Clinical trial NCT02044510
Conditions: Urinary Bladder, Neurogenic
Keywords: Multiple Sclerosis Spinal Cord Injuries mirabegron Urodynamics
Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Start date: 2014-07-01; Completion date: 2018-02-01
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed study is a randomized, double blind placebo controlled multicenter study to determine the effectiveness of mirabegron in the treatment of neurogenic bladder dysfunction. Patients will be randomized into one of two trial arms: mirabegron 25mg for two weeks, with escalation to 50mg for the remaining 8 weeks, or matched placebo capsule for two weeks, with placebo escalation for the remaining 8 weeks. Each of these trial arms will be stratified based on whether the patient is already taking an anticholinergic medication or not. The study will treat a total of 144 patients (72 with placebo, 72 with mirabegron). The study hypothesis is that mirabegron will result in a statistically superior (increased) urodynamic bladder capacity.

The study duration is 12 weeks, with a 1-4 week run in period where no active or placebo treatment will be administered. The primary outcome measure will be based on an increase in urodynamic bladder capacity. Secondary outcome measures will be additional urodynamic parameters, urinary symptom scales, urinary quality of life indices, and voiding diary results.

Patients who are over 18 years of age with a diagnosis of multiple sclerosis (MS) or spinal cord injury (SCI) will be eligible to participate. All eligible patients will have urodynamic studies performed within 4 weeks of trial enrollment, and at the end of study (week 9-10). Adverse events and study outcomes will be assessed at predefined study time points.

Detailed description:

Arms: arm 1: Patients randomised to this arm start with mirabegron 25mg PO daily for two weeks, and then at 2 weeks titrate to 50mg PO daily, and maintain that dose for the duration of the study (8 additional weeks). arm 2: Inert placebo pill, matching active treatment pill.
Interventions: intervention 1: Mirabegron intervention 2: Placebo
Intervention descriptions: intervention 1: Mirabegron 25mg PO daily for 2 weeks, with dose increase to Mirabegron 50mg PO daily for the remaining 8 weeks. intervention 2: Matched placebo capsules to the intervention arm

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Clinical Protocol 
 
Urodynamic and clinical efficacy of Mirabegron among neurogenic bladder patients 
 
 
Version Date 
Sept 30, 2014 
 
 
 
 
 
 


 
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Table of Contents 
CONTACT INFORMATION .............................................................................................................................................................. 3 
PRINCIPLE INVESTIGATOR ........................................................................................................................................................................................... 3 
PARTICIPATING INVESTIGATORS ................................................................................................................................................................................ 3 
CLINICAL PROTOCOL OVERVIEW ............................................................................................................................................... 4 
BACKGROUND ................................................................................................................................................................................... 5 
OBJECTIVES ........................................................................................................................................................................................ 6 
PRIMARY OBJECTIVE ..................................................................................................................................................................................................... 6 
SECONDARY OBJECTIVES .............................................................................................................................................................................................. 6 
SPECIFIC HYPOTHESIS ................................................................................................................................................................... 8 
PRODUCT DESCRIPTION ................................................................................................................................................................ 9 
STUDY JUSTIFICATION .................................................................................................................................................................10 
RISK ASSESSMENT .........................................................................................................................................................................12 
POTENTIAL SPECIFIC RISKS ....................................................................................................................................................................................... 12 
METHODS TO MINIMIZE RISK .................................................................................................................................................................................... 12 
STUDY DESIGN .................................................................................................................................................................................14 
INCLUSION CRITERIA .................................................................................................................................................................................................. 14 
EXCLUSION CRITERIA ................................................................................................................................................................................................. 14 
POINT OF ENROLLMENT ............................................................................................................................................................................................. 16 
SAMPLE SIZE ................................................................................................................................................................................................................ 16 
MEDICATION PREPARATION AND ALLOCATION .................................................................................................................................................... 16 
DESCRIPTION OF STUDY TIMELINE AND PATIENT VISITS ...................................................................................................................................... 17 
STUDY TIMELINE SUMMARY ..................................................................................................................................................................................... 19 
CRITERIA AND PROCEDURES FOR WITHDRAWAL ................................................................................................................................................... 20 
SAFETY MONITORING AND REPORTING OF ADVERSE EVENTS .............................................................................................................................. 20 
STATISTICAL CONSIDERATIONS ...............................................................................................................................................22 
STUDY VARIABLES ....................................................................................................................................................................................................... 22 
INVESTIGATOR RESPONSIBILITIES .........................................................................................................................................24 
SIGNATURE PAGE ...........................................................................................................................................................................25 
REFERENCES ....................................................................................................................................................................................26 


 
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Contact Information 
 
Principle Investigator 
Blayne Welk, MD FRCSC MSc 
Assistant Professor, Division of Urology 
Western University 
 
Room B4-667 
St Joseph's Health Care 
268 Grosvenor Street London ON N6A 4V2 
Phone: 519 646-6367 
Fax: 519 646-6037 
Blayne.welk@sjhc.london.on.ca 
  
Participating Investigators 
Dr Duane Hickling 
Assistant Professor, Division of Urology 
Ottawa University 
 
The Ottawa Hospital Civic Campus 
Department of Urology 
1053 Carling Avenue 
Ottawa ON K1Y 4E9 
Phone: 613 761-4000 
Fax: 613 761-4350 
duanehickling@gmail.com 
 
Dr Karen Ethans 
Associate Professor, Department of Medicine 
University of Manitoba 
 
Room RR143A 
Health Sciences Centre 
800 Sherbrook St 
Winnipeg, MB R3A 1M4 
Phone: 204 787-5135 
Fax: 204 787-1476 
KEthans@exchange.hsc.mb.ca 
 


 
4
Clinical Protocol Overview 
 
The proposed study is a randomized, double blind placebo controlled multicenter study to determine 
the effectiveness of mirabegron in the treatment of neurogenic bladder dysfunction. Patients will be 
randomized into one of two trial arms: mirabegron 25mg for two weeks, with escalation to 50mg for 
the remaining 8 weeks, or matched placebo capsule for two weeks, with placebo escalation for the 
remaining 8 weeks. Each of these trial arms will be stratified based on whether the patient is already 
taking an anticholinergic medication or not. The study will treat a total of 144 patients (72 with 
placebo, 72 with mirabegron).  The study hypothesis is that mirabegron will result in a statistically 
superior (increased) urodynamic bladder capacity. 
 
The study duration is 12 weeks, with a 1-4 week run in period where no active or placebo treatment 
will be administered. The primary outcome measure will be based on an increase in urodynamic 
bladder capacity. Secondary outcome measures will be additional urodynamic parameters, urinary 
symptom scales, urinary quality of life indices, and voiding diary results. 
 
Patients who are over 18 years of age with a diagnosis of multiple sclerosis or spinal cord injury will be 
eligible to participate. All eligible patients will have urodynamic studies performed within 4 weeks of 
trial enrollment, and at the end of study (week 9-10). Adverse events and study outcomes will be 
assessed at predefined study time points. 


 
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Background 
 
A variety of neurologic diseases can lead to bladder dysfunction, however spinal cord injury (SCI) and 
multiple sclerosis (MS) are most often associated with significant bladder dysfunction and urinary 
morbidity (renal dysfunction, incontinence, and urinary tract infection)(1). In addition to conservative 
measures, first line therapy for many neurogenic bladder patients involves the use of anticholinergic 
medications. Anticholinergic medications have been primarily studied for the more common indication 
of overactive bladder(2). In small clinical trials and case series, these medications have demonstrated 
improvements in urgency incontinence, and urodynamic parameters (such as bladder capacity and 
detrusor pressure) among neurogenic bladder patients(3). However, anticholinergic medications have 
a number of undesirable side effects, including dry mouth and constipation. This has been shown to 
significantly limit medication compliance among both the general population(4), and neurogenic 
bladder patients(5). Despite treatment with anticholinergic medication, many patients still have 
bothersome urinary symptoms(3). 
 
Mirabegron is a Beta-3 agonist, which is the first of a new class of overactive bladder medication. It was 
approved by Health Canada for the treatment of overactive bladder in 2012. Beta-3 receptors are 
primarily found in the bladder, and mediate bladder relaxation. Mirabegron has 33-100x selectivity for 
the Beta-3 receptor compared to Beta-1 or Beta-2(6).  Clinical trials have shown it is efficacious for the 
treatment of overactive bladder symptoms in the general population with minimal side effects and an 
excellent safety profile(7,8). Common adverse events related to mirabegron appear to be limited to 
urinary tract infection, hypertension, headache and gastrointestinal upset, which all occur at rates 
similar to placebo(9). There is currently no evidence (or registered clinical trials) evaluating the use of 
mirabegron among neurogenic bladder patients, making this a novel and exciting area of study. 
 
 


 
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Objectives 
 
Primary objective 
 
Examine the change in urodynamic bladder capacity associated with mirabegron use among 
neurogenic bladder patients. 
 
Urodynamics are a clinical study of bladder function. A small catheter is placed in the bladder and 
another in the rectum, and saline is infused into the bladder at a standard rate while a pressure 
transducer measures bladder pressure. Standard and accepted operating procedures for the 
performance of urodynamic testing have been established(10). 
 
Urodynamic studies are an essential part of the urologic evaluation of patients with neurogenic disease 
due to the risk of urologic complications such as renal dysfunction and urinary incontinence related to 
impaired bladder compliance and high pressure neurogenic detrusor overactivity(11). It is a 
recommended test in the guidelines published by the American Urologic Association(12). It is standard 
practice to perform this study in order to assess baseline bladder function, and to assess treatment 
response. 
 
Given the fact that many patients with neurogenic bladder dysfunction do not have normal perception 
of urinary function, an objective measure of bladder function is essential. Urodynamic bladder capacity 
is a good parameter to evaluate as the primary outcome for this study given the known effect of 
alternative medications on bladder capacity, and the desirable associated clinical benefit of increased 
bladder capacity (such as increased time between voids, reduced risk of renal damage, and reduced 
risk of urinary incontinence). Patients are often followed with further urodynamic studies to assess the 
effectiveness of interventions aimed at improving bladder function. Among neurogenic bladder 
patients, urodynamic parameters have good measurement characteristics(13). 
Secondary objectives 
 
Examine the clinical effectiveness of mirabegron for treating the symptoms of urinary 
frequency, urgency, and urge incontinence among neurogenic bladder patients. 
 
The assessment of voiding function is complex, and individual measures may be inadequate. Multiple 
secondary outcomes are included to assess for a clinically meaningful level of improvement in bladder 
function. 
 
• 
Secondary urodynamic characteristics will be assessed (volume at first episode of detrusor 
overactivity, maximum detrusor pressure, volume at maximum detrusor pressure, bladder 
sensation, and bladder compliance). 
• 
The 3 day voiding diary is a simple patient maintained record of fluid intake, voided volume 
and incontinence episodes. This measure has an acceptable reliability when used in clinical 
study(14).  This will be used to assess number of episodes of urgency incontinence, urinary 
frequency, longest time between voids, functional capacity, and mean voided volume.  
• 
Quantification of urinary incontinence will be assessed with pad weights(15).  This will 
determine the amount of urinary incontinence that occurs over a 24hr period. The 24hr pad 
test is stable over time, and has good reliability(16). 
• 
Patient reported outcome measures will be used to assess incontinence related quality of life, 
overall urinary quality of life, and specific urinary symptoms. 


 
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o Quality of life will be measured with the Incontinence quality of life measure (I-QOL), 
and the SF-Qualiveen. The I-QOL is an incontinence specific quality of life tool that has 
been shown to be a valid, reliable and responsive measurement among patients with 
neurogenic bladder dysfunction(17). The SF-Qualiveen is a urinary specific quality of 
life measure developed and studied specifically for neurogenic bladder patients; 
validity, reliability and responsiveness have been established(18) (19,20). 
o The Neurogenic bladder symptom score (NBSS) is a symptom specific measure of 
urinary symptoms developed for patients with neurogenic bladder dysfunction with 
demonstrated validity and reliability (Reference in press, Journal of Urology). 
• 
The patient perception of bladder condition is a commonly used measure in the assessment of 
oral medications for the treatment of overactive bladder symptoms(21). 
 
• 
Examine the tolerability and adverse effects associated with mirabegron use among neurogenic 
bladder patients. 
 
o Adverse events related to mirabegron will be monitored. Patients will be actively 
monitored for hypertension, tachycardia, and urinary retention. Other adverse events 
will be monitored by passive reporting.  
 
 


 
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Specific Hypothesis 
 
The primary hypothesis for effectiveness is that patients treated with mirabegron will have an 
increased urodynamic bladder capacity at 10 weeks compared to the placebo group.  The null 
hypothesis is H0: pmirabegron – pplacebo ≤ 0. The alternative hypothesis is HA: pmirabegron – pplacebo > 0. 
 
 


 
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Product Description 
 
Mirabegron is a selective beta-3 agonist that is indicated for the treatment of overactive bladder, with 
symptoms of frequency, urgency and urgency incontinence. It is provided as a single extended release 
oral pill that may be taken with or without food. It has no significant affinity for other pharmacologic 
targets. Peak plasma concentrations occur at 3-5 hrs among health adults. Steady state concentrations 
occur within 7 days of once daily dosing. Mirabegron has been studied in over 10,000 human subjects, 
at doses from 25-200mg. The incidence of adverse events in the mirabegron 25-50mg dose groups is 
comparable to placebo groups. The most frequently reported adverse event was hypertension. Most of 
the events were mild or moderate in intensity.  
 
Mirabegron is registered for the treatment of OAB in Canada. No actions have been required for safety 
reasons concerning withdrawal, rejection, suspension or failure to obtain a renewal of a marking 
authorization. There have been no restrictions on distribution, clinical study suspension, dosage 
modification, indications, or formulation changes. 
 
Further product details are included in the product monograph (Appendix 5). 
 
 


 
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Study Justification 
 
Patients with neurogenic bladder dysfunction consist primarily of patients with spinal cord injuries 
(SCI) or multiple sclerosis (MS)(1). These conditions lead to damage to the upper motor neurons, 
which can cause varying patterns of bladder dysfunction. Common symptoms among patients with MS 
include urgency, urgency incontinence, and increased urinary frequency, which is the result of 
neurogenic detrusor overactivity. Common symptoms among patients with SCI depend on the level of 
the injury and the method of bladder management. Most patients will have neurogenic detrusor 
overactivity, and often will have coexisting detrusor-sphincter dyssynergia. This leads to an inability to 
both store and void urine. Given the lack of urinary sensation, the primary symptom for these patients 
is often urinary incontinence. Patients may be started on intermittent catheterization to improve 
voiding. 
 
For both MS and SCI patients, the symptoms of urinary incontinence or urgency/frequency are usually 
treated with anticholinergic medication. There are several medications available (such as oxybutynin 
and tolterodine). Health Canada approval of these medications is based on a labeled indication for the 
treatment of overactive bladder symptoms, however these medications have been studied in patients 
with neurogenic bladder dysfunction(3). These studies have demonstrated patient perceived 
improvement, increased bladder capacity, and lower maximum detrusor pressure, however they are 
also associated with a higher incidence of adverse events related to anticholinergic side effects.  
 
Previous clinical experience with mirabegron has been in clinical trials for the treatment of overactive 
bladder (OAB) symptoms. Three large randomized trials have been completed(7,8,22). In these OAB 
studies, there was a trend towards better efficacy with the 50mg dose, and given the increased dose 
requirements for anticholinergic medications in the neurogenic bladder population(23), a dose 
titration to a maximal dose of 50mg was selected. Mirabegron has been evaluated in a Phase II RCT in 
combination with solifenacin (an anticholinergic medication) for OAB patients(24). The combination of 
mirabegron and solifenacin resulted in an improvement in voided volume and a reduction in voiding 
frequency, with adverse events in keeping with monotherapy. Synergy between anticholinergic 
medications and mirabegron has not been evaluated in the neurogenic bladder population. 
 
Mirabegron is hypothesized to be effective in reducing the symptoms of neurogenic bladder 
dysfunction. In an animal model of SCI, mirabegron has a beneficial effect on urodynamic parameters 
without affecting voiding parameters(25). Mirabegron may have a beneficial safety and tolerability 
profile among patients with neurogenic bladder dysfunction. Evidence from patients with overactive 
bladder suggests adverse events with mirabegron are very similar to placebo(7,9). 
 
A placebo controlled trial is the most methodologically sound trial design for this clinical study. Among 
all trials involving over active bladder symptoms, there is a significant placebo response (usually 20-
30%)(26), which makes a noninferiority trial design impractical at this preliminary stage. In addition, 
there are no adequately powered and well conducted randomized clinical trials that have established 
the efficacy of anticholinergic medication among this population, and meta-analyses of the available 
data on anitcholinergics have confidence intervals with large bounds, indicating the imprecision of our 
current knowledge about their effect sizes(3). This also makes direct comparison to another 
medication in a clinical trial setting difficult. As this is the first study to investigate the efficacy of this 
medication in this population, it is important to establish basic efficacy before proceeding with further 
study. The placebo arm is limited to 10 weeks, which allows for a dose titration and an adequate 
medication trial of 6-8 weeks of the full dose mirabegron (in the OAB trials the maximum effect of this 
medication was seen after 4-6 weeks(22)), at which point if there is no response the trial is over, and 
different therapy can be pursued at the discretion of the treating physician. Although urinary 


 
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symptoms are often bothersome in this population, they are not dangerous, and current clinical 
practice would include a trial of anticholinergic medication in a similar manner. 
 
 


 
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Risk Assessment 
 
All activities performed within the scope of this study will comply with recognized Good Clinical 
Practice guidelines and applicable regulatory requirements. 
Potential specific risks 
 
Potential risks related to the use of mirabegron include: 
• 
Hypertension 
• 
Increased heart rate 
• 
Urinary retention 
• 
Unknown effect on sperm, ovum, and pregnancy 
 
Potential risks related to urodynamic studies include: 
• 
Urinary tract infection 
• 
Hematuria 
• 
Mild pelvic discomfort 
• 
Autonomic dysreflexia (among SCI patients only) 
 
Methods to minimize risk 
 
Potential risks related to the use of mirabegron will be minimized by exclusion criteria and active 
monitoring. Mirabegron has an acceptable safety profile based on previous animal and human 
studies(9). 
 
Patients with uncontrolled hypertension (defined as screening visit BP >180mmHg systolic or 
>110mmHg diastolic) will be excluded at screening. BP will be monitored at the +2 week followup, and 
if a normotensive patient becomes hypertensive, or there is a significant increase in blood pressure 
after multiple readings, the medication will be discontinued and considered an expected adverse event 
(details in safety monitoring section). In clinical studies for OAB, a mean increase of 1mmHg was seen 
in systolic and diastolic BP; new onset hypertension was reversible upon discontinuation of the 
medication(9). 
 
Patients will have their heart rate monitored at screening. Those with a resting heart rate >100bpm 
after repeat measurements will be excluded. Patients with a history of tachyarrhythmia’s will be 
excluded. HR will be monitored at the 2 week followup, and if their resting HR is >100 bpm after 
multiple readings, the medication will be discontinued and considered an expected adverse event. 
 
A clinical safety study in patients with bladder outlet obstruction did not demonstrate an increase in 
urinary retention(27), however it has been reported in postmarketing experience with mirabegron. 
Patients with a post void residual >250mL who are not already using intermittent catheters will be 
excluded from the study. All patients will be instructed on the signs and symptoms of urinary retention. 
Post void residual will be reassessed at the 2 week followup. Patients who develop urinary retention 
(defined as signs and symptoms of urinary retention with a post void residual >250mL, or an 
asymptomatic PVR >400mL) will discontinue medication and be considered as an expected adverse 
event.  
 
Patients of child bearing potential will have a pregnancy test done on screening and monitored 
throughout the trial through health review at each visit. Male and female patients who are planning on 


 
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conceiving will be excluded from this study. Female patients must agree to use an effective form of 
contraceptive between the screening visit and continued throughout the study period and for 28 days 
after the final dose of study drug. Male subjects with a partner of childbearing potential must also use 
an effective form of contraceptive between the Screening visit and continued throughout the study 
period and for 28 days after the final dose of study drug.  All male participants will be provided with 
Letters of Information to be given to all of their female sexual partner(s) who are of child bearing 
potential. Male subjects also must not donate sperm starting at screening and throughout the study 
period and for 28 days after the final study drug is taken. 
 
All patients will be counseled about the risks related to urodynamic studies. Urodynamic studies are 
performed under the supervision of a urologist, and carried out by nurses trained in the urodynamic 
equipment. The risks are generally mild and infrequent(10,28). Patients will be assessed for 
symptomatic urinary tract infection prior to urodynamics, and if necessary, the urodynamic study will 
be delayed in order to initiate antibiotic treatment. After urodynamics, the urine will be assessed and if 
there is significant hematuria, this will be monitored and treated if necessary. Patients will be informed 
that there may be some mild pelvic discomfort associated with bladder filling that will be relieved at 
the end of the study. SCI patients with complete injuries above the level of T6 will be monitored for 
symptoms of autonomic dysreflexia related to bladder filling (headache, flushing, sweating, nausea). If 
these symptoms occur, the study will be terminated, and the bladder drained. 
 
Patients will have baseline laboratory tests (creatinine, AST, ALT, GGT, total bilirubin), ECG, and 
urinalysis done prior to randomization, and at visit 3 (2 weeks after the initiation of the study 
medication).  
 
 
 
 
 


 
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Study Design 
 
This clinical study will be a randomized, double blind placebo controlled multicenter study to 
determine the effectiveness of mirabegron for the symptoms of neurogenic bladder dysfunction among 
patients with SCI or MS. Patients will be randomized at study enrollment to either placebo or 
mirabegron treatment arms. The proposed study size is 144 patients, with an included 20% margin to 
account for those that may withdraw or be lost to followup. Randomization of SCI and MS patients will 
be stratified to ensure approximately equal distribution of these patient groups between trial arms, 
and approximately equal distribution of patients who are currently taking bladder specific 
anticholinergic medication versus those who are not taking anticholinergics. This study has been 
registered with clintrials.gov NCT02044510. 
 
Inclusion criteria 
 
• 
Diagnosis of traumatic or nontraumatic suprasacral SCI or multiple sclerosis (based on a 
neurologist assessment and/or the McDonald criteria)(29) 
• 
Age >18 years 
• 
Stable method of bladder management for >3months (either spontaneous or provoked voiding, 
or intermittent catheterization). 
• 
Bothersome urinary symptoms (urinary frequency, urgency, or urgency incontinence based on 
standard ICS definitions(30)) and completed 3 day voiding diary demonstrating at least 1 
episode of non-stress based urinary incontinence over the 72hr period (this may be urgency 
based incontinence or unaware incontinence). 
• 
Patient is able to read and speak English 
 
Exclusion criteria 
 
Based on Screening visit history: 
• 
Participation in another drug or device study in the 60 days prior to the screening visit. 
• 
Previous urologic surgery: Transurethral prostatectomy, bladder augmentation, 
sphincterotomy, bladder neck sling, artificial urinary sphincter, catheterizable channel, 
implantable electrostimulator/neuromodulator 
• 
Current use of  suprapubic catheter/foley catheter 
• 
Unstable cardiac disease (uncontrolled hypertension, myocardial infarction, unstable angina, 
severe congestive heart failure (NYHA 3 or 4), ventricular arrhythmia (such as torsades de 
pointes), or stroke within the last 6 months) 
• 
Clinically significant abnormal ECG 
• 
The investigator believes the patient has an increased risk of QT prolongation (based on review 
of the screening ECG and patients concurrent medications) 
• 
History of significant renal dysfunction within 1 year, or serum creatinine >150umol/L at 
screening visit (visit 1). 
• 
History of significant liver disease within 1 year, or serum AST/ALT >2 times upper limit of 
normal, GGT >3 times upper limit of normal, total bilirubin >2 times upper limit of normal at 
screening visit (visit 1). 
• 
History of pelvic radiation 
• 
History of bladder cancer 
• 
History of a concurrent malignancy or cancer (except noninvasive skin cancer) within the last 5 


 
15
years.  Subjects with a history of cancer are considered eligible if the subject has undergone 
potentially curative therapy and the subject has been considered disease free for at least 5 
years (with the exception of basal cell or squamous cell carcinoma of the skin).  
• 
Patient has a history of interstitial cystitis/pelvic pain syndrome 
• 
Patient has a history of acute or chronic urinary retention within the last 3 months, and is 
currently not using intermittent catheters 
• 
Patient has a history of a tachyarrhythmia 
• 
Patient has a history of glaucoma 
• 
Patient has a medical condition that may cause noncompliance with the study protocol 
• 
In the opinion of the Investigator the patient has a history of significant stress urinary 
incontinence 
• 
Patient has signs and symptoms of an active urinary tract infection (symptoms of dysuria, foul 
smelling urine, cloudy urine, increased spasticity, increased autonomic dysreflexia, self 
reported fever, increased incontinence, back/suprapubic pain). 
o Patient will submit urine for culture and sensitivity, undergo treatment, and will be 
eligible for rescreening after treatment. 
• 
Female patient who is pregnant or breastfeeding, or plans to become pregnant. 
• 
Male patient who is planning on fathering a child during the study or for 28 days after the last 
dose of study drug, or who is planning to donate sperm 
• 
Patient refuses to provide written consent 
• 
Patient will be unable or unwilling to complete the questionnaires and study visits  
• 
In the opinion of the study investigator, it is not in the patient’s best interest to be enrolled in 
this study. 
 
Based on medication and allergy review 
• 
The new addition of an anticholinergic medication, or a change to anticholinergic dose, within 
the last 30 days, (bladder specific anticholinergics include oxybutynin, tolterodine, 
fesoterodine, solifenacin, darifenacin, trospium, hyoscine, oxybutynin gel or patch, atropine, 
benzatropine). If previously used and discontinued, these medications must have been stopped 
for >2 weeks 
• 
Newly added bladder active medication (or dose change) within the last 2 months (Tamsulosin, 
Silodosin, Terazosin, Baclofen, Diazepam, amitriptyline, Finasteride, Dutasteride, 
DDAVP/desmopressin) 
• 
Use of flecainide, propafenone, donepezil, thioridazine, tramadol, aripiprazole, desipramine, 
imipramine, venlafaxine or digoxin 
• 
Intravesical onabotulinum toxin use within the last 1 year 
• 
Intravesical oxybutynin within the last 3 months 
• 
Patient has a previous history of treatment with mirabegron 
• 
Patient has a known allergy to mirabegron or a previous adverse reaction to a beta 3 agonist. 
 
Based on physical exam 
• 
Patient has a postvoid residual > 250mL at study enrollment after repeated tested (1 attempt to 
re-void to ensure complete emptying of the bladder) and is not using intermittent catheters 
• 
Patient has a resting BP >180 mmHg systolic and/or >110 mmHg diastolic after 2 minutes of 
sitting quietly 
• 
Patient has a resting heart rate >100bpm after 2 minutes of sitting quietly 
• 
In the opinion of the study investigator, it is not in the patient’s best interest to be enrolled in 
this study based on a clinically significant abnormality on physical exam. 
 
 


 
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Point of enrollment 
 
Patients who meet the inclusion/exclusion criteria are eligible for entry into the study. They will have 
the study protocol and potential risks and benefits explained to them. Patients who agree to participate 
will be given a letter of information, and required to sign an informed consent document. Official 
enrollment and randomization occurs at the initial urodynamic appointment, after completion of the 
urodynamics study. If a patient withdraws between screening and enrollment, that spot will reopen in 
order to achieve the total study sample size of 144 randomized patients.  
 
Sample size 
 
A two sample t-test was used to calculate sample size. Patients on anticholinergics versus those not on 
anticholinergics will be analyzed as separate populations. Based on previous clinical trials in SCI and 
MS patients(31,32), an estimated mean end of study bladder capacity of 250mL (placebo) versus 
325mL (mirabegron), and a standard deviation of 100 was assumed; a two sided alpha of 0.05, and 
80% power would require a total of 58 patients. Accounting for a dropout rate of 20%, and to equal 
stratification among SCI and MS patients, and anticholinergic users versus anticholinergic nonusers a 
total sample size of 144 patients is required (36/group: SCI on anticholinergics, MS on anticholinergics, 
SCI not on anticholinergics, MS not on anticholinergics). 
 
 
Medication Preparation and Allocation 
 
Medication preparation will be done by the clinical trial pharmacists at St Joseph’s Health Care London. 
Commercially sourced mirabegron (myrbetriq) 25mg and matching inert placebo pill (both supplied by 
Astellas Inc) will be repackaged and dispensed in a blinded manner. Medication will be placed in 
identical containers, and labeled by study treatment assignment number (TAN). The clinical trial 
pharmacist at St Joseph’s Health Care London, who will not be involved in any study data collection or 
interpretation, will maintain a master list of treatment allocations for emergency unblinding. This 
clinical pharmacist will provide medication kits for other participating centers and will be responsible 
for appropriate labeling of the medication containers. These medication kits will be shipped to 
participating centers using a commercial temperature sensitive shipping service. 
 
All subjects who sign a consent form will received a subject number (01, 02, 03…). Once they are 
randomized, they will receive a treatment assignment number (TANs) based on having a diagnosis of 
either MS or SCI. There will be two block randomization schedules, one for MS patients, and one for SCI 
patients. Subjects will be assigned the next sequential TAN in either the MS or SCI group (so that 
approximately 36 SCI and 36 MS patients who are not on anticholinergics are randomly assigned 
placebo or mirabegron, and 36 SCI and 36 MS patients who are on anticholinergics are randomly 
assigned placebo or mirabegron). The randomization schedules will be computer generated by the 
clinical trial pharmacist, and kept confidential from all study investigators and other blinded study 
staff. TANs will be assigned so that 8 approximately equal groups of patients are created: placebo MS 
not on anticholinergics, placebo SCI not on anticholinergics, mirabegron MS not on anticholinergics, 
mirabegron SCI not on anticholinergics, placebo MS on anticholinergics, placebo SCI on 
anticholinergics, mirabegron MS on anticholinergics, mirabegron SCI on anticholinergics. Each TAN 
will correspond to a vial containing a 3 week supply of assigned medication (either placebo or 
mirabegron 25mg), and then a separate vial containing the 8 weeks of dose escalated medication 
(either placebo or mirabegron 50mg, matching the assignment from the initial 3 week phase). An extra 


 
17
7  day supply of medication will be included. 
 
If it is medically necessary to unblind a patient in an emergency, the St Josephs Hospital Pharmacist 
will be contacted to unblind the patient. The reason for unblinding shall be recorded, and the study 
investigator informed as soon as possible. Pharmacy staff may unblind patients without prior 
permission of the study investigator. 
Description of study timeline and patient visits 
 
Visit 1: Screening 
• 
Review of letter of information 
• 
Signing informed consent form 
• 
Medical history/Physical exam 
• 
Point by point review of inclusion and exclusion criteria 
• 
Assessment of BP (2min of sitting quietly, BP measured using standard office equipment 
consisting of a noninvasive, appropriately sized BP cuff in both arms. The arm with the highest 
diastolic will be used for the duration of the study. If the first reading is >140/>90mmHg, then a 
second reading will be obtained). 
• 
Assessment of HR (2min of sitting quietly, HR measured using radial pulse for 30 sec) 
• 
Assessment of PVR (not applicable for patients using intermittent catheterization.) Patient will 
be asked to void to completion, and 3 measurements obtained using calibrated, noninvasive 
bladder scanner are performed. If the average of these measurements is >250mL, then patient 
is asked to revoid and measurements are repeated. 
• 
Assessment of pregnancy by urine dip stick 
• 
Serum bloodwork drawn for creatinine, AST, ALT, GGT, total bilirubin 
• 
Urinalysis 
• 
ECG 
• 
Symptomatic UTI screening (symptoms of dysuria, foul smelling urine, cloudy urine, increased 
spasticity, increased autonomic dysreflexia, self reported fever, increased incontinence, 
back/suprapubic pain). If based on the clinical judgment of the supervising physician, a 
symptomatic UTI is suspected, a urine dip and urine culture will be done as per standard 
clinical practice. If the supervising physician wishes, they may wait for culture results, or 
initiate treatment, and reschedule study visit. 
• 
Patient will complete the following questionnaires: I-QOL, SF-Qualiveen, NBSS, and PPBC 
(Appendix 1). 
• 
Patients will be instructed on how to carry out the 24hr urinary pad test, and will return with 
this for the next visit (Appendix 2). 
• 
Patients will be instructed on how to complete the 3 day voiding diary, and will return with this 
for the next visit (Appendix 3). 
 
Visit 2 (within 1-4 weeks of screening. Set as week 0) 
• 
Review of 3 day voiding diary to ensure patient meets voiding diary eligibility criteria  
• 
Collection of 24hr urinary pad test material 
• 
Review of medication or health changes 
• 
Symptomatic UTI screening (symptoms of dysuria, foul smelling urine, cloudy urine, increased 
spasticity, increased autonomic dysreflexia, self reported fever, increased incontinence, 
back/suprapubic pain). If based on the clinical judgment of the supervising physician, a 
symptomatic UTI is suspected, a urine dip and urine culture will be done as per standard 
clinical practice. If the supervising physician wishes, they may wait for culture results, or 
initiate treatment, and reschedule urodynamics. 


 
18
• 
Randomization and 3 week medication supply (blinded placebo or mirabegron 25mg 
provided). Reminded to bring pill container to next visit. 
• 
Urodynamic assessment (Appendix 4) 
 
Visit 3 (2-3 weeks) 
• 
Review of medication or health changes/Physical exam 
• 
Pill count to assess medication compliance 
• 
Passive reporting of adverse events 
• 
Measurement of HR, BP, and PVR 
• 
Serum bloodwork drawn for creatinine, AST, ALT, GGT, total bilirubin 
• 
Urinalysis 
• 
ECG 
• 
Symptomatic UTI screening (symptoms of dysuria, foul smelling urine, cloudy urine, increased 
spasticity, increased autonomic dysreflexia, self reported fever, increased incontinence, 
back/suprapubic pain). If based on the clinical judgment of the supervising physician, a 
symptomatic UTI is suspected, a urine dip and urine culture will be done as per standard 
clinical practice. If the supervising physician wishes, they may wait for culture results, or 
initiate treatment. 
• 
8 week medication supply with a dose escalation (placebo capsule or 50mg mirabegron 
provided). Reminded to bring pill container to next visit. 
• 
Reminded to provide a voiding diary and 24hr pad test for next visit 
 
Visit 4 (9-10 weeks) 
• 
Review of medication or health changes 
• 
Pill count to assess medication compliance 
• 
Passive reporting of adverse events 
• 
Measurement of HR, BP, and PVR 
• 
Symptomatic UTI screening (symptoms of dysuria, foul smelling urine, cloudy urine, increased 
spasticity, increased autonomic dysreflexia, self reported fever, increased incontinence, 
back/suprapubic pain). If based on the clinical judgment of the supervising physician, a 
symptomatic UTI is suspected, a urine dip and urine culture will be done. If the supervising 
physician wishes, they may wait for culture results, or initiate treatment, and reschedule 
urodynamics. 
• 
Assessment of pregnancy by urine dip stick 
• 
Urodynamic assessment (Appendix 4) 
 


 
19
 
Study Timeline Summary 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
 
-1 to -4 wks 
0 wk 
+2-3 wks 
+9-10 wks 
Event 
Screening 
Randomization 
Followup 
End of Study 
visit 
Informed consent/LOI 
X 
 
 
 
Medical History/Physical 
Exam 
X 
 
X 
 
Inclusion/Exclusion check 
X 
 
 
 
Medication/Health review 
 
X 
X 
X 
BP/HR Measurement 
X 
 
X 
X 
PVR 
X 
X 
X 
X 
Urine Pregnancy test 
X 
 
 
X 
Bloodwork 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
ECG 
X 
 
X 
 
Urine infection screen (Hx, 
Dip, C&S PRN) 
X 
X 
X 
X 
IQOL 
X 
 
 
X 
SF-Qualiveen 
X 
 
 
X 
NBSS 
X 
 
 
X 
PPBC 
X 
 
 
X 
24hr urinary pad test 
Provided & 
Return with 
visit 2 
X 
Provided & 
Return 
with visit 4 
X 
3 day voiding diary 
Provided & 
Return with 
visit 2 
X 
Provided & 
Return 
with visit 4 
X 
Randomization 
 
X 
 
 
Adverse event assessment 
 
 
X 
X 
Medication compliance 
assessment 
 
 
X 
X 
Initial study drug (3 week 
supply, placebo or 
mirabegron 25mg) 
 
X 
 
 
Dose escalation (8 week 
supply placebo or mirabegron 
50mg) 
 
 
X 
 
Urodynamic study 
 
X 
 
X 
 
 
 


 
20
Criteria and procedures for withdrawal 
 
A patient may withdraw from the clinical trial at any time without prejudice or loss of care. The 
treating urologist may decide to withdraw a patient rom the clinical trial at any time based on their 
best medical judgment. Reasons for study exit will be obtained. If a patient is lost to followup or fails to 
appear for a scheduled post treatment assessment, every effort will be made to locate the patient 
before patient will be considered to have exited the trial. 
 
Patient will stop participation in the clinical study, and the study medication will be discontinued if 
there is: 
• 
An adverse event (an allergic reaction thought to be from the study medication, a significant 
increase in heart rate or blood pressure, an episode of acute urinary retention, a new 
asymptomatic PVR >400mL, a significant increase in serum liver function tests, (defined as an 
increase of serum AST/ALT >2 times upper limit of normal, GGT >3 times upper limit of 
normal, total bilirubin >2 times upper limit of normal), or a clinically significant abnormal ECG 
in the opinion of the investigator. 
• 
A medical necessity to add an excluded medication before the termination of the study. 
• 
A medical necessity to change the dose of an established anticholinergic medication used for 
bladder symptoms during the study. 
• 
The patient voluntarily withdraws from the study. Patients who do not undergo randomization 
will be replaced. 
• 
The subject is unable to mentally or physically tolerate the study medication or study 
procedures. 
• 
Pregnancy during the study.  The patient will be asked to immediately report this information 
to the study coordinator, and will be withdrawn from the study. The patient will be followed 
based on standard clinical practice.  
• 
There is a new medical condition which in the judgment of the supervising urologist makes 
them ineligible for further participation. 
Safety monitoring and reporting of adverse events 
 
All adverse events (expected and unexpected) should be reported as soon as possible by trial 
personnel. Monitoring for adverse events will occur between randomization (visit 2) and the final 
study visit (visit 4). The appropriate adverse event record will be completed and submitted to the 
principle investigator (including information on the adverse event, onset date, duration, severity and 
course of action taken). The local investigator will be responsible for informing their local ethics 
committee, and the principle investigator will be responsible for informing his REB and Health Canada. 
 
The following will be considered serious adverse events: any event that results in death or is life 
threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in 
significant disability/incapacity, or is an important medical event in the judgment of the treating 
physician. 
 
Study specific expected adverse events that will be monitored include: 
• 
Allergic reaction 
• 
Tachycardia (>100bpm on the lowest of two measurements) 
• 
Hypertension 
o Patient was previously normotensive (<140/<90 mmHg) and now has BP >140 mmHg 
systolic and/or >90mmHg diastolic with at least a 10mmHg increase in systolic and/or 
diastolic BP. 


 
21
o BP has increased >20mmHg systolic or >10mmHg diastolic as compared to baseline. 
• 
Elevated post void residual 
o >400mL without symptoms  (pelvic pain, voiding small amounts, constant sense of 
bladder fullness, overflow incontinence) 
• 
Urinary retention 
o >250mL with symptoms (pelvic pain, voiding small amounts, constant sense of bladder 
fullness, overflow incontinence) 
• 
Liver function tests (an increase of serum AST/ALT >2 times upper limit of normal, GGT >3 
times upper limit of normal, total bilirubin >2 times upper limit of normal) at visit 3. 
• 
ECG (a clinically significant change in the opinion of the investigator). 
 
Nonstudy specific expected adverse events that may occur include common medical complications 
associated with SCI and MS patients. These include development or worsening of pressure sores, 
spasticity, chronic pain, depression, renal stones, cardiac complications, pneumonia, autonomic 
dysreflexia, deep vein thrombosis, limb fractures, increased neurologic impairment, numbness, visual 
loss/double vision, impaired balance, and cognitive decline (33,34). 
 
Specific expected minor adverse events that may occur include: 
CNS: dizziness, headache 
Cardiac: palpitations 
ENT: nasopharyngitis, upper respiratory tract infection 
Occular: dry eyes, blurred vision 
GI: diarrhea, constipation, nausea, abdominal pain 
GU: urinary tract infection 
MSK: arthralgia, back pain 
Other: fatigue 
Urodynamic complications (urinary infection after urodynamics, gross hematuria, autonomic 
dysreflexia). 
 
Estimated incidence of minor mirabegron related adverse events as listed below based on 1375 
patients treated for overactive bladder symptoms(22). 
 
 
 
 
!
!
Placebo (%) 
Myrbetriq 25 mg 
(%) 
Myrbetriq 50 mg (%) 
Number of Patients 
1380 
432 
1375 
Hypertension* 
7.6 
11.3 
7.5 
Nasopharyngitis 
2.5 
3.5 
3.9 
Urinary Tract Infection 
1.8 
4.2 
2.9 
Headache 
3.0 
2.1 
3.2 
Constipation 
1.4 
1.6 
1.6 
Upper Respiratory Tract 
Infection 
1.7 
2.1 
1.5 
Arthralgia 
1.1 
1.6 
1.3 
Diarrhea 
1.3 
1.2 
1.5 
Tachycardia 
0.6 
1.6 
1.2 
Abdominal Pain 
0.7 
1.4 
0.6 
Fatigue 
1.0 
1.4 
1.2 
*Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring 
predominantly in subjects with baseline hypertension. 
!


 
22
Statistical considerations 
 
The primary analysis set for efficacy will be the full analysis set (defined as all randomized subjects). 
Results will be stratified based on whether the patient is taking an existing anticholinergic medication 
or not, and these two groups will be analyzed as individual populations. The primary outcome will be 
maximum cystometric capacity, as determined by urodynamic studies. Cystometric capacity will be a 
continuous variable, measured to the nearest whole number. Analysis will be an intention to treat 
analysis; statistical analysis for the primary endpoint will be a linear regression model, with 
adjustment for any unbalanced covariates (such as baseline bladder capacity). The linear regression 
model will be the maximum cystometric capacity as predicted by placebo versus mirabegron 
randomization. The per protocol analysis (for efficacy) will consist of all patients who were compliant 
with mirabegron dosing (defined as 80-100% of medication compliance based on pill counts) 
compared to placebo. A planned subgroup analysis of the primary outcome among MS and SCI patients 
will also be performed. SAS 9.2 will be used for all statistical analysis. 
 
Study variables 
 
Primary outcome 
• 
Cystometric bladder capacity (continuous, mL). Measured as the infused volume + the diuresed 
volume, based on the amount of urine drained from the bladder at the end of the urodynamic 
study. 
 
Secondary outcomes 
• 
Urodynamic 
o Volume at first episode of detrusor overactivity (based on investigator interpretation of 
filling volume at which detrusor overactivity starts, continuous, mL) 
o Maximal detrusor pressure (based on investigator interpretation of change in Pdet from 
start of filling to end of filling once any detrusor overactivity has stopped, continuous, 
cmH2O) 
o Bladder sensation (based on patient reported first sensation, first desire to void, and 
strong desire to void; may only available for MS patients, continuous, mL) 
o Bladder compliance (based on investigator calculated change in volume / change in 
pressure, continuous, mL/cmH2O) 
o Bladder compliance (based on end fill pressure, cmH2O) 
 
• 
Voiding diary 
o Number of episodes of urgency incontinence in 3 days (count) 
o Number of days without any urgency incontinence (count) 
o Average daily micturition frequency (count of number of voids from awakening in the 
morning to falling asleep at night averaged over 3 days), or Frequency of CIC (count, if 
applicable) 
o Average time between voids (each interval between daytime voids in minutes will be 
averaged over 3 days) 
o Maximal functional capacity (maximum voided volume over the 3 days, continuous, mL) 
o Median voided volume (median of all daytime voids over 3 days), or Median 
catheterized urine volumes (continuous, mL, if applicable) 
o Nocturia (number of voids/Catheters between falling asleep and awakening in the 
morning to start the day) 
 


 
23
• 
24hr pad weights (continuous measure of total weight of incontinence pads, sealed in plastic 
bags, minus the weight of each dry incontinence pad multiplied by the number of pads) 
 
• 
PROM 
o IQOL total score 
o SF-Qualiveen total score 
o NBSS total score and domain scores (incontinence and storage & voiding domains) 
o PPBC score (continuous score, responder analysis with 2 point change (major change) 
being defined as response) 
 
• 
Safety variables (frequency, severity, and causal likelihood of all adverse events) 
o Severity will be assessed based on the following scale: 
▪ 
Mild: no disruption of normal activities 
▪ 
Moderate: Effect on daily activities 
▪ 
Severe: inability to perform daily activities 
o Causal relationship 
▪ 
Not related: the adverse event’s timing, nature, and patient’s past history makes 
it unlikely that there is causal relationship to the study protocol/medication. 
▪ 
Possible: the adverse event’s timing, nature, and patient’s past history 
potentially represents a causal relationship to the study protocol/medication, 
but may also be explained by other illnesses or medications. 
▪ 
Probable: the adverse event’s timing, nature, and patient’s past history makes it 
likely that there is a causal relationship to the study protocol/medication. 
 
 


 
24
Investigator Responsibilities 
 
Each site investigator must ensure that the procedures outlined in this study protocol are adhered to. 
Study procedures are designed to ensure the investigator abides by GCP guidelines. Compliance with 
these regulations constitutes compliance with the ethical principles in the Declaration of Helsinki. All 
relevant Canadian legal and regulatory requirements will be met. 
 
Each investigator must ensure that proper source documentation for all activities performed in 
relation to this study are properly maintained and stored in a secure location. The investigator will 
transfer relevant data from source documents to the case report forms. The following source 
documents must be kept for a minimum of 25 years after completion of the clinical trial: 
• 
Signed consent forms 
• 
Subject ID codes, screening log, and enrollment log 
• 
REB communications 
• 
Case report forms 
 
The Investigator must ensure that institutional regulations and the Informed Consent Form clearly 
permit study-related monitoring and REB review by providing direct access to source data and 
documents.  
 
Each site will need to obtain REB approval prior to initiating this study. The primary investigator will 
provide appropriate documentation and administrative assistance during the competition of the ethics 
form. 
 
The principal investigator will be responsible for maintaining the clintrials.gov registration, and 
obtaining a Letter of No Objection from Health Canada. A copy of this letter will be provided to each 
site prior to start of the study. 
 
 
 


 
25
Signature page 
 
I have read this study protocol, I understand and agree to its content, and I will work according to this 
study protocol and according to the principles of good clinical practice. 
 
 
 
Investigator 
 
 
Name  
_______________________________________ 
 
Signature 
_______________________________________ 
 
Date 
 
_______________________________________ 
 
 
 


 
26
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Tyagi P, Tyagi V, Chancellor M. Mirabegron: a safety review. Expert Opin Drug Saf. 2011 
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Winters JC, Dmochowski RR, Goldman HB, Herndon CDA, Kobashi KC, Kraus SR, et al. 
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European Urology. 2013 Feb;63(2):296–305.  
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27. 
Nitti VW, Rosenberg S, Mitcheson DH, He W, Fakhoury A, Martin NE. Urodynamics and 
Safety of the β3-Adrenoceptor Agonist Mirabegron in Males with Lower Urinary Tract 
Symptoms and Bladder Outlet Obstruction. J Urol. 2013 Oct;190(4):1320–7.  
28. 
Almallah YZY, Rennie CDC, Stone JJ, Lancashire MJM. Urinary tract infection and patient 
satisfaction after flexible cystoscopy and urodynamic evaluation. Urology. 2000 Jul 
1;56(1):37–9.  
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Stohrer M, Madersbacher H, Richter R, Wehnert J, Dreikorn K. Efficacy and safety of 
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Deffontaines-Rufin S, Weil M, Verollet D, Peyrat L, Amarenco G. Botulinum toxin A for 
the treatment of neurogenic detrusor overactivity in multiple sclerosis patients. Int braz 
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Differential diagnosis of suspected multiple sclerosis: a consensus approach. 2008. pp. 
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29
 

ICF_001.pdf: 
URODYNAMIC AND CLINICAL EFFICACY OF MIRABEGRON AMONG NEUROGENIC 
BLADDER PATIENTS 
LETTER OF INFORMATION/ CONSENT FORM 
dated 30 September 2014 page 1 of 6 
Patient Initials _  
__  
_ 
 
 
 
URODYNAMIC AND CLINICAL EFFICACY OF MIRABEGRON AMONG NEUROGENIC BLADDER 
PATIENTS 
 
LETTER OF INFORMATION 
INVESTIGATOR 
Dr. Blayne Welk 
Assistant Professor of Urology, Department of Surgery, The University of Western Ontario 
Urologist, St. Joseph’s Hospital, St. Joseph’s Health Care London 
You have been invited to participate in a research study to determine the effectiveness of the drug 
Mirabegron in the treatment of neurogenic bladder dysfunction. Since you have symptoms of frequency, 
urgency and/or urgency incontinence (ie leaking before you reach the toilet) this study is being offered for 
your consideration. This letter describes the study and your role in it. Please read this letter carefully and 
ask any questions you have regarding the information it contains. 
PURPOSE OF STUDY 
The purpose of this study is to examine how Mirabegron works in the treatment of bladder problems 
among patients with neurologic disease. 
Mirabegron is a “beta-3 adrenoreceptor agonist” and it belongs to a new class of medication for the 
treatment of overactive bladder (OAB). It works by relaxing the bladder muscle and therefore may help to 
relieve bladder symptoms. It has only recently been available in some countries including Canada (it was 
first available in Japan in 2011). Mirabegron is approved by Health Canada for sale by prescription. The 
information from this study is needed to find out whether the medication is effective in treating symptoms 
of neurogenic bladder dysfunction. 
NUMBER OF PEOPLE 
Up to 144 participants, both men and women will take part in this study, at multiple Canadian centres. We 
expect to enroll approximately half of the participants here at St. Joseph’s Hospital. 
PARTICIPATION 
If you agree to participate and are eligible for the study, you will be randomly, by chance (like the flip of a 
coin) be selected to receive either Mirabegron 25 mg initially then increased to 50mg or Placebo. A placebo 
is a pill that looks like the real medication but does not contain active ingredient and therefore does not 
actively treat your condition. If you receive placebo, your condition may go untreated and your symptoms 
may not improve. 
The best way to determine if this treatment is effective is to analyze and compare the results from each 
group of patients. 
The study is double-blind, which means that neither you nor your study doctor will know if you are 
receiving active medication or placebo. This is to assure an objective evaluation of the study medication 
effect by you and your study doctor. However, if a medical emergency occurs during the study period that 


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requires knowledge of the study medication or placebo assigned to you, your study doctor will be able to 
get this information. 
STUDY SCHEDULE 
This study will be conducted over a 12-week period with 1 screening visit, plus 3 study visits in the Urology 
Clinic at St. Joseph’s Hospital. 
VISIT 1 
To determine if you are eligible for this study, after your consent has been documented, details about you 
will be collected including your age and gender, along with your height and weight. You will be asked 
detailed questions about your medical history, symptoms, including any medications you may take 
(prescribed, over-the-counter and herbal medications). 
 
If you are taking any medication that is not allowed to be taken in this study, you may not be able to 
participate in the study, or you may be asked to stop this medication if you and your doctor agree it is safe 
to do this. 
 
The study doctor will perform a physical examination. Your blood pressure and heart rate will be measured. 
If you are female of child bearing potential, a urine pregnancy test will be performed. Your post-void 
residual (PVR) (volume of urine remaining in your bladder after you have voided) will be measured using a 
BladderScan/ultrasound (sound waves) probe that is placed on your lower abdomen (belly). You will be 
asked to complete 4 questionnaires to assess the impact of your bladder problems on your quality of life. 
These will take ½ to 1 hour to do at Visit 1 and 4. 
The screening visit will take a total of approximately 1-2 hours. 
VISITS 2-4 
You will be scheduled to be seen in the Urology Clinic at St. Joseph’s Hospital for study visits 2-4 that will 
take 2-3 hours each. At visit 3 and 4, you will be required to return all unused study medication (including 
the empty containers). 
A medication and a health review will be done. Your PVR urine volume will be measured. If you are a 
woman of child bearing potential and the study doctor feels it is necessary, a urine pregnancy test will be 
done. A urodynamic study will be performed at visits 2 and 4. Urodynamics are a test to see how the 
bladder behaves. It is common test that is usually done during the assessment of patients with a 
neurogenic bladder. The test involves placing a small catheter (tube) into the bladder and another catheter 
into the rectum. The bladder is filled with sterile fluid, and the bladder pressures and volumes are recorded 
on a computer. The attached study schedule shows the timing and testing done at each of the study visits 
PATIENT RESPONSIBILITIES 
Use of Contraceptives / Pregnancy 
If you are a woman of childbearing potential, you must use a highly effective method of birth control, which 
includes established use of oral, injected or implanted hormonal methods of contraception, placement of 
an intrauterine device (IUD) or intrauterine system (IUS). Birth control must be practiced from screening 
and throughout the study period and for 28 days after the final study drug is taken. Your study doctor will 
discuss with you what is considered highly effective contraceptives. Any woman who finds that she has 
become pregnant while taking part in the study should immediately tell her study doctor and must stop 
study medication. If you do become pregnant during this trial, you will be asked to provide information 
about your pregnancy and outcome. 


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Female participants must not donate ova eggs starting at screening and throughout the study period and 
for 28 days after the final study drug is taken. Women who are nursing (breastfeeding), pregnant or plan on 
becoming pregnant during the study or for 1 month after, must NOT participate in this study. 
Male participants with a partner of childbearing potential must also use an effective contraceptive from 
screening and continue throughout the study period and for 28 days after the final dose of study drug. All 
male participants will be provided with Letters of Information to be given to all of their female sexual 
partner(s) who are of child bearing potential. 
Male participants must not donate sperm starting at screening and throughout the study period and for 28 
days after the final study drug is taken. Men who are planning on fathering a child during the study or for 
28 days after the final study drug is taken, must NOT participate in this study. 
Voiding Diary 
For 3 days prior to Visits 2 and 4, every time you urinate, you will need to record the following into the 
diary: 
1. 
Date, time, and volume of urine; 
2. 
Rate the sense of urgency (difficulty in postposing urination); 
3. 
Rate the leakage of urine; 
4. 
Date, time and volume of fluid intake. 
Each 24 hour period starts at midnight and ends at midnight the next day. Diary may be kept on 
consecutive or nonconsecutive days. A new diary will be given to you at visits 1 and 3 and results brought 
back at visits 2 and 4. 
Urinary Pad Test 
Prior to visit 2 and 4 you will be asked to collect all incontinence pads used in a 24 hour period. You must 
use the same brand and type of incontinence pad during each 24 hour period. You will be supplied with a 
large zip-lock bag in which to store the used pads. The 24 hour period shall start once you awaken to start 
the day, and remove your overnight pad. All pads used during the day, night, and the first pad the next 
morning will be sealed in the zip lock bag. Mark the time and date when you begin and complete the test. 
An empty unused pad will be returned in a separate bag. A new bag will be given to you at visit 3 and the 
bag with any used pads must be brought back at visit 4. If you do not regularly use pads, we will provide a 
pad for you to wear for the 24hr period. 
Study Medication 
You will have to take 1 dose of study drug, each day, at the same time each day. The study drug is to be 
swallowed whole, not chewed. 
Other Medications, Treatments and Concerns 
If you are taking other medication for bladder dysfunction such as anticholinergic medication, you must let 
your study doctor know if you make any changes to the dose of this medication, or if you stop taking it. You 
must consult with your study doctor before making any changes, including starting any new medications 
(this includes over-the-counter medications as well as medications you received on prescription) or 
considering any procedures or surgeries for the bladder during the study. You must let the study nurse 
know about any change in your regular medications. 
Throughout the study, you must let the study doctor know of any illnesses, complaint or abnormalities that 
you experience, whether or not you think it may be related to the study. 


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RISKS 
As with all medications, Mirabegron can cause side effects. The possible common side effects are: 
increased blood pressure (7.5-11.3%), common cold symptoms (3.5-3.9%), urinary tract infection (2.9-4.2%) 
and headache (2.1-3.2%). More uncommon side effects can include: skin rash (hives) (<1%),  
hypersensitivity (swelling of eyelids, difficulty breathing) (<1%), urinary retention (the inability to empty 
your bladder) (<1%), heart palpitations (<1%), constipation (1.6%), diarrhea (1.2-1.5%), upper respiratory 
tract infection (1.5-2.1%), fatigue (1.2-1.4%) and body aches (1.3-1.6%), dizziness (2.6-2.7%), dry eyes 
(0.49%), blurred vision (0.49%) and abdominal pain (0.6-1.4%). Overall this medication is well tolerated. 
There may be unknown risks associated with the use of this medication, including the unknown effect of 
long term use and cancer risk, and/or interactions with other medications. The effect of Mirabegron on 
sperm, ovum, and pregnancy is unknown. 
 
There are no side effects associated with placebo however, without active medication you may not 
experience an improvement in your bladder symptoms. 
 
The risks associated with the urodynamic assessment are minimal. Some may experience discomfort during 
the insertion of the catheters. There is a risk of a urinary tract infection. There may some mild burning with 
urination after the test. The urine may be stained with blood for a few days. Patients with certain types of 
spinal cord injuries are at risk of having a sudden onset of high blood pressure, flushing of the face, slow 
heart rate, nausea, and sweating above the level of the injury. This is known as autonomic dysreflexia, and 
if this occurs the urodynamic study is stopped and the bladder is drained. Your symptoms will usually 
resolve at this point. 
There may be risks or side effects that are unexpected or unknown at this time. 
BENEFITS 
The medicine used in this study may help with your bladder symptoms. However, it cannot be guaranteed 
that you will benefit personally from the study medication. The information obtained from this study may 
help to treat future patients. 
STANDARD OF CARE/ALTERNATIVE TREATMENTS 
The standard of care for patients with neurogenic bladder symptoms includes a number of alternative 
treatments that are available, including other medications, and surgery. If your symptoms remain 
unchanged during the study you may consider an alternate treatment. If you have any questions about 
these alternatives you should ask your study doctor for additional information. 
 
CONFIDENTIALITY 
Your personal physician may be informed if you agree that you are participating in the study. 
Representatives of regulatory authorities (such as Health Canada, the Ethics board , may inspect the study 
files and your medical records to ensure that the results of the study have been properly recorded. Only 
study related medical records will be looked at. 
The study doctor will keep any personal health information about you in a secure and confidential location 
for a minimum of 25 years as required by Canadian law. A list linking your study number with your name 
will be kept by the study doctor in a secure place, separate from your study file.Appropriate precautions 
will be taken to maintain confidentiality of your medical records and personal information. The inclusion of 


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your initials, gender and age may allow someone to link the data and identify you. While we will do our 
best to protect your information there is no guarantee that we will be able to do so. 
Your personal information will not be shared with others unless disclosure is required by law, for example, 
if a court of law orders the disclosure. 
The results of this research may be published in scientific journals or presented at medical meetings, but 
your identity will not be disclosed in such publications or presentations. 
OTHER INFORMATION 
The urine samples collected from female patients will be used only for determining pregnancy status for 
the purposes of this study. 
VOLUNTARY PARTICIPATION/WITHDRAWAL 
Participation in this study is voluntary. You may refuse to participate, refuse to answer any questions or 
withdraw from the study at any time with no effect on your future care. To protect the integrity of the 
study, you will not be able to withdraw your data from the study after your data has been sent for analysis. 
If you withdraw from the study, you will be asked to consider coming for a follow-up visit, if possible, 2 
weeks later. You may also be withdrawn from this study without your permission, if, in the opinion of the 
investigator, further participation will not be in your best interest. 
During the course of the research project, new information may become available about the study 
medication which may influence your willingness to continue to participate in the study. If this happens, 
your study doctor will tell you about it and discuss with you as to whether or not you wish to continue in 
the study. If you decide to continue in the study, you will be asked to sign a new consent form. 
You do not waive any legal right by signing the consent form. Every precaution will be taken to prevent any 
injury to you during the study. However, if an injury does occur, you will obtain medical care in the same 
way that you normally would obtain your medical care. 
STUDY COSTS/COMPENSATION 
All study tests, examinations and medical care required as part of this study are provided at no cost to you. 
All study medication will be provided free of charge to you during the study. You will not be paid for your 
time, or reimbursed for any travel expenses for taking part in this study. However, you will be given a 
parking pass for the hospital parking garages to cover your parking costs for the study visits. 
CONTACTS/MORE INFORMATION 
Please keep this Letter of Information and if you have any questions, at any time during this study, contact 
Dr. Blayne Welk at 519-646-6367 
Urology, St. Joseph’s Hospital, 268 Grosvenor Street, London, Ontario, N6A 4V2 
or Mary McKibbon, the study nurse working with Dr. Welk at 519-646-6100 ext 65308 
In case of emergency, please go to your nearest hospital emergency department. 
If you have any questions concerning your rights as a research participant or the conduct of the study you 
may contact Dr. David Hill, Scientific Director, Lawson Research Institute at 519-646-4716. 


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URODYNAMIC AND CLINICAL EFFICACY OF MIRABEGRON AMONG NEUROGENIC BLADDER 
PATIENTS 
 
CONSENT FORM 
 
 
 
I, 
have 
read the Letter of Information, have had the nature of the study explained to me and I 
agree to participate. All questions have been answered to my satisfaction. 
 
☐ I consent to have my primary doctor notified of my participation in this study 
☐ I Do Not consent to have my primary doctor notified of my participation in this study 
 
 
 
 
 
 
 
Date 
Signature of Participant 
 
 
 
 
 
 
Name of person responsible for 
obtaining this consent (PRINT) 
 
 
 
 
 
 
Date 
Signature of person responsible for 
obtaining this consent