Clinical trial NCT03149809
Conditions: Overactive Bladder Parkinson Disease
Keywords: Urinary incontinence Parkinson disease Overactive urinary bladder Nocturia
Sponsor: VA Office of Research and Development
Start date: 2018-03-01; Completion date: 2023-09-08
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The impact of urinary symptoms in Parkinson disease (PD) extends beyond worsened well-being. Urinary symptoms common in PD, especially incontinence and nocturia, are major risk factors for falls likely due to the combination of urinary urgency and impaired mobility (and falls are a leading cause of mortality in PD), for spouse/caregiver stress due to decreased mutuality in the relationship, and for institutionalization, largely due to increased disability. Additionally, most medications currently recommended for urinary symptoms in PD are anticholinergic and have the potential to worsen the progressive cognitive and autonomic burdens of the disease. Veterans with PD are also more likely to rely solely on VA for their health care than Veterans without PD. Thus, optimizing the care of urinary symptoms for Veterans with PD becomes imperative, particularly for VA. Using a non-inferiority design, this proposal seeks to demonstrate the comparative effectiveness of pelvic floor muscle exercise-based behavioral therapy versus drug therapy to treat urinary symptoms in PD.

Detailed description:
The number of persons with Parkinson Disease (PD) in the United States is expected to double by 2030 as the population ages. Importantly, this increase in the prevalence of PD will have greater impact within the Department of Veterans Affairs (VA) because the Veteran population is older than the general population and Veterans with PD are more likely than those without PD to rely solely on VA for their health care. While PD is often characterized by the motor symptoms of the disease (tremor, bradykinesia, rigidity), non-motor symptoms such as urinary symptoms correlate more closely with impaired well-being as the disease progresses. However, the impact of urinary symptoms in PD extends beyond worsened well-being. The urinary symptoms of overactive bladder (OAB), including urgency, frequency, and nocturia, with or without urinary incontinence, are the most common urinary symptoms of PD. OAB symptoms are associated with falls (a cause of increased mortality in PD), with spouse/caregiver stress, and, ultimately with institutionalization, thus it is critical that we optimize the care of urinary symptoms for Veterans with PD.

Several studies suggest abnormal central nervous system processing of sensory input from bladder afferent nerves contributes to OAB symptoms in PD, possibly because of delayed recognition of bladder fullness. This mirrors findings in non-PD populations with OAB. In the non-PD OAB population, pelvic floor muscle contractions diminish bladder muscle contraction and recent evidence demonstrates that behavioral training with pelvic floor muscle exercises improves the cortical integration of bladder afferent signals. Pelvic floor muscle exercise-based behavioral therapy for OAB symptoms requires individuals to learn a motor skill and implement an adaptive behavioral strategy to delay the need to void. Because of its effectiveness compared to drug therapy, pelvic floor muscle exercise-based behavioral therapy is recommended first-line in men and women with OAB who do not have PD. However, the most recent clinical guidelines for the treatment of urinary symptoms in PD recommend treatment with anticholinergic drugs. While some anticholinergic drugs are effective in reducing symptoms of OAB, it is important to note that there is a glaring lack of an empirical evidence base to promote these drugs in the setting of PD given that they add to the anticholinergic burden of antiparkinsonian therapy, and may worsen the cognitive and autonomic burdens of the illness. Therefore, randomized controlled trials (RCTs) are needed to optimize treatment paradigms for urinary symptoms in PD.

The investigators propose a three-site, RCT conducted at the Atlanta (lead site), Birmingham and Richmond VA's to establish non-inferiority of pelvic floor muscle exercise-based behavioral therapy compared to drug therapy for OAB symptoms in adults with PD. Groups will be stratified by OAB symptom severity, PD motor symptom severity, gender, and site. The investigators will randomize 90 participants in order to complete the study in 80 participants, assuming 85% power and a non-inferiority margin for the OAB symptom score of 15% at 12-weeks. The primary outcome measure will be urinary symptom severity as measured by the International Consultation on Incontinence Questionnaire (ICIQ)-OAB symptom score collected at 3 time points during the study: baseline, 6 weeks, and 12 weeks. The investigators' benchmark for successful treatment will be a 2 point reduction in the ICIQ-OAB symptom score, which corresponds with perceived benefit in preliminary studies of behavioral therapy treatment for OAB symptoms in PD. To evaluate the primary efficacy outcome, the investigators will utilize a random effects mixed model and adjust for baseline OAB symptom score severity. Additionally, in order to better understand central control mechanisms of bladder function, the investigators will determine if domain-specific cognitive function impacts the response to exercise-based behavioral therapy or drug therapy for urinary symptoms. At baseline and 12 weeks, randomized participants will undergo a brief neuropsychological battery. Understanding how domain-specific cognitive function impacts response to treatment may inform new targets for rehabilitation therapy.

Arms: arm 1: Pelvic floor muscle exercise-based behavioral therapy arm 2: Daily solifenacin drug therapy
Interventions: intervention 1: solifenacin intervention 2: Pelvic floor muscle exercise-based behavioral therapy
Intervention descriptions: intervention 1: Antimuscarinic bladder relaxant, antagonizes bladder muscarinic receptors intervention 2: Multicomponent intervention including fluid management, constipation management and behavioral techniques incorporating pelvic floor muscle-exercise based urge suppression and self-monitoring to reduce overactive bladder symptoms

Protocol documents:
Prot_SAP_000.pdf: 
1
Behavioral or Solifenacin Therapy for Urinary Symptoms in Parkinson’s Disease
PI: Camille Vaughan, MD
Protocol Version  7-28-2022
Background:  The number of persons with Parkinson Disease (PD) in the United States is expected to double 
by 2030 as the population ages1,2.  Importantly, this increase in the prevalence of PD will have greater impact 
within the Department of Veterans Affairs (VA)2 because the Veteran population is older than the general 
population and Veterans with PD are more likely than those without PD to rely solely on VA for their health 
care3.  While PD is often characterized by the motor symptoms of the disease (tremor, bradykinesia, rigidity), 
non-motor symptoms such as urinary symptoms correlate more closely with impaired well-being as 
the disease progresses4. The urinary symptoms of overactive bladder (OAB), including urgency, frequency, 
and nocturia, with or without urinary incontinence, are the most common urinary symptoms of PD4,5.  Because 
OAB symptoms, such as incontinence and nocturia, are associated with falls6,7 8 (a cause of increased 
mortality in PD9), spouse/caregiver stress10, and, ultimately institutionalization11,12, it is critical that we optimize 
the care of urinary symptoms for Veterans with PD. This proposal directly addresses VA Rehabilitation R&D 
RFA RX-17-002 that calls for “…new approaches to improving…aspects of physical functioning that result from 
PD…that jeopardize patients’ safety, independence and well-being.”  
Several studies suggest abnormal central nervous system processing of sensory input from bladder 
afferent nerves contributes to OAB symptoms in PD, possibly because of delayed recognition of bladder 
fullness5,13,14. This mirrors findings in non-PD populations with OAB15,16.  In the non-PD population, pelvic floor 
muscle contractions diminish bladder muscle contraction and recent evidence demonstrates that behavioral 
training with pelvic floor muscle exercises improves the cortical integration of bladder afferent signals16.  
Because of its effectiveness compared to drugs, pelvic floor muscle exercise-based behavioral therapy 
is recommended first-line in men and women without PD who have OAB 17-23. 
Pelvic floor muscle exercise-based behavioral therapy for urinary symptoms requires individuals to learn 
a motor skill and implement an adaptive behavioral strategy incorporating pelvic floor muscle contraction to 
delay the need to void when urgency strikes. The PI’s research group demonstrated the feasibility and 
preliminary efficacy of pelvic floor muscle exercise-based behavioral therapy to treat urgency incontinence in 
adults with PD24.  However, the most recent clinical guidelines for the treatment of urinary symptoms in PD 
recommend treatment with anticholinergic drugs25. While some anticholinergic drugs are effective in reducing 
symptoms of OAB, it is important to note that there is a glaring lack of an empirical evidence base to promote 
these drugs in the setting of PD given that they add to the anticholinergic burden of antiparkinsonian therapy, 
and may worsen the cognitive and autonomic burdens of the illness. Therefore, randomized controlled trials 
(RCTs) are needed to optimize treatment paradigms for urinary symptoms in PD.
Multiple studies in other areas of rehabilitation medicine demonstrate adults with PD can learn and 
implement a motor skill as part of a strategy to address symptoms that impair independence and well-being 
(e.g. balance, voice training26-28).  Despite the potential for cognitive decline, which occurs in up to 75% of PD 
patients within 10 years of diagnosis29, there is evidence of neuroplasticity in patients with PD and structural 
benefit from learning motor skills as demonstrated through functional imaging studies30,31.  Our preliminary 
studies suggest adults with PD and mild cognitive dysfunction can successfully implement behavioral therapy 
for urinary symptoms. Understanding the neural mechanisms for this phenomenon would greatly inform 
adapting rehabilitation-based interventions for patients with both motor dysfunction and declining cognitive 
functioning.  Aim 2 will build on this line of inquiry and set the stage for mechanistic studies of central nervous 
system control of bladder function in PD.  For Aim 2 we include a detailed evaluation of cognitive function, 
which will inform future studies and practice paradigms in this vulnerable Veteran population. 
The long term goal of the PI’s research group is to alleviate urinary symptoms as a contributor to 
disability among Veterans with PD and contribute to understanding of the brain-bladder connection in the 
setting of neurodegenerative disease. We propose the following specific aims:
Specific Aim #1: Using a RCT, determine non-inferiority of pelvic floor muscle exercise-based 
behavioral therapy versus drug therapy for urinary symptoms in PD.  We hypothesize that pelvic floor 
muscle exercise-based behavioral therapy will reduce urinary symptom severity with a difference compared to 


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drug therapy that does not exceed the non-inferiority margin of a validated OAB questionnaire. The primary 
outcome, OAB severity, will be measured using the OAB symptom questionnaire (International Consultation on 
Incontinence-OAB (ICIQ-OAB) symptom score) with a non-inferiority margin of 15%.  
Specific Aim #2 (mechanistic aim): Determine if domain-specific cognitive function impacts the 
response to exercise-based behavioral therapy or drug therapy for urinary symptoms. 
Aim 2.a. Do higher baseline motor skill learning capacity and executive function scores predict better 
outcomes in the exercise-based behavioral therapy versus drug therapy group?
Aim 2.b. Compared to exercise therapy, does anticholinergic drug treatment for urinary symptoms worsen 
executive function and PD motor symptom severity?
Research Design and Methods
We propose a three-site, RCT conducted at the Atlanta (lead site), Birmingham and Richmond VA medical 
centers to establish non-inferiority of pelvic floor muscle exercise-based behavioral therapy compared to drug 
therapy for urinary symptoms in adults with PD.  Groups will be stratified by OAB symptom severity, PD motor 
symptom severity, gender, and site.  We will randomize 90 participants in order to complete the study in 80 
participants, assuming 85% power and a non-inferiority margin for the OAB symptom score of 15% at 12-
weeks.  The primary outcome measure will be urinary symptom severity as measured by the ICIQ-OAB 
symptom score32,33 collected at 3 time points during the study: baseline, 6 weeks, and 12 weeks.  PFME-
based behavioral therapy will occur over 3 visits conducted during the first 6 weeks as was performed in the 
BETTER2 PD study.  Participants in the drug therapy group will also have 3 visits during the first 6 weeks in 
order to individually titrate solifenacin drug therapy according to a validated symptom scale.  Solifenacin has 
been selected because this bladder-selective anticholinergic drug (less risk of cognitive side effects) is the only 
drug with published evidence of potential efficacy in PD34.  At baseline, randomized participants will undergo a 
brief neuropsychological battery adapted from our current study to assess cognitive factors that may predict a 
preferred treatment strategy.  At the 12-week assessment, the brief neuropsychological battery and MDS-
UPDRS will be repeated in order to assess any change associated with treatment allocation.  Follow-up visits 
will occur at weeks 4 and 8 to ascertain side effects and assess treatment adherence.  
Participants: Participants will be men and women with PD.  Based on our experience in the BETTUR PD and 
BETTUR2 pilot studies, we anticipate screening 180 participants to account for attrition and achieve the 
intended sample size.  During FY16, 541, 399, and 112 unique Veterans with PD were seen at the Atlanta VA, 
Birmingham VA, and Richmond VA PADRECC, respectively.  We anticipate up to half of the participants for 
the proposed trial will be Veterans; however, based on our extensive experience in recruiting for clinical trials 
focused on urinary symptoms, we propose recruiting Veterans and non-Veterans at study initiation.  In order to 
meet recruiting targets for two recent, multi-site GRECC continence studies (ProsTel, and BETTUR2), 
recruitment was extended to non-Veterans in order to achieve the intended sample size.  Additionally, 
university affiliates in Atlanta (Emory), Birmingham (University of Alabama at Birmingham), and Richmond 
(Virginia Commonwealth University) have active movement disorders programs, which enhance the overall 
resources available to the study. With the approval of the IRB and VA Research and Development Committees 
following a partial HIPAA waiver, we will perform a computer-based screening using the VA Corporate 
Database Warehouse to screen afore-mentioned veterans who live close to the Medical Center. Also, we will 
use data pull with real Social Security Numbers (SSNs) from VA’s Information and Computing Infrastructure 
(VINCI) to enhance recruitment goals within the VISN. Subject eligibility is dependent upon a confirmed 
diagnosis of Parkinson’s disease by a movement disorder neurologist. After viewing the records in CPRS or in 
the academic affiliate health system electronic medical record, the coordinator will make contact with the 
neurologist of potential subjects. With neurologist approval, an IRB-approved letter will be sent to the patient 
informing them of the study and providing a phone contact for study staff.  The letter will include information 
that if study staff do not hear from the patient within 10 days, they will contact them by phone to inquire about 
interest in the study.   
Potential subjects may also be referred to the study by their physician either at the host VAMC or academic 
affiliate.  The study will use an approved flyer as advertisement.  Potential subjects may contact study staff by 
phone to determine eligibility or to inquire more about the study. Staff will respond to phone inquiries from 
patients who self-identify as interested, explain the study, and pre-screen them for eligibility. Those who qualify 


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preliminarily will be scheduled for a full evaluation and will be mailed an advance copy of the consent form 
along with a “first appointment letter.” Informed Consent discussion will be conducted during the first visit and if 
the potential participant consents to participate in the study they will be further evaluated clinically for eligibility 
based on specific inclusion/exclusion criteria per study protocol. 
Inclusion criteria: 

Clinical diagnosis of PD determined by a board-certified neurologist with specialty training in movement 
disorders

An ICIQ-OAB Symptom Score of ≥ 7, which indicates clinically significant symptoms of OAB, defined as 
presence of urinary urgency with or without urgency incontinence usually with increased daytime frequency 
and nocturia in the absence of infection or other obvious pathology32,35.
Exclusion criteria: 

Significant cognitive impairment, as indicated by a Montreal Cognitive Assessment36 (MoCA) score of < 18 
(or <14 for the MoCA Blind), which is the recommended diagnostic cutpoint for dementia in PD37.

Previous intensive pelvic floor muscle exercise training

Clinically significant depression as measured by a Geriatric Depression Scale-Short Form38 score ≥ 10 
which could affect motivation to fully engage in the intervention

Use of an indwelling urinary catheter

Post-void residual (PVR) urine measurement by bladder ultrasound of ≥ 150 mL

Severe uterine prolapse past the vaginal introitus

Poorly controlled diabetes defined by a hemoglobin A1c (HgbA1c) of >9.0% within the last 3 months.  
Participants with poorly controlled diabetes will be offered enrollment if the OAB symptoms persist after 
improvement in diabetes control 

Chronic renal failure and on hemodialysis

Genitourinary cancer with ongoing surgical or external beam radiation treatment

Previous artificial urinary sphincter, sling procedure or implanted sacral neuromodulation device

History of bladder-injection of botulinum toxin in the last 12 months

Any unstable health condition expected to result in hospitalization or death within in the next 3 months as 
determined by site principal investigator.

Hypersensitivity to drug class

Contraindication to the study drug (solifenacin) including: narrow angle glaucoma, history of gastric 
retention, history of acute urinary retention requiring catheterization

Current use of a bladder relaxant – permitted to enroll after one-week washout

Hematuria on microscopic examination in the absence of infection.  A urologic consultation will be 
recommended and enrollment will depend on clearance by a urologist and agreement by the site PI that 
entry into the treatment protocol is not contraindicated

If on diuretic, dose should be stable for at least 4 weeks

If taking an alpha-blocker, dose should be stable for at least 4 weeks

If taking dutasteride or finasteride, dose should be stable for at least 6 months

Women who are pregnant, or breast-feeding, or planning to become pregnant. *Women of child-bearing 
age must agree to use of birth-control while enrolled
Figure 1: Schematic of the Study Design
*Visits 1,2,and 7 will require in-person procedures.  All other visits may be conducted by phone/telehealth.


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During the first visit, potential participants will receive an explanation of the study procedures and complete 
informed consent to participate.  Baseline assessments will include the following:
Baseline assessments: 
1. Seven-day bladder diary includes daily participant-reported voids and incontinent episodes, with ratings of 
associated urgency, and wake time and bedtime to assess daytime frequency and nocturia.  A single 24-hour 
frequency-volume chart will be included in the 7-day diary at baseline, week 6, and week 12. Participants will 
measure their urine output with each void for a 24-hour period (first void after rising until the first morning void 
the following day) using a receptacle marked in 25 mL increments.
2.  The Movement Disorder Society – Unified Parkinson Disease Rating Scale (MDS-UPDRS) includes 40 
items which are a combination of questions regarding activities of daily living and a physical examination of 
motor function by the investigator39.  This updated UPDRS includes a question about urinary symptoms.  A 
modified Hoehn and Yahr (H&Y) scale is included as part of the MDS-UPDRS.  The modified H&Y scale 
provides a score determined during the physical examination.  These instruments will be completed during the 
second clinic visit in order to be performed during a ‘defined on’ period.    
3. The ICIQ-OAB questionnaire is a 4-question assessment of OAB symptoms and the degree to which they 
bother the respondent (urgency, frequency, nocturia, UI)32,33.  The ICIQ-OAB questionnaire requires about 5 
minutes to complete and will serve as the primary outcome for the study.  The participants will complete the 
ICIQ-OAB-QOL questionnaire40 at home, which requires about 20 minutes.  The ICIQ questionnaires have 
been validated in men and women, but not in Parkinson’s disease specifically.  These questionnaires will be 
completed at baseline, 6 weeks and 12 weeks.  
4.  The UAB Study of Aging Life Space Assessment will be used to assess individual mobility and need for 
assistance within the participant’s home and community, thus providing a validated assessment of individual 
independence41.  It is designed to identify the distance through which a person reports moving during the 4 
weeks prior to the assessment.  Life-Space 0 indicates movement restricted to one’s bedroom increasing to 
Life-Space 5 indicating travel outside of one’s town.  A score is generated by assigning a value to each Life-
Space level based on the frequency of travel to that Life-Space level and degree of independence in getting 
there.  The assessment, which can be performed in less than 5 minutes, leads to a score ranging from 0 
(“totally bedbound”) to 120 (“traveled out of town every day without assistance”).
5.  The MoCA test is more sensitive to detect mild cognitive impairment than another brief screening measure, 
the Mini-Mental Status Exam, in PD patients37 and is recommended by the Parkinson Study Group42.  The 
MoCA test is designed to assess executive function, higher level language abilities, memory, and complex 
visuospatial processing, which are areas that may be affected more commonly in PD dementia. 
6.  The Geriatric Depression Scale-Short Form is a 15-question assessment that has been validated in older 
adults and is recommended as a screening test for depression in adults with PD43.
7.  The Self-Efficacy for Managing Chronic Disease questionnaire is a 6-item questionnaire developed 
through the Stanford Patient Education Research Center.  It covers several domains that are common across 
many chronic diseases, symptom control, role function, emotional functioning and communicating with 
physicians44.
8. Physical Exam and Laboratory testing

Urinalysis (for all participants) and pregnancy test (for women of child-bearing age).   If bacteriuria 
is suggested by screening urinalysis45, a culture will be sent and bacteriuria (>100K colony forming 
units) will be eradicated by a 7-day antibiotic course with permission/notification sent to their 
primary care provider.  Participants will be re-assessed for UI following treatment.  Participants with 
unexplained, persistent hematuria will be referred for an appropriate evaluation.

HgbA1c if the participant is diabetic and has not had an HbgA1c in the 3 months prior to enrollment.

Basic metabolic panel if the participant has not had an assessment in the 6 months prior to enrollment.
Enrollment and Neuropsychological Assessment:
One week later, potential participants will return for visit two.  Study staff will review the completed bladder 
diary, questionnaires, and PVR and will determine if the participant qualifies for the study.  Once enrolled, 
participants will undergo a brief neuropsychological battery and a motor task of procedural learning.  These 
tests will be administered by a research assistant so that the principal investigator is blinded to baseline 
performance on the SRTT and cognitive function. The selected tests correspond with the battery piloted in the 
PI’s current Rehab R&D CDA-2 study and are manageable for participants with PD. These assessments will 


5
allow for exploratory analyses beyond the planned tests of implicit memory and executive function to assess 
for correlation between baseline cognitive function and ability to implement the behavioral therapy intervention.  
For instance, if the implementation of the behavioral intervention correlates with tasks of motor procedural 
learning, we might not expect it to correlate with tasks of declarative memory, thus providing further evidence 
that the task is one of implicit memory.  Further, several of the tests have been linked with specific 
neuroanatomical regions of the brain and could provide preliminary data to support future studies involving 
functional imaging.  The neuropsychological assessment will be repeated at visit 7 (12 weeks) in order to 
determine any change from baseline.  
While solifenacin is a bladder-selective anticholinergic drug with less risk of negative cognitive impact than 
other anticholinergic bladder relaxants, the 12-week re-assessment of cognitive function in this study is 
important to understand the potential drug impact on cognition in the PD population.  Persons with PD are at 
increased risk of developing cognitive impairment and are more susceptible to anticholinergic side effects of 
these medications (such as delirium, constipation, and dry mouth29,46-48).  Each testing session will last 
approximately 75 minutes, with breaks included to reduce fatigue.  The measures are described below:
1.  The SRTT is a task of motor procedural learning in which participants are asked to press one of four keys 
on a response box which correspond to a lighted stimulus49.  Unknown to the participant, the light stimuli occur 
in a sequence and thus reaction time improves as the participant performs multiple blocks of the sequenced-
based task.  This learning is demonstrated by an increase in reaction time when the stimuli are presented in a 
random order after repetitions of the sequenced-based task.  The task is typically measured in millisecond 
response times.  The SRTT can be administered in approximately 30 minutes and has been used in multiple 
studies of procedural learning among PD participants50,51.  A response box for the SRTT is available for 
purchase from Psychology Software Tools Inc.  The software to collect, store, and analyze the SRTT reaction 
times is also available for purchase from this company.  A standard operating system installed on a laptop 
computer is sufficient to allow for data collection and initial analysis of reaction time. Once reaction times for 
the sequenced and random blocks have been calculated, these data will be entered into the Redcap database.  
2.  The CERAD Word List subtest52 requires the subject to recall 10 words that are presented over three 
trials, followed by short-delay recall and recognition memory. Left entorhinal cortex volume is significantly 
correlated with immediate recall on this task53.
3.  The Nonverbal/Spatial Selective Reminding Test54 taps spatial memory by requiring the subject to recall 
a dot pattern. Performance on this measure has been found to discriminate patients with right versus left 
temporal lobe epilepsy55.
4.  The Wisconsin Card Sorting Test56 will be used to assess hypothesis generation and response shifting.  
Perseverative errors on this task are related to the volume of prefrontal cortex and frontal white matter
hyperintensities in adults 50-81 years old57,58.   Perseverative errors will be residualized on the total number of 
errors to control for overall level of performance.
5. The Subject Ordered Pointing Task will assess working memory. Subject Ordered Pointing is sensitive to 
middorsolateral prefrontal cortex lesions in monkeys and humans, and activates dorsolateral prefrontal cortex 
on positron emission tomography in normal adults.
Randomization:  At the second visit, eligible participants will be randomized to one of two groups: treatment 
with PFME-based behavioral therapy or solifenacin drug therapy.  Participants will be stratified by site, gender, 
UI severity (< or ≥ a score of 9 on the ICIQ-OAB), and PD motor symptom severity (MDS-UPDRS < 33 on the 
part 3 motor score)59.  Participants will be randomized through computer-generated block randomization in 
groups of six. Based on preliminary data showing these cut points approximate the means among our 
randomized participants, we do not anticipate four stratification variables will present a challenge to 
recruitment.  While participants will not be blinded to treatment group, the interventionist will be blinded to the 
participant’s performance on the neuropsychological tests and SRTT performance.
Data Management: Participants’ assessment data will be kept in a locked cabinet behind a locked door at 
each site of the Birmingham/Atlanta GRECC and the Richmond PADRECC.  Bladder diaries will be scored by 
a research assistant who is blinded to the assigned treatment group.  Data from the Birmingham and 
Richmond sites will be uploaded to a secure VA server in the form of PDF documents scanned on a VA device 
behind the VA firewall.  Deidentified data will be entered and verified in Redcap by research staff at the Atlanta 
site, which will ensure accuracy of the data.  A standard form will be used to record the date and reason for all 


6
exclusions and dropouts, and these data will also be entered into the master database. Four times per year the 
PI will meet with the Atlanta-based data manager to review accrual, data entry, and eligibility criteria and 
examine the database for outliers or database entry errors at each site.  The Redcap database will then be 
converted and data analyses will be completed in SAS 9.4 (SAS Institute, Cary, NC).  Additional details 
regarding confidentiality of patient data are included in the Human Subjects plan.
Specific Aim #1: Using a RCT, determine non-inferiority of pelvic floor muscle exercise-based 
behavioral therapy versus drug therapy for urinary symptoms in PD.
  
Rationale: The use of anticholinergic drugs for UI in PD, which are currently recommended by guidelines, 
increase polypharmacy and may add to the cognitive and autonomic burdens of PD.  Impaired cognition and 
polypharmacy are recognized risk factors for medication non-adherence in PD and could lead to treatment 
failure for OAB60.  PFME-based behavioral therapy, while more labor-intensive, is free of drug side effects for 
patients.  The PI’s pilot studies demonstrate that adults with PD and UI can learn and implement PFME-based 
behavioral therapy resulting in significant decreases in UI and OAB symptoms. Given the efficacy of the URGE 
PD drug trial, a comparative effectiveness trial of behavioral therapy and drug therapy for bothersome urinary 
symptoms is a logical next step to better inform treatment guidelines for Veterans with PD.  Based on our 
preliminary data showing similar effect sizes between behavior and drug therapy, a non-inferiority design is 
proposed. A non-inferiority design provides the most critical information needed to inform clinical guidelines 
without exposing additional participants to drug therapy. The reason for not including a behavior therapy plus 
drug condition is that we wish to disentangle the contributions of baseline levels of motor symptoms and 
cognitive scores on outcomes, hopefully gaining an understanding of which treatment might be more effective 
for which patients in light of the potential of drug side effects. 
Intervention: Once randomized, both groups will participate in a 12-week study (Figure 1). Study visits (either 
in-clinic or via phone) will occur every two weeks for the first 8 weeks followed by a final in-clinic assessment at 
12-weeks.  Participants will be compensated $50 upon completion of first visit procedures, $50 for second visit 
procedures and $60 for completion of visit 7 procedures with a maximum of $160 for  completion of all study 
visits (includes screening and follow-up visits).  
Primary Outcome: The ICIQ-OAB questionnaire is a previously validated symptom questionnaire that has 
been used in the PI’s previous studies related to urinary symptoms in PD32,33.  The ICIQ-OAB validation 
protocol states that a clinically meaningful improvement includes a statistically significant decrease in the 
symptom score paired with reduction in bother and improvement in QOL61.  To provide additional evidence of 
clinical meaningfulness of the ICIQ-OAB based outcome data, the ICIQ OAB-QOL and bother scores will be 
re-administered at the conclusion of the trial as secondary outcome measures.  Validated patient benefit and 
satisfaction questionnaires62 will also be used at the fifth(midpoint of the study) and final visits. Participants in 
the behavioral group will also be asked to submit a daily record of their completed PFME to document 
adherence with recommended exercise targets.  Adherence among participants in the drug therapy group will 
occur via pill counts.  As evidenced by Tables 2-4, we have experience with all these measures and 
procedures.
Behavioral Intervention:  Exercise-based behavioral therapy using PFME
Participants who are randomized to exercise-based behavioral therapy will receive a comprehensive training 
program administered individually by a trained nurse practitioner interventionist to address UI and other LUTS.  
Participants will be taught PFME as well as urge suppression strategies to overcome the urge to void.  Initial 
instruction in PFME will involve rectal (or vaginal) palpation to confirm contraction of appropriate muscle 
groups.  The proposed method for teaching PFME and urge suppression strategies and reinforcing these 
techniques is based on the protocol used by Burgio et al20,23,24.  Recommendations for PFME will include 45 
exercises every day divided into manageable sessions, typically sets of 15 exercises, 3 times per day.  
Completing 45 exercises will require 7-10 minutes daily to complete.
Urge suppression strategies involve teaching participants to respond adaptively to the sensation of 
urgency.  Instead of rushing to the toilet, which increases intra-abdominal pressure and leads to visual cues 
that can elicit incontinence, participants will be instructed to pause, sit down, if possible, relax the entire body, 
and contract the pelvic floor muscles repeatedly to diminish urgency, inhibit detrusor contraction, and prevent 
urine loss (“freeze and squeeze”).  This technique typically leads to the diminution of urgency within 1 minute.  
When the urgency subsides, participants are instructed to proceed to the toilet at a normal pace.  Participants 


7
with stress-related urine loss will also be instructed how to contract pelvic floor muscles immediately prior to 
precipitants of stress leakage (sneezing, coughing, or laughing).  Other behavioral techniques introduced at 
the randomization visit for participants in the behavioral therapy group will include instruction on the 
management of constipation, fluid intake modification, or scheduled voiding (attempting to void on a 
predetermined schedule). Participants in the behavioral therapy group will maintain a 7-day bladder diary for 
eight weeks after randomization to mirror the behavioral intervention in the BETTUR and BETTUR2 studies.
The intervention will be initiated at the 2nd clinic visit (randomization visit).  Participants will complete the 
Patient Global Symptom Control instrument at the 5th visit (week 6 - midpoint of study) to assess whether 
behavioral therapy is providing control of OAB symptoms; responses to the statement, "This treatment has 
given me adequate control of my overactive bladder symptoms" range from 1 (disagree strongly) to 5 (agree 
strongly).  Participants will be offered an additional session of PFME training if they meet at least one of the 
following criteria: a) the participant desires further reinforcement of the pelvic floor muscle techniques, or b) the 
participant reports a Patient Global Symptom Control score of 1 to 3.  
Drug Intervention: Solifenacin
Participants who are randomized to drug therapy will receive solifenacin at visit 2 (randomization visit).  The 
starting dose will be 5 mg by mouth once daily.  Participants in the drug therapy group will not receive any of 
the educational or exercise components of behavioral therapy.  Participants will complete a 7-day bladder 
diary at baseline, 6 weeks, and 12 weeks post-randomization, which will include a single 24-hour frequency 
volume chart at each time point.  At visit 5 (week 6 – midpoint of study) solifenacin dose escalation to 10 mg 
will be allowed if the Patient Global Symptom Control score is 1 to 3, indicating inadequate symptom control, 
and the participant reports that the side effects of drug therapy are tolerable. Individual titration of drug therapy 
mirrors the study design from Urge PD, which was the first pilot randomized controlled trial of a bladder 
relaxant drug in a Parkinson’s patient population34,63.  Additionally, individual titration of drug therapy mirrors 
clinical practice and the methodology for behavioral therapy implementation, which also involves individual 
titration of exercise-based strategies depending on symptom response.  Failure to individually titrate drug 
therapy could bias the results of the study toward behavioral therapy.  An assessment for adverse drug events 
will occur at each in-clinic or telephone visit after randomization using a standardized checklist.  If any 
participant experiences adverse events after the dose increase, he/she may return to the 5mg daily dose or 
discontinue the medication.  If the medication is discontinued, the participant will be offered the opportunity to 
continue the study for data collection only.  
Power Analysis:  The power analysis is informed by the ICIQ-OAB symptom score reduction observed in the 
BETTUR PD and BETTUR2 studies of behavioral therapy for urinary symptoms in PD.  Based upon the 
bladder diary-derived UI frequency data (consistent measure used in both behavioral and drug trials), the effect 
of behavioral therapy and drug therapy to reduce UI frequency is similar.  The ICIQ-OAB symptom score range 
is 0-16, with higher scores indicating worse symptoms.  A score ≥ 
7 would indicate clinically significant OAB symptoms (urgency, 
frequency, urgency UI, nocturia) occurring on average at least 
sometimes.  In our previous studies, we have observed a 2-3 
point reduction in the symptom score, which represents a 12%-
19% reduction from baseline24,64.  The minimally clinically 
important difference for the ICIQ-OAB is defined as a statistically 
significant reduction in the symptom score that is accompanied 
by a reduction in bother and improvement in OAB-specific 
QOL.  Because the observed reduction ≥ 2 points represents a 
statistically and clinically meaningful difference, we propose a 
non-inferiority margin of 15%.  Thus, we will randomize 90 
participants in order to complete the interventions in 80 participants, which assumes 85% power and a non-
inferiority margin on the OAB symptom score of 15% at 12-weeks post-randomization.  Table 6 indicates that 
the proposed sample size will permit an assessment of non-inferiority within a range of potential non-inferiority 
margins that correspond to outcome assessments in our pilot studies. 
Table 6: Sample Size per Group to Declare 
Non-Inferiority with 85% power
Margin of Non-Inferiority 
Between Groups at 12 weeks
(Assumes OAB Symptom Score at 
baseline of = 8.1)
Standard 
Deviation of 
12 week 
ICIQ-OAB 
Symptom 
Score
10%
12.5%
15%
20%
1.0
23
16
11
7
2.0
89
59
40
24
3.0
198
131
88
52


8
Table 7: Summary Outcome Assessments
Outcome Assessment 
Baseline
Visit 1/Visit 2
2 weeks
Visit 3
4 weeks
Visit 4
6 weeks
Visit 5
8 weeks
Visit 6
12 weeks
Visit 7
ICIQ-OAB 
X
X
X
7-day Bladder Diary (drug)
X
X
X
7-day Bladder Diary 
(behavioral)
X
X
X
X
7-day PFME Record
(behavioral)
X
ICIQ-OAB QOL
X
X
X
Benefit & Satisfaction 
X
X
Life Space Assessment
X
X
X
Self Efficacy for Chronic 
Disease Management
X
X
Patient Global Symptom Control 
Score
X
X
Adverse Event checklist
X
X
X
X
X
X
Adherence Questionnaire
X
X
X
Neuropsychological battery
X
X
MDS-UPDRS
X
X
Data Analysis:
Primary Outcome for Aim 1:  To evaluate the impact of treatment within group, we will first use a random 
effects mixed model with adjustment for baseline OAB symptom severity to compare mean ICIQ-OAB 
symptom scores across the three time points. In order to test for non-inferiority of behavioral therapy compared 
to drug therapy, we will assess the difference in the mean 12-week post-randomization ICIQ-OAB symptom 
score between groups using a two-sample t-test, assuming a non-inferiority margin of 15% and a standard 
deviation of 2.0 points. The significance level of the test will be set at an α of 0.025 for a one-sided test of 
significance.  
Secondary Outcomes: The pre-treatment and post-treatment frequency of UI based on the bladder diary will be 
used to calculate a percentage change for each participant ([pre-treatment frequency – post-treatment 
frequency]/[pre-treatment frequency] x 100%).  Based on pilot study results, non-normality of the diary data is 
anticipated and thus the Wilcoxon rank sum test will be used for bladder diary-reported outcomes (UI, urgency, 
nocturia).  Questionnaire-based secondary outcomes (ICIQ-OAB bother score, ICIQ-QOL, benefit and 
satisfaction, self-efficacy, voided volume, and the Life Space Assessment) will be assessed between groups 
using a t-test.  Twenty-four hour voided volume measures will permit an evaluation of nocturnal urine 
production as a confounding factor for response to treatment among persons with nocturia.  Nocturnal urine 
production includes the sum of all voided volumes after going to bed with the intention of sleeping and the 
subsequent first voided volume the next morning.  Additionally, an evaluation of change in mean voided 
volume provides an objective measure of functional bladder capacity.
Self-assessed adherence to exercise or drug therapy will be assessed through questionnaires (both 
groups) and with exercise records or pill counts depending on group allocation.  Data will be calculated as 
medians (and inter-quartile range), and compared using Kruskal-Wallis test for continuous variables or chi-
square test (Fisher’s exact when expected cell counts were <5) for categorical variables.  Adverse event 
questionnaires will be administered at each in-clinic or phone visit after treatment allocation.  The number of 
times a specific side effect is reported after the baseline assessment will be summed and presented as a 
continuous variable.  Comparisons between groups of the proportion of participants reporting specific side 
effects will be performed by Fisher’s exact test.
[Specific Aim #2 (mechanistic aim): Determine if domain-specific cognitive function impacts the 
response to exercise-based behavioral therapy or drug therapy for urinary symptoms. 
Aim 2a: Do higher baseline motor skill learning capacity and executive function scores predict better 
outcomes in the exercise-based behavioral therapy versus drug therapy group?


9
Rationale:   In spite of the potential for cognitive impairment, which occurs in up to 75% of PD patients within 
10 years of diagnosis29, some PD patients demonstrate evidence of neuroplasticity and benefit from learning 
motor skills as demonstrated through functional imaging studies30,31.  Understanding whether baseline domain-
specific cognitive function is associated with successful implementation of behavioral therapy among adults 
with PD is important to understand the central control of bladder function and identify new targets to augment 
rehabilitation therapy in the setting of a neurodegenerative disease. While participants with significant cognitive 
impairment (MoCA < 18) will be excluded, this exclusion criterion will not eliminate participants with mild 
cognitive impairment.  The range of MoCA scores among current completers of the BETTUR2 PD study (n=26) 
is 18 to 29 (mean=24.6 ± 2.9).  Among the 11 participants randomized to behavioral therapy in the BETTUR2 
PD study who had a MoCA score between 18-26 (includes the screening cutpoint for mild cognitive impairment 
in PD37), the median reduction in weekly UI frequency eight weeks after randomization was 88% (IQR 42%-
100%), suggesting that even mild cognitive impairment does not interfere with learning a behavioral therapy 
intervention.  
The neuropsychological assessment in the proposed study is a unique approach to further characterize 
domain-specific cognitive function as a predictor of the ability to use exercise-based behavioral therapy.  The 
baseline neuropsychological battery will provide additional domain-specific measures of cognitive function 
(SRTT, executive function, word retrieval) that will be analyzed in the context of the ability to learn and 
implement the exercise-based behavioral strategy.  These preliminary data will provide further evidence to 
support or refute the hypothesis that learning the PFME-based adaptive strategy is a procedural task and that 
implementation of the task uses implicit memory rather than explicit memory systems.  Further, because 
several of the selected tests have neuroanatomical correlates, these data could support the design of future 
studies involving functional brain imaging to understand mechanisms of learning in the context of 
neurodegenerative disease, thus building on imaging studies in non-PD populations with OAB15,16. 
Measures: Participants in both groups will complete the SRTT (task of procedural learning) in addition to a 
neuropsychological battery that will include evaluations of executive function and explicit memory at baseline.  
These assessments mirror the evaluation included in the BETTUR2 study, which will ultimately increase the 
power of the evaluation to determine mediators impacting implementation of behavioral therapy for urinary 
symptoms in persons with PD.  
Data Analysis: The analysis for Aim 2a will determine if baseline cognitive function scores mediate successful 
outcome in the behavioral therapy group.  Based on previously published research and our pilot studies, 
successful implementation of behavioral therapy will be defined as achieving at least a 2-point reduction in the 
ICIQ-OAB symptom score24,61,64.  Cognitive function will be evaluated as a continuous and categorical measure 
(MoCA 18-24 vs 25-30).
To explore other potential characteristics of successful behavioral therapy implementation, we will 
examine baseline characteristics that differ between those in the behavioral therapy group who demonstrate at 
least a 2-point improvement (reduction) in ICIQ-OAB symptom score versus those who report less 
improvement.  Baseline characteristics will include gender, age, PD severity as measured by the MDS-UPDRS 
motor part 3 score (mild vs. moderate), depression as well as the pre-specified measures of cognitive function 
(SRTT and Wisconsin Card Sort Test).  Baseline characteristics will be compared using chi-square or t-tests as 
appropriate.  
We will examine the correlation between cognitive function tests of procedural learning and executive 
function with change in ICIQ-OAB score after behavioral therapy.  Performance on the SRTT will be assessed 
as the mean change in time (milliseconds) between random and sequential tasks.  Performance on the 
Wisconsin Card Sort Test will be assessed using the perseverative errors score.  We will correlate these 
measures with the change in ICIQ-OAB score between baseline and 12-weeks post-randomization.  
Baseline characteristics which are significantly associated with successful implementation of behavioral 
therapy will be included as part of a multivariable logistic regression model including SRTT performance, 
Wisconsin Card Sort Test perseverative errors score in order to determine if these cognitive domains are 
important in the central nervous system control of OAB symptoms in response to behavioral therapy.  
Aim 2b: Compared to exercise therapy, does anticholinergic drug treatment for urinary symptoms 
worsen executive function and PD motor symptom severity?


10
Rationale: The standard treatment recommendation for urinary symptoms in PD is anticholinergic drug 
therapy, despite the fact that, guidelines for OAB in older adults without PD recommend an initial trial of 
behavioral therapy, which is free of any drug side effects17,18.   Anticholinergic bladder relaxants block the 
action of acetylcholine by competitively binding the muscarinic receptors in the bladder, leading to bladder 
smooth muscle relaxation.  Muscarinic receptors are also involved in cognitive functioning and the use of older 
antimuscarinic bladder relaxants has been associated with an increased risk of cognitive side effects such as 
delirium and confusion65.  Chronic use of anticholinergic medications is associated with accelerated cognitive 
decline in PD48.  Newer anticholinergic bladder relaxants, such as solifenacin, are designed to have less risk of 
cognitive side effects because they specifically antagonize bladder muscarinic receptor subtypes instead of 
those in the central nervous system65.  As shown earlier in the URGE PD data, solifenacin reduced urgency UI 
in persons with PD and symptoms of OAB in a RCT; however, no cognitive assessments were conducted thus 
precluding a careful assessment of the impact of this drug on potential cognitive side effects34. The proposed 
neuropsychological battery will include domain-specific assessments that will provide a unique opportunity to 
assess if bladder selective anticholinergic drug therapy has any measurable effect on cognition in PD. 
It is well established that anticholinergic drug therapy also reduces the motor symptoms of PD66.  
Anticholinergic drugs are used alone and in combination as treatments for motor symptoms in PD, particularly 
tremor66.  However, there is increasing concern that the overall burden of anticholinergic therapy paradoxically 
can have significant negative impacts on motor symptoms, by increasing the risk of falls, fractures, and 
postural instability47,67. Indeed, one study found that adding a central cholinesterase inhibitor decreased the 
risk of falls by 50% among persons with PD and a history of frequent falls68.  The addition of anticholinergic 
drug therapy for urinary symptoms leads to an overall increase in anticholinergic burden, particularly for 
conditions impacted by muscarinic receptors.  
Regardless of whether behavioral therapy proves to be inferior or non-inferior to drug therapy, 
understanding the potential association of drug therapy with cognition or PD motor symptom severity are 
important factors for patients and providers to determine next steps for treatment69.
Measures: Participants in both groups will complete a baseline and 12-week neuropsychological battery as 
previously described including the MoCA test, SRTT, CERAD Word List subtest, Nonverbal/Spatial Reminding 
Test, Wisconsin Card Sort Test, and the Subject Ordered Pointing task.  We will use the Anticholinergic Risk 
Scale47 to calculate an overall anticholinergic drug score for participants in both groups based on medications 
listed at the randomization visit as a potential effect modifier.  The MDS-UPDRS will be repeated at the 12-
week visit.  Thus, the behavioral therapy group will serve as a control group to assess the potential impact of 
solifenacin drug therapy on domain-specific cognitive function and PD motor symptom severity.
Data Analysis: [The analysis for aim 2b will generate data informing how central cognitive control of sensory 
integration and motor function are involved in the response to drug therapy.]  Baseline and 12-week post-
randomization cognitive tests will be evaluated using paired t-tests to assess for change within the drug group 
and two-sample t-tests for differences across groups (the behavioral therapy group will serve as a control for 
this analysis).  Because cognitive impairment in PD most often manifests as impaired executive function, we 
will focus on tests of this domain, such as the Wisconsin Card Sort Test or the Subject Ordered Pointing Task 
in our evaluation of impact on cognition.  The clock-draw test, as a component of the MoCA, is another 
assessment of executive function that is often performed in clinical practice.  If changes are noted on domain-
specific assessments of the neuropsychological battery, we will also examine correlation with clock draw 
scores obtained through the MoCA test. The Anticholinergic Risk Scale will be assessed based upon 
medications at randomization. The Anticholinergic Risk Scale score will be included in a multivariable model 
including baseline characteristics associated with changes in cognitive function in bivariable analyses.  
To assess the potential impact on motor symptoms, we will assess the change in the motor symptom 
subscale of the MDS-UPDRS (part 3 score).  Similar to the cognitive testing, baseline and 12-week post-
randomization assessments will be evaluated using paired t-tests to assess for change within the drug group 
and two-sample t-tests for difference across groups, with the behavioral therapy group serving as a control for 
this analysis.  Previous research suggests an increase in the MDS-UPDRS part 3 score of 4.6 points is 
associated with clinically relevant decline in motor function70.
Visit Schedule
Visit 1: Baseline (One phone/telehealth session and one in-person session)


11
Explanation of study procedures and consent to be a participant
Interview: Demographics, continence and medical history, MoCA, LSA, GDS
Physical: Height, weight, vital signs, cardiac, pulmonary, and abdominal exam, genital and rectal exam, 
basic neurologic exam, MDS-UPDRS, determination of post-void residual by bladder ultrasound
Laboratory Examination: Urinalysis and BMP and HgbA1c if indicated
Education: How to complete bladder diary, handout take-home questionnaires (ICIQ-OAB and OAB-QOL)
Visit 2 (Part 1) : Randomization
Interview: Collect and review 7-day bladder diary, ICIQ questionnaires
Physical: Vital signs; review laboratory results; determination of post-void residual by bladder ultrasound if 
not conducted at first visit; 
Procedure: Randomization (Behavioral Therapy or Drug Therapy)
Behavioral Therapy 
Drug Therapy
Visit 2 (Part 2):  Behavioral Therapy 
Randomization
Procedure: Neuropsychological battery, SRTT, 
Pelvic floor muscle exercise training
Education: specific behavioral techniques for 
constipation, modification of fluid intake or timed 
voiding
Visit 2 (Part 2) :  Drug Therapy  Randomization
Procedure: Neuropsychological battery, SRTT
Education: Medication 
Visit 3:  Behavioral Therapy (2 weeks)
Interview: Review PFME record, address new 
problems, reinforce practice at home and verbal 
feedback regarding muscle control
Education: Urge suppression strategy, management 
of stress-related urine loss (if applicable)
Visit 3:  Drug Therapy (2 weeks)
Interview: Medication Management, Medication Side 
Effects
Education: Medication & Bladder Diary & Forms (to 
return at Visit 5) 
Visit 4:   Behavioral Therapy (4 weeks)
Interview: Review PFME record, address new 
problems, offer additional manual training session if 
subject is not satisfied with treatment or has < 25% 
reduction in episodes of UI based on bladder diaries.   
Education: Reinforce strategy and PFME 
Visit 4:   Drug Therapy (4 weeks)
Interview:  Medication Management, Medication Side 
Effects
Education: Medication and Reminder to complete 
Bladder Diary
Visit 5:  Behavioral Therapy (6 weeks)
Interview:  Discuss new problems, Satisfaction & 
Benefit questionnaire  
Education:   Reinforce PFME and urge strategy, 
Bladder Diary & Forms (to return at Visit 7)
Visit 5:  Drug Therapy (6 weeks)
Interview:  Collect and review bladder Diary; 
Medication Management,  Satisfaction & Benefit 
questionnaire
Education: Medication & Bladder Diary & Forms (to 
return at Visit 7)
Visit 6:   Behavioral Therapy (8 weeks)
Interview: Review PFME record, address new 
problems, offer additional manual training session if 
subject is not satisfied with treatment or has < 25% 
reduction in episodes of UI based on bladder diaries.   
Education: Reinforce strategy and reminder to 
complete diary and forms
Visit 6:   Drug Therapy (8 weeks)
Interview: Medication Management & Medication 
Side Effects
Education:  Medication and Reminder to complete 
Bladder Diary
Visit 7: Behavioral Therapy (12 weeks)
Interview: Collect and Review diary, collect follow-up 
questionnaires (ICIQ and satisfaction & benefit), 
administer LSA, constipation, self-efficacy and 
adherence questionnaires
Procedure: Repeat neuropsychological battery
Visit 7: Drug Therapy (12 weeks)
Interview: Collect and Review diary, collect follow-up 
questionnaires (ICIQ and satisfaction & benefit), 
administer LSA, self-efficacy, and constipation 
questionnaires
Procedure: Repeat neuropsychological battery


12
Human Subjects:
a. Risk to Subjects
Human Subjects Involvement and Characteristics:  Men and women with PD recruited from the Atlanta, 
Birmingham, Richmond, and Philadelphia VAMCs as well as in the surrounding community.  We propose 
randomizing 90 participants to either exercise-based behavioral therapy or drug therapy with Solifenacin.  In 
order to complete the study in 80 participants, we anticipated having to screen approximately 180 PD patients 
to identify those with clinically significant OAB symptoms, and enroll approximately 45 participants in each 
group.  These estimates are based on our experiences in the BETTUR PD and BETTUR2 pilot studies.  In the 
BETTUR PD study, 33 individuals were screened to enroll 20 participants.  Of the 20 participants who were 
enrolled, 17 completed the study demonstrating a 15% drop out rate once enrolled. To date, in the BETTUR2 
study, we have screened 107 individuals to randomize 51 participants and have had 6 participants drop out 
(11.7% rate).
During FY16, 541 unique Veterans with PD were served by the Atlanta VA and surrounding CBOCs.  
For the BETTUR PD pilot, 14 of the 32 screened subjects were recruited from the Atlanta VA after mailing 
letters to 360 Veterans identified with a diagnosis of PD in the Metro Atlanta area in FY08.  Recruitment was 
extended to a university-based movement disorders clinic to achieve the intended sample size of 20 enrolled 
subjects.  For the BETTUR2 study, of the 65 persons who have undergone screening procedures thus far, 25 
were Veterans and 40 were recruited from university-based movement disorders clinics in Atlanta and 
Birmingham in order to maximize the team’s ability to recruit the intended sample size. Thus, we propose to 
recruit both Veterans and non-Veterans for the proposed study from the outset.  The university affiliates in 
Atlanta (Emory), Birmingham (University of Alabama at Birmingham), Richmond (Virginia Commonwealth 
University), Philadelphia (University of Pennsylvannia) all have active movement disorders programs, which 
enhance the overall resources available to the study.
The sample size is informed by the ICIQ-OAB symptom score reduction observed in the BETTUR PD 
and BETTUR2 studies of behavioral therapy for urinary symptoms in PD.  Based upon the bladder diary-
derived UI frequency data (consistent measure used in both behavioral and drug trials), the effect of behavioral 
therapy and drug therapy to reduce UI frequency is similar24,34.  The ICIQ-OAB symptom score range is 0-16, 
with higher scores indicating worse symptoms.  A score ≥ 7 would indicate clinically significant OAB symptoms 
(urgency, frequency, urgency UI, nocturia) occurring on average at least sometimes.  In our previous studies, 
we have observed a 2-3 point reduction in the symptom score, which represents a 12%-19% reduction from 
baseline24,64.  The minimally clinically important difference for the ICIQ-OAB is defined as a statistically 
significant reduction in the symptom score that is accompanied by a reduction in bother and improvement in 
OAB-specific QOL.  Because the observed reduction (12%-19%) represents a statistically and clinically 
meaningful difference, we propose a non-inferiority margin of 15%.  Thus, we will randomize 90 participants in 
order to complete the interventions in 80 participants, which assumes 85% power and a non-inferiority margin 
on the OAB symptom score of 15% at 12-weeks post-randomization. 
Sources of Materials:  The patients involved in this study will be seen in the Atlanta and Birmingham 
VAMC/GRECC Continence Clinics and the Philadelphia and Richmond PADRECCs. No tissue, blood, or urine 
samples will be stored during the study period as part of the protocol. For purposes of this research, baseline 
and treatment data will be stripped of all patient identifiers and each participant will be given a unique identifier 
for the study.  Patient records will be stored in a locked cabinet in a locked office and will be accessible only to 
the Principal Investigator, Interventionist, Research Coordinator, Patient Recruiter, Site PI’s (Markland, Lehosit, 
and Morley) and co-investigators (Johnson, Goode, Burgio, Baron).  Computer-based records will be 
maintained through the Veteran’s Administration Computerized Patient Record System (CPRS), a secure 
network with password protection.     
Potential Risks:  Behaviorally-based intervention and treatment for urinary symptoms is both low risk and side 
effect free.  During the course of a study in which questionnaires are used and bladder diaries are a source of 
outcome measure, some participants may find questions uncomfortable or find documenting voiding habits 
burdensome.  Rectal or vaginal manual biofeedback occurs during a physical exam.  The participant is 
instructed to squeeze against the interventionist’s finger to isolate their pelvic floor muscles through a 
contraction.  Similar techniques have been utilized in previous studies of exercise-based behavioral training for 
Physical: Vital signsEducation: Reinforce strategy
Physical: Vital signsEducation:  Medication 
completion


13
urge incontinence and have shown clinically significant improvement with minimal discomfort20,23.  The 
discontinuation rate for enrolled subjects was 15% or less.  
Solifenacin has been FDA-approved for OAB symptoms since 200471.  The most common side effects 
include dry mouth and constipation71.  In a small study of adverse events among older (> 65 yrs old) versus 
younger (≤ 65 yrs old) adults taking solifenacin or oxybutynin, solifenacin was associated with lower incidence 
of side effects than oxybutynin72.  Older and younger adults taking solifenacin had similar rates of treatment-
emergent dry mouth.  Another study of solifenacin or oxybutynin  versus placebo among older adults with mild 
cognitive impairment showed no impact of solifenacin at a dose of 5 mg daily (10mg daily was not tested) on 
tests of executive function, working memory or reaction time compared to placebo73.  In the Urge PD study, 
which evaluated solifenacin in persons with PD, 1/9 individuals reported constipation, 2/9 reported dry mouth 
and 1/9 experienced urinary retention34.   
b.  Adequacy of Protection from Risks
Recruitment and Informed Consent:  Subjects for the current study have been recruited through the Movement 
Disorders clinics at the Atlanta VAMC, Birmingham VAMC, Philadelphia, and Richmond VAMC, where each 
site has at least one board-certified movement disorders neurologist.  For the BETTUR PD pilot, recruitment 
was extended to the Movement Disorders clinic at Emory University because of slow recruitment at the Atlanta 
VAMC.  For the BETTUR2 study, although an additional recruitment site was added at the Birmingham VA, 
both sites requested permission to recruit non-Veterans through their university-affiliated movement disorders 
program in order to reach the target sample size. 
Fliers are posted in the medical center as well as a PowerPoint slide ad that is broadcast throughout 
the medical center closed circuit television system.  Per VA procedures and with permission from the primary 
neurologist, letters are sent to Veterans with a diagnosis of PD, who are identified in the corporate data 
warehouse and confirmed through chart review, to inform them about the study and offer contact information 
for study staff.  Study teams have also partnered with the Michael J Fox Foundation Fox Trial Finder and local 
Parkinson Support Groups in order to let the local community know about the study.  All patients will have the 
opportunity to give informed consent after discussion with the study PI or research assistant in a private 
examination room.  As a three-site VA study, study procedures and the informed consent form will be approved 
by the Central VA Institutional Review Board and the VA Research and Development committee at each site.  
All subjects will be given a copy of the consent to keep for their records.  
Protection Against Risk:  For purposes of this research, baseline and treatment data will be stripped of all 
patient identifiers and each participant will be given a unique identifier for the study.  Patient records will be 
stored in a locked cabinet in a locked office and will be accessible only to the Principal Investigator, 
Interventionist, Research Coordinator, Patient Recruiter, and Site PI’s (Markland, Lehosit, and Morley) and co-
investigators (Johnson, Goode, Burgio, Baron).  Computer-based records will be maintained through the 
Veteran’s Administration Computerized Patient Record System (CPRS), a secure network with password 
protection.

Only personnel who are qualified and IRB approved and trained for maintaining the privacy of each 
participant will be permitted to view records.  

Each participant will be assigned a unique study ID that will be used on all study documents.  

All identified patient data will be maintained on a secure VA research server at each site. 

A separate tracking database with patient identifiers that provide a link to the unique study IDs will be 
stored on a secure VA research server at each study site.  

Participant study documents which are identified by the participant’s unique study ID, will be scanned 
on a VA device behind the VA firewall and uploaded to an Atlanta VA research server that is accessible 
to BOSS PD study personnel from each study site who are credentialed through the VA Research 
service at each site.

Only deidentified data will be entered into the Redcap database by study personnel who are 
credentialed through the Atlanta VA Research service.
At all visits (in-clinic and telephone) after the baseline assessment, we will incorporate a standardized 
side effects checklist that has been used by the Continence research team for studies involving anticholinergic 
bladder relaxant therapy.  The most common side effects reported by persons taking solifenacin are dry mouth 
and constipation.  The risk of acute urinary retention will be reduced by excluding those with a baseline post-


14
void residual of ≥ 150 mL by bladder ultrasound.  All adverse events and severe adverse events will be 
reported to the IRB, VA ORD, and the DSMB per VA policies.
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