 2004). Post-void 
residual (PVR) will be assessed. Laboratory testing will include CBC, CMP, and urinalysis 
(U/A) by dipstick with reflex to urine culture if positive. Pre-menopausal women will have 
urine hCG measured. 
 
The voiding diary will be dispensed to the patient and training will be provided on how to 
complete the diary, including instruction on how to measure void volume. The PowerPoint 
presentation of pelvic floor exercises will also be shown to the patient and each patient will be 
provided a copy to take home.  
 
7.4 Baseline-(Visit 2) -Treatment Initiation  
 
7.4.1 Confirmation of Eligibility 
 


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Patients who are deemed eligible in the screening visit will go home to complete a 72-hour 
voiding diary and return for Visit 2 within 7-14 days after Visit 1. At visit 2, final eligibility 
will be confirmed by a review of the voiding diary. Subjects eligible to continue will have 
urinary urgency as evidenced by at least 8 episodes of urgency scores of 2 or greater in 72 
hours AND will have urinary frequency as evidenced by having EITHER 8 or more episodes 
of micturition per 24 hours averaged over 72 hours OR 2 or more episodes of urinary 
incontinence in 72 hours. In addition to confirming eligibility, the diary scoring will provide 
the baseline values of mean daily OAB-SCS, number of micturitions per 24 hours, number of 
incontinence episodes per 24 hours, and mean volume per micturition. 
 
In addition to the diary review, medications will be reviewed again to ensure stability of the 
PD medication regimen and absence of any prohibited medications. Vital signs will again be 
measured. At any visit, if a patient is found to have systolic blood pressure over 165, diastolic 
blood pressure over 100 or heart rate over 100, he or she will be withdrawn from the study. 
 
7.4.2 Baseline Assessments 
 
Following confirmation of eligibility, an eligible patient will complete the baseline 
assessments of the OAB-q, NMSS, and PPBC during Visit 2. 
 
7.4.3 Phone visit 1 
 
Phone visit 1 will take place 28-32 days after Visit 2 and no less than 72 hours prior to Visit 3. 
Patients will be prompted to resume the voiding diary for 72 hours. Screening for AEs will 
also take place during this phone visit.  
 
7.5 Treatment titration 
 
7.5.1 Visit 3 
 
Visit 3 will occur 32-40 days after Visit 2. This visit will include the same assessments as 
Visit 2, including review and entry of data in the voiding diary (mean daily OAB-SCS, 
number of micturitions per 24 hours, number of incontinence episodes per 24 hours, and mean 
volume per micturition). Visit 3 will also include review of current medication list, 
measurement of vital signs, PVR, OAB-q, NMSS, PPBC, and SGI-C. Screening for AEs will 
also take place during this visit. This will include assessment of symptoms of urinary tract 
infection and if, in the opinion of the study physician, urinalysis is indicated, dipstick will be 
performed with reflex to urine culture if positive. In pre-menopausal women, screening for 
pregnancy risk will be performed and if, in the opinion of the study physician, pregnancy 
testing is indicated, urine hCG will be measured. 
 
In addition, at Visit 3, all patients who have tolerated mirabegron 25 mg daily or matching 
placebo (no adverse events on this dose) will be up-titrated to mirabegron 50 mg daily (for 
those in the active drug arm) or matching placebo (for those in the placebo arm). This will be 
dispensed as two 25-mg tablets or, for those in the placebo arm, two placebo tablets. Only 


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those without any AE on 25 mg daily or matching placebo will be eligible to increase the 
dose.  
 
7.5.2 Phone Visit 2 
 
Phone Visit 2 will occur 70-74 days after Visit 2 and no less than 72 hours prior to Visit 4. 
Patients will be prompted to resume the voiding diary for 72 hours. Screening for AEs will 
also take place during this phone visit.  
 
7.6 Final Assessment (Visit 4) 
 
Visit 4, the final visit will occur 74-82 days after Visit 2. Visit 4 will include review and entry 
of data in the voiding diary, review of current medication list, physical examination including 
measurement of vital signs, PVR, OAB-q, NMSS, PPBC, and SGI-C. Screening for AEs will 
also take place during this visit. This will include assessment of symptoms of urinary tract 
infection and if, in the opinion of the study physician, urinalysis is indicated, dipstick will be 
performed with reflex to urine culture if positive. In pre-menopausal women, screening for 
pregnancy risk will be performed and if, in the opinion of the study physician, pregnancy 
testing is indicated, urine hCG will be measured. 
 
7.7 Unscheduled Visits 
 
Subjects may return to the clinic for safety evaluation or to receive additional study 
medication as needed. Unscheduled visits will include a review of concomitant medications 
and any adverse effects, and, if needed in the estimation of the study physician, physical 
examination in whole or in part.   
 
8. STUDY POPULATION 
 
The population for this study is PD patients with symptoms of OAB who meet all of the 
following inclusion criteria and who do not meet any of the following exclusion criteria. 
 
8.1 Inclusion Criteria 
 
An eligible patient: 
 
• Has signed and dated an IRB-approved informed consent form before any protocol-
specific screening procedures are performed. 
• Has a diagnosis of PD consistent with UK PD Society Brain Bank criteria 
• Is aged 30 years or older 
• Has had no change in PD medications during the 4 weeks preceding screening, with no 
dose changes during the study, except that PRN (as needed) doses of 
carbidopa/levodopa will be allowed to address periodic worsening of parkinsonian 
symptoms.  


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• Is willing and able to complete micturition diary 
• Has urinary urgency as defined by having 8 or more entries of bladder urgency score > 
2 in a 72-hr voiding diary during screening period 
• Has micturition frequency as defined by having 8 or more episodes of micturition per 
24 hours, averaged over 72 hours; OR by having at least 2 episodes of incontinence in 
72 hours as documented in the voiding diary during screening period 
• May use other medications that could influence bladder function, other than those 
specifically prohibited, as long as the dose is stable for 4 weeks preceding screening, 
with no dose changes during the study. 
• Has valid health insurance coverage at the time of study enrollment and expects this 
coverage to remain valid for the duration of the study period. 
 
8.2 Exclusion Criteria 
 
A patient will be excluded from the study if he or she meets any of the following: 
 
• Is a woman who is breast-feeding, pregnant, or has the potential to become pregnant 
during the course of the study (fertile and unwilling/unable to use effective 
contraceptive measures). 
• Has cognitive deficits that, in the opinion of the study physician, would interfere with 
the subject’s ability to give informed consent or perform study testing. 
• Has at screening a systolic blood pressure > 165 or a diastolic blood pressure > 100 
• Has at screening a heart rate > 100 
• Has a history of allergy to Mirabegron   
• Has at screening a post-void residual > 200ml 
• Has at screening evidence of a urinary tract infection 
• Has at screening evidence of chronic inflammation such as interstitial cystitis, bladder 
stones, previous pelvic radiation therapy, or previous or current malignant disease of 
the pelvic organs 
• Has received intravesical botulinum toxin treatment within six months prior to 
screening. 
• Has the presence of an Interstim device 
• Uses an indwelling catheter or self-catheterization 
• Concurrent use of thioridizine, flecainide, propafenone, or Digoxin 
• Concurrent use of warfarin (Coumadin) 
• Use of one of the anti-cholinergic bladder medications specified below within 14 days 
of the screening visit. Subjects who have used one of these medications in the past but 
discontinued it at least 14 days prior to the screening visit will not be excluded. 
• Has at screening an estimated glomerular filtration rate (eGFR) < 60, or AST or ALT 
> 2x upper limit of normal 
• Has any other serious and/or unstable medical condition 
• Has participated in other drug studies or has used other investigational drugs within 30 
days prior to Screening Visit 
• Prohibited anti-cholinergic bladder medications: 


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Darifenacin (Enablex) 
Fesoteridine (Toviaz) 
Flavoxate (Urispas) 
 
Oxybutynin (Ditropan, Ditropan XL, Oxtyrol, Uromax, Apo-Oxybutynin, 
Riva-Oxybutynin, Cystrin) 
Solifenacin (Vesicare) 
Tolterodine (Detrol, Detrol LA, Detrusitol, Unidet) 
Trospium (Sanctura, Sanctura XR) 
 
8.3 Removal of Patients from Study  
 
A patient will be considered to have completed the study when he or she has completed all 
study visits through the final visit. Every patient has the right to discontinue study 
participation at any time at his/her own request, or may be withdrawn at any time at the 
discretion of the investigator for safety, behavioral, or administrative reasons. Criteria for 
early termination include, but are not limited to, < 36 hours of time covered in a bladder diary, 
poor adherence to study medication (less than 70% of study medication consumed), loss of 
health insurance coverage, and safety issues related to study-related or non-study related 
adverse events.  
 
If a patient has a clinical necessity to alter their standard PD medications, the patient will be 
withdrawn from the trial so that changes may be made, except that occasional additional doses 
of carbidopa/levodopa will be allowed if needed to address periodic worsening of 
parkinsonian symptoms. Additional doses of carbidopa/levodopa taken during the 72-hour 
diary periods will be recorded in the diary. If a patient is withdrawn due to an adverse event, 
the event will be followed, when possible, until resolution. Patients who withdraw from the 
study may be replaced, but withdrawn patients will not be re-entered into the study. 
 
All data generated up to the time of discontinuation from the study will be analyzed and the 
reason(s) for discontinuation will be recorded.  
 
8.4 Screen failures / Rescreening  
 
Subjects who screen fail because they do not meet inclusion criteria or because of certain 
exclusions, e.g. presence of urinary tract infection, may rescreen after 30 days at the discretion 
of the investigator.  
 
9. 
TREATMENTS 
 
9.1 Behavioral Modification with Pelvic Floor Exercise (BM-PFE) Educational Material 
 
We will produce a 15-20 minute presentation, written by a physical therapist, utilizing a 
PowerPoint presentation.  Slides will include images such as pelvic floor anatomy as well as 
outlines of key points.  Participants will be given a paper copy of the presentation to take 


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home for reference and to help them with a home bladder exercise regimen. The following 
topics are part of this presentation:   
 
• Bladder health: What’s normal?  
• Bladder dietary irritants 
• Bladder retraining and urge delay techniques 
• Pelvic floor anatomy and function 
• How to perform a “Kegel” 
• “Kegel” home exercise program 
• Pelvic floor exercises with functional activities 
• Maintaining your home exercise program 
 
Subjects will have the opportunity to ask the study physician follow-up questions as needed. 
 
9.2 Investigational drug  
 
The study medication and matching placebo will be provided by Astellas.  The active 
medication will be mirabegron 25 mg po daily from Baseline Visit (Visit 2) to Titration Visit 
(Visit 3). At the Titration Visit, all patients who have tolerated mirabegron 25 mg daily (no 
adverse events on this dose) will be up-titrated to mirabegron 50 mg daily. This will be 
dispensed as two 25-mg tablets or, for those in the placebo arm, two placebo tablets. Only 
those without any AE on 25 mg daily or matching placebo will be eligible to increase the 
dose. The research pharmacist will dispense the active or placebo medication at randomization 
and again at the Titration Visit.  An extra 5-day supply of medication will be provided for 
each study period to allow a window for scheduling of appointments.  
 
9.3 Randomization and Blinding 
 
Following confirmation of eligibility at Visit 2, an eligible patient will be randomized in a 1:1 
randomization scheme to receive mirabegron 25 mg daily or placebo. Randomization will 
occur at the research pharmacy of EvergreenHealth using a computer-generated 
randomization list.  The pharmacist will maintain a codebook indicating the treatment 
allocation of each subject.  Study medication will be delivered by the research pharmacist to 
the research study staff from the research pharmacy (a separate locked room containing only 
research medications).  The investigating physicians, nurse and research coordinator will be 
blinded as to treatment arm until the code is broken.  The randomization code may be broken 
by the investigator only in a medical emergency. The reasons for this will be documented 
carefully. The subjects will receive identical appearing active or placebo study medication 
tablets, with identification known only to the research pharmacist. 
 
9.4 Concomitant Therapy 
 
All concomitant therapy will be documented.  Prohibited will be concurrent (defined as 
“within 14 days of screening”) use of antimuscarinics listed in Appendix 3: oxybutynin 
(Ditropan®, Ditropan XL ®, Oxytrol ®, Uromax ®, apo-oxybutynin, riva-oxybutynin, 


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Cystrin ®), tolterodine (Detrol®, Detrol LA®, Detrusitol ®, Unidet®), fesoterodine 
extended-release (Toviaz®), solifenacin (Vesicare®), trospium (Sanctura®, Sanctura XR®), 
flavoxate (Urispas®), and darifenacin extended release (Enablex®). Also prohibited will be 
concurrent use of thioridizine, flecainide, propafenone or Digoxin; and intravesical botulinum 
toxin treatment within the previous six months. Medications that are likely to influence 
bladder function may not be initiated between screening and study completion. They may be 
continued with no dose changes during the study. 
 
9.5 Treatment Compliance 
 
Patients will be asked to return all unused medication and all medication bottles, including 
empty bottles, at each visit and at the end of the study and the quantity of returned medication 
will be documented. 
 
10. DESCRIPTION OF ASSESSMENTS 
 
10.1 Safety Monitoring 
 
Safety will be monitored by adverse event (AE) reporting, physical examination, vital signs, 
laboratory evaluation, and evaluation of post-void residual. 
 
10.1.1 Physical Examination 
 
A general physical examination will be performed at Visit 1 (Screening Visit) and Visit 4 
(Final Visit). This exam will include, at minimum, HEENT, heart, lungs, abdomen, 
musculoskeletal, and neurologic systems. Subjects with a range of health conditions that may 
put the patient at risk for adverse outcomes will be excluded, as listed under Exclusion 
Criteria. 
 
10.1.2 Vital Signs 
 
Vital signs (blood pressure, heart rate, and respiratory rate) will be measured at each clinic 
visit. Subjects with BP > 165 systolic or > 100 diastolic or those with HR > 100 will be 
excluded at screening or discontinue study medication if this occurs while on study 
medication. However, they may complete other elements of the study. 
 
10.1.3 Laboratory Evaluations 
 
All subjects will undergo baseline testing with CBC, CMP, and urinalysis by dipstick with 
reflex to urine culture if positive.  Subjects with screening estimated glomerular filtration rate 
(eGFR) < 60, or AST or ALT > 2x upper limit of normal will be excluded.  
 
10.1.4 Pregnancy Status 
 


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All pre-menopausal women will have pregnancy screening with urine hCG at baseline (Visit 
1). At Visits 3 and 4, pre-menopausal women will have screening for pregnancy risk and if, in 
the opinion of the study physician, pregnancy testing is indicated, urine hCG will be 
measured. A positive urine hCG will result in discontinuation of the study drug and 
withdrawal of the subject from the study. 
 
10.1.5 Post-void Residual 
 
PVR will be measured by a bladder scan after urination at Visits 1, 3, and 4. Subjects with 
PVR > 200 mL will be excluded at screening or will discontinue study medication if this 
occurs while on study medication. Symptoms of urinary retention will be monitored 
throughout the study and may lead to early discontinuation of study medication; however, 
such subjects may complete other elements of the study.  
 
10.1.6 Adverse Events 
 
Subjects will be monitored for adverse events throughout the trial. The occurrence of adverse 
events will be ascertained by observation, telephone monitoring and questioning by the 
investigator. Safety assessments will consist of monitoring and recording all adverse events, 
including serious adverse events.  
 
An adverse event (AE) is any symptom, physical sign, or medical condition that emerges 
during the study or, if present at screening, worsens during the study, regardless of the 
suspected cause. Adverse events include adverse drug reactions, illness with onset during the 
study, exacerbations of pre-existing conditions or clinically significant changes in physical 
examination or significantly abnormal objective test findings. Medical conditions/diseases 
present before starting study treatment are only considered adverse events if they worsen after 
starting study treatment. All adverse events will be recorded and graded as mild, moderate or 
severe by the principal investigator in accordance with general guidelines of clinical research, 
outlined here: 
 
• MILD: An event that causes transient or minimal symptoms and that does not 
interfere with daily activities. 
• MODERATE: An event that causes symptoms sufficient to interfere with but not 
prevent daily activities. 
• SEVERE: An event that prevents normal, everyday activities. 
 
Adverse events will also be classified by their relationship to the study medication by the 
principal investigator in accordance with general guidelines of clinical research, outlined here: 
 
• Definitely Unrelated: The AE is definitely not related to the drug. This designation is 
reserved for those events that do not follow a reasonable temporal sequence following 
drug administration (e.g. occur prior to study treatment) or for those events that cannot 
be even remotely related to study participation. 


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• Unlikely related: There is no reasonable association between the study treatment and 
the suspected event and the event could have been produced by the patient’s clinical 
state or other therapy administered to the patient. 
• Possibly related: The suspected AE may or may not follow a reasonable temporal 
sequence from study treatment administration but seems to be the type of reaction that 
cannot be dismissed as unlikely. The event could have been produced or mimicked by 
the patient’s clinical state or other therapy administered to the patient. 
• Probably related: The suspected AE follows a reasonable temporal sequence from 
study treatment administration, abates upon discontinuation of the treatment, and 
cannot be reasonably explained by the known characteristics of the patient’s clinical 
state or other treatments. 
• Definitely related: The suspected AE follows a reasonable temporal sequence from 
study treatment administration, abates upon discontinuation of the treatment, and, if 
appropriate, resumes upon re-introduction of the treatment. Additionally, the suspected 
AE cannot be reasonably explained by the known characteristics of the patient’s 
clinical state or other treatments. 
 
The principal investigator and all other research staff except the research pharmacist will be 
blinded towards randomization of active drug versus placebo until after completion of study.   
 
10.1.7 Serious Adverse Events 
 
A serious adverse event (SAE) is any AE that meets one of more of the following criteria: 
 
• Is fatal or life-threatening 
• Requires hospitalization or prolongs a current hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly 
• Requires medical or surgical intervention to prevent one of the above outcomes 
 
If any SAE occurs, the treatment status of the subject(s) may be revealed, as clinically 
indicated.  If a patient discontinues medication use due to an AE, the event will be followed, 
when possible, until resolution. No interim analysis of safety data is planned because the 
entire study will be conducted over 2 months. However, the frequency of AEs will be under 
continuous scrutiny during the trial with comparison to AE rates that have been recorded in 
published PD drug trials.  
 
10.1.7.1 Serious Adverse Events Reporting 
 
The FDA will be informed of SAEs as soon as possible or within 15 calendar days. In 
addition, the Investigator will notify the FDA of any unexpected fatal or life-threatening 
experience associated with the use of the drug as soon as possible, or within 7 calendar days, 
by telephone or facsimile. When the principal investigator has determined that an SAE 
requires reporting to the FDA (unexpected and possibly related to study drug), the following 
actions will be taken: 


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• Telephone the FDA immediately (day of awareness) in the case of reportable death or 
life-threatening events. 
• Complete FDA Form 3500. 
• Send the completed Form 3500 to the FDA (preferably by fax at 1-800-FDA-0178) 
within the timelines mentioned above. 
• Attach the photocopy of all examinations, medical notes and records related to the 
SAE and document the dates these were made. For laboratory results, include the 
laboratory normal ranges. For hospitalizations, Admission H&P, Discharge Summary, 
Consultative reports, etc. could be very helpful. In the case of a fatal event, provide an 
autopsy report, when it becomes available. 
 
10.2 Efficacy Assessments 
 
10.2.1 OAB-SCS 
 
The primary outcome measure will be the change in the mean daily Overactive Bladder-
Symptom Composite Score (OAB-SCS) from baseline to visit 4. . One of the secondary 
outcome measures will be the change in the mean daily OAB-SCS from baseline to visit 3. 
The OAB-SCS requires subjects to record the severity of urgency of each micturition over a 
72-hour period as follows: 1 = no urgency (normal voiding); 2 = mild (could postpone voiding 
for as long as necessary without fear of incontinence); 3 = moderate (could postpone voiding 
for a short while without fear of leakage); 4= severe (could not postpone, had to rush to the 
toilet); 5= urgency incontinence (could not make it to the toilet without some leakage). The 
total score is derived by adding the urgency rating of each micturition over a 72-hour period 
as recorded in a voiding diary. In this way, the OAB-SCS accounts for both frequency and 
urgency in OAB, and is therefore a more accurate assessment of OAB than measurements of 
urgency alone (Starkman 2008). Mean daily OAB-SCS is total 72-hour score divided by 3. 
For incomplete days, the daily score will be adjusted to equal [(total score for the incomplete 
day / actual number of hours recorded) x 24 hours] (Zinner 2005). 
 
10.2.2 Voiding Diary 
 
In addition to the OAB-SCS, the voiding diary will be used to record number of micturition 
episodes per 24h, number of incontinence episodes per 24h, and volume per micturition. The 
change in these variables from baseline to visit 3 and from baseline to visit 4 will be 
secondary outcome measures. (The voiding diary will also record frequency of Kegel 
exercises and PRN doses of carbidopa/levodopa, but these will be controls, not outcome 
measures.) 
 
10.2.3 OAB-q 
 
The Overactive Bladder questionnaire symptom severity scale (OAB-q) measures the impact 
of bladder symptoms by asking patients to rate the severity of eight OAB symptoms on a 6-


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point scale. The questionnaire has been validated for use in the general population (Coyne 
2002) and in patients with Parkinson disease (Iacovelli 2010).  
 
10.2.4 NMSS 
 
The NMSS is a validated rating scale of non-motor symptoms in Parkinson disease 
(Chaudhuri 2007). It rates the severity and frequency of 30 symptoms in 9 domains, including 
3 symptoms of overactive bladder. The other domains it evaluates are cardiovascular, 
sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, 
gastrointestinal, sexual function, and miscellaneous (pain, sense of smell, change in weight, 
and excessive sweating). Severity is rated from 0 (none) to 3 (major source of distress) and 
frequency is rated from 1 (rarely, <1/week) to 4 (very frequent, at least daily). The score on 
each item is the product of the severity and frequency ratings. The total score for the NMSS is 
the sum of all item scores.   
 
10.2.5 PPBC 
 
The PPBC asks patients to rate the severity of their bladder symptoms on a 6-point scale, from 
“My bladder condition does not cause me any problems at all” to “My bladder condition 
causes me many severe problems.” This single-item, global measure has been validated for 
use in a general population with OAB (Coyne 2006).  
 
10.2.6 SGI-C 
 
The Subject’s Global Impression of Change will be assessed by asking a single question at 
visit 3 and visit 4.: “Since starting the study drug, how have your bladder symptoms 
changed?” Answers will be on a 7-point scale: 1 = much improved; 2 = somewhat improved; 
3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = somewhat worse; and 7 = 
much worse.  
 
11. DATA MANAGEMENT AND STATISTICAL ANALYSIS 
 
Statistical analysis will be performed by a consulting statistician contracted with 
EvergreenHealth.  
 
11.1 Sample Size Considerations 
 
This is a prospective, double-blinded, randomized controlled pilot study. The purpose is to 
test a hypothesis in a preliminary fashion and to assess for safety in this population with a 
specific neurological disease. As such, a power calculation may be irrelevant. However, a 
small number of subjects (e.g. less than 10) may cause significant sampling error to miss a 
treatment effect or common safety issue. Some entities that establish criteria for level of 
evidence consider a sample size of 20 subjects in each arm to be a minimum representative 
population to be considered for Class III or better classification of Level of Evidence.  
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11.2 Study Population 
 
The study population will include all patients who pass screening and undergo randomization. 
Data will be analyzed in an intent-to-treat fashion. 
 
11.3 Baseline and Demographic Characteristics 
 
The following characteristics will be summarized descriptively for placebo and drug groups: 
• Demographics (age, gender, race) 
• Parkinson disease characteristics at baseline (disease duration, date of onset, initial 
symptom, PD type [tremor-dominant or akinetic-rigid], modified Hoehn and Yahr 
stage in the ON state, and MDS-UPDRS part 3 score in the ON state) 
• Levodopa-equivalent daily dose (LEDD) 
• Other medications used for OAB 
 
11.4 Safety Analysis 
 
AEs will be summarized by treatment group (study drug or placebo) and by dose. Changes in 
vital signs (BP, HR, RR) and changes in post-void residual will be analyzed to detect 
differences between active drug and placebo.   
 
11.5 Efficacy Analysis 
 
Outcome measures are described in section 10.2. Analysis of primary and secondary outcome 
measures will include: 
• Summary statistics (n, mean, standard deviation, median, minimum and maximum) at 
baseline, visit 3 and visit 4 by treatment.  
• Summary of % change from baseline to visit 3 and 4. 
• Significance testing 
 
The primary time points for all comparative measures will be Baseline Visit (Visit 2), 
Titration Visit (Visit 3) and Final Visit (Visit 4). Outcome measures will be compared 
between groups using analysis of covariance (ANCOVA) or other method as deemed 
appropriate by the consulting statistician. Demonstration of superiority will depend on 
achieving statistical significance for the primary endpoint. Level of significance will be 
defined as p = 0.05. All statistical tests will be two-sided.  
 
12. STUDY MANAGEMENT 
 
12.1 Ethics and Good Clinical Practice 
 
This study will be performed according to the principles of Good Clinical Practice [Chapter 2 
of the ICH Harmonized Tripartite Guideline for Good Clinical Practice (GCP)], the 


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declaration of Helsinki, and national laws and regulations about clinical studies. The study 
may not start without written approval from the appropriate Institutional Review Board or 
Independent Ethics Committee. 
 
12.2 Informed Consent 
 
For each trial patient, written informed consent will be obtained before any study-related 
activity is commenced. Both the informed consent form (ICF) and an oral explanation that 
occurs as part of the informed consent process will include information about the study 
objective, the nature and duration of the study, the action of the study drug, potential risks, 
inconveniences, adverse effects, and alternatives. The patient will be informed that he or she 
is free to withdraw from the study at any time without consequence.  
 


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13. 
Iacovelli E, Gilio F, Meco G et al. (2010). Bladder symptoms assessed with 
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Khullar V, Amarenco G, Angulo JC, et al. Efficacy and tolerability of 
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Kowal SL, Dall, TM, Chakrabati R, et al. The current and projected economic 
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14. APPENDICES 
 
14.1 Schedule of assessments 
14.2 Voiding Diary  


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14.3 Prohibited meds