Conditions: Multiple Sclerosis
Keywords: Multiple Sclerosis Overactive Bladder Incontinence Voiding Bladder Urgency Pelvic Floor Exercises
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if treatment with Mirabegron will improve urinary urgency control beyond that achieved with pelvic floor exercises alone

Detailed description:
A randomized 1:1 placebo controlled 10-week study of mirabegron as add-on therapy to an educational intervention on behavioral modification including pelvic floor exercise (BM-PFE) to a cohort of 40 Multiple Sclerosis (MS) subjects with overactive bladder (OAB). Trial will last approximately 12 weeks for each subject, including screening period and treatment period.

Active drug will be mirabegron 25mg daily with optional up-titration to 50mg daily after approximately 5 weeks. Subjects will be randomized at the Baseline Visit based on recordings in a voiding diary kept for 72 continuous hours in the screening period.

Voiding diaries of a 72 hour period each will be utilized during the screening period, between Phone Visit 1 and Titration and between Phone Visit 2 and Final Visit. In the diaries, subjects will record the time of each micturition and/or urgency episode, urine volume with each void (when available), any episode of incontinence, and the severity of urgency (Overactive Bladder Symptom Composite Score, mean of 72 hour total daily cumulative score.

Primary outcome will be average daily OAB-SCS total score, Final Visit vs. Baseline. This accounts for the frequency, urgency and incontinence components of OAB.

Arms:
arm 1: Mirabegron - 25mg (one tablet) taken by mouth daily with option to up-titrate to 50mg daily (two tablets) taken by mouth daily arm 2: Placebo - one tablet taken by mouth daily and two tablets taken by mouth daily if subject chooses up-titration

Interventions: intervention 1: Mirabegron intervention 2: Placebo
Intervention descriptions: intervention 1: see detailed information in associated Arm Description intervention 2: Sugar pill manufactured to mimic Mirabegron 25mg tablet.

Protocol document:
Prot_SAP_000.pdf: 
Confidential 
Protocol: TRB2013/MIRROR Trial 
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Page 1 of 17 
 
 
 
 
 
Protocol Title: Pilot study of Mirabegron and behavioral 
modification including pelvic floor exercise for overactive 
bladder in multiple sclerosis (MIRROR) 
 
 
 
 
Protocol No.:   
TRB2013 
 
Phase:  
 
IV 
 
Investigators:  
Theodore R. Brown, MD, MPH1 
Virginia I. Simnad, MD, M.Sc1 
 
 
Date:  
 
08-March-2016 
 
 
 
Version 2 
 
Affiliation: 
 
1EvergreenHealth MS Center, EvergreenHealth Neuroscience Institute 
 
 
 
EvergreenHealth, Kirkland, WA 
 
 
Contact:  
 
Theodore R. Brown, MD, MPH 
 
 
 
Director of Neurorehabilitation 
 
 
 
EvergreenHealth MS Center 
 
 
 
Suite 300 
 
 
 
12039 Northeast 128th Street 
 
 
 
Kirkland, WA 98034 
 
 
 
USA 
 
 
 
Ph: 425-899-5350 
 
 
 
Fax: 425-899-5354 
 
 
 
TRBrown@evergreenhealth.com 
 
 
 
 
 
 
 
 
 
 


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Protocol Summary 
 
STUDY DRUG 
 
Mirabegron 25-50mg daily 
TITLE 
 
Pilot study of mirabegron and behavioral modification including pelvic 
floor exercise for overactive bladder in multiple sclerosis (MIRROR) 
STUDY OVERVIEW 
A multi-center, randomized 1:1 placebo controlled 10-week study of 
mirabegron as add-on therapy to an educational intervention on behavioral 
modification including pelvic floor exercise (BM-PFE) to a cohort of 40 
MS subjects with overactive bladder (OAB). 
Active drug will be mirabegron 25mg daily with optional up-titration to 
50mg daily after approximately 5 weeks.  Subjects will be randomized at 
the Baseline Visit based on recordings in a voiding diary kept for 72 
continuous hours in the screening period. 
Voiding diaries of a 72 hour period each will be utilized during the 
screening period, between Phone Visit 1 and Titration and between Phone 
Visit 2 and Final Visit. In the diaries, subjects will record the time of each 
micturition and/or urgency episode, urine volume with each void (when 
available), any episode of incontinence, and the severity of urgency 
(Overactive Bladder Symptom Composite Score, OAB-SCS): 1 = no 
urgency (normal voiding); 2 = mild (could postpone voiding for as long as 
necessary without fear of incontinence); 3 = moderate (could postpone 
voiding for a short while without fear of leakage); 4= severe (could not 
postpone, had to rush to the toilet); 5= urgency incontinence (could not 
make it to the toilet without some leakage) Each voiding event is 
multiplied by the score for the event and then all events are summed to 
generate a total daily OAB-SCS cumulative score). 
Primary outcome will be average daily OAB-SCS total score, Final Visit 
vs. Baseline. This accounts for the frequency, urgency and incontinence 
components of OAB. 
RATIONALE 
This design will demonstrate the effects of behavioral modification, 
including pelvic floor exercise on OAB through the placebo arm of the 
study.  Adding mirabegron may yield greater results than BM-PFE alone.  
The standard starting dose is 25mg daily.  An optional up-titration to 50mg 
is included, since some patients may respond better to the higher dosage.  
This titration will occur at about 5 weeks to allow a balanced period of 
time for recording response to the two dosages. 
STUDY HYPOTHESIS 
 
 
Treatment with Mirabegron will improve urinary urgency control beyond 
that achieved with pelvic floor exercises alone. 
STUDY SUBJECTS 
 
40 subjects with multiple sclerosis and OAB complaints.   
DESIGN 
Multiple-dose, randomized, placebo-controlled prospective, single-site, 
investigator-initiated trial. 
DURATION OF STUDY 
 
Approximately 10 weeks (active treatment) 


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TREATMENT REGIMEN 
 
Group A will receive Mirabegron 25mg daily 
Group B will receive placebo 
Group A and B will receive the same baseline education in pelvic floor 
exercise based on viewing of an instructional presentation plus take-home 
printed material. 
TRIAL PERIODS 
 
Screening Period 
 Screening  to Baseline 
Treatment Period 
 Baseline to Final Visit (or Study Drug Discontinuation), includes 
Baseline, Phone Visit 1, Titration Visit, Phone Visit 2 and Final 
Visit 
INCLUSION AND EXCLUSION 
CRITERIA 
Inclusion Criteria 
 Confirmed diagnosis of MS (no sub-type restrictions) 
 Age ≥18 
 No change in disease modifying therapy in 60 days.  
 Patient willing and able to complete micturition diary  
 Urinary urgency (8 or more entries of bladder urgency score ≥2) in 
72hr voiding diary recorded during screening period 
 Micturition frequency ≥ 8 / day or incontinence ≥ 2 episodes in 72 
hour voiding diary recorded during screening period 
 At least 36 hours of voiding activity recorded in 72 hour voiding 
diary during screening period 
 Non-antimuscarinic medications that are likely to influence bladder 
function may not be initiated between screening and study 
completion.  They may be continued with no dose changes during 
the study.  
 Discontinued use of antimuscarinics at least two weeks prior to 
screening 
 Able to give informed consent 
 
Exclusion Criteria 
 Females who are breast-feeding, pregnant or have potential to 
become pregnant during the course of the study (fertile and 
unwilling/unable to use effective contraceptive measures) 
 MS exacerbation within 30 days of screening 
 Cognitive deficits that would interfere with the subject’s ability to 
give informed consent or perform study testing 
 Screening blood pressure > 165 systolic or 100 diastolic 
 History of allergy to Mirabegron 
 Screening post-void residual > 200ml 
 Evidence of urinary tract infection at screening 
 Evidence of chronic inflammation such as interstitial cystitis, 
bladder stones, previous pelvic radiation therapy, or previous or 
current malignant disease of the pelvic organs 
 Intravesical botulinum toxin treatment within the previous six 
months of screening. 
 Presence of InterStim device 
 Use of indwelling catheter or self-catheterization 


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 Concurrent use of thioridizine (Mellaril® or Mellaril-S®, flecainide 
(Tambocor®), propafenone (Rythmol®) or digoxin (Lanoxin®) 
 Concurrent use of antimuscarinics: oxybutynin (Ditropan®, 
Ditropan XL ®), tolterodine (Detrol®, Detrol LA®), fesoterodine 
extended-release (Toviaz®), solifenacin (Vesicare®), trospium 
(Sanctura®, Sanctura XR®), darifenacin extended release 
(Enablex®) 
 Screening estimated glomerular filtration rate (eGFR) < 60, AST  
or ALT > 2x upper limit of normal 
 Any other serious and/or unstable medical condition 
NO. OF SUBJECTS 
 
N= 40.  This will include 20 subjects taking mirabegron and 20 subjects 
taking placebo.   
EFFICACY 
(Outcome measures) 
 
Primary Outcome Measure: 
 Primary outcome will be Average daily OAB-SCS total score, 
Baseline vs. Final Visit 
 
Secondary Outcome Measures based on voiding diary, compared to 
Baseline: 
 Titration Visit: Average daily OAB-SCS total score  
 Titration and Final Visit: A) mean # of micturitions/day; B) Mean 
number of incontinence episodes/day; C) Mean volume 
voided/micturition  
 
Secondary Outcome Measures based on the following assessments at 
Titration Visit and Final Visit compared to Baseline: 
 Qualiveen Questionnaire 
 Subject Global Impression (single question) 
 PFE adherence question 
 Bladder Management Difficulties Questionnaire – Short Form 
(SCI-QOL v1.0) 
 
Exploratory Outcome Measures based on the following assessments at 
Titration Visit and Final Visit compared to Baseline: 
 Bowel Management Difficulties Questionnaire – Short Form  
      (SCI-QOL v1.0) 
STATISTICAL METHODS 
See Statistics section 


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SAFETY 
 
All subjects will undergo baseline blood testing, CBC and CMP.  Subjects 
with screening estimated glomerular filtration rate (eGFR) < 60, or AST or 
ALT > 2x upper limit of normal will be excluded.  At screening, subjects 
reporting dysuria, fever or abdominal pain will undergo urine analysis,  
culture and sensitivity at the discretion of the principal investigator.  
Subjects with blood pressure > 165 systolic or > 100 diastolic will be 
excluded at screening or will discontinue study drug if this occurs during 
treatment period. However, they may complete other elements of the study.  
Subjects with screening post-void residual > 200ml will be excluded.  
Symptoms of urinary retention will be monitored throughout the study and 
may lead to early discontinuation of study drug; however, such subjects 
may complete other elements of the study.  Subjects with a range of health 
conditions that may put the patient at risk for adverse outcomes will be 
excluded, as listed under Exclusion Criteria.  Female subjects will undergo 
urine pregnancy testing if they are deemed to have any risk of being 
pregnant or becoming pregnant during the study.   
ESTIMATED BUDGET 
 
A budget estimate will be provided separately 
SCHEDULE OF EVENTS 
Refer to the Schedule of Study Assessments, Appendix 2 for timing of 
procedures 
STUDY TIMELINE 
Start-up 2 months, period of enrollment 22 months, data analysis and final 
report 3 months 
 
Appendices 
Appendix 1: Subject Diary  
Appendix 2: Schedule of Study Assessments 
Appendix 3: Prohibited medications and medications that may not be initiated between 
screening and study completion, but may be continued with no dose changes during the 
study.   
 
Objective  
To assess the effect of pelvic floor exercise education with or without mirabegron (MBG) on 
overactive bladder symptoms in people with multiple sclerosis (MS) based on the OAB 
Symptom Composite Score. 
 
Background 
There are 400,000 Americans with MS and past and current surveys indicate that more than 
80% report some bladder dysfunction, including 61% with urinary urgency.1,2,3  In MS, 
immune dysregulation and neurodegeneration in the central nervous system impairs normal 
micturition.  Symptoms include frequency and/or urgency of urination, hesitancy in starting 
urination, nocturia and incontinence. Urological studies have shown the most common 
complaint is urinary urgency due to overactive bladder (OAB), with urinary retention less 
common.  This is supported by urodynamic findings of detrusor hyperreflexia in 68% of a 
MS cohort.4,5  One study suggests that detrusor hyperreflexia is more severe when related to 
MS than when idiopathic.6  Urinary urgency and urge-incontinence symptoms have markedly 
negative impacts on physical functioning and mental-functioning health-related quality of life 
metrics in MS.7  


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Potential treatments for OAB include behavioral modification, pelvic floor rehabilitation, oral 
or intravesical anticholinergic medications, desmopressin, duloxetine, intravesical injection 
of botulinum toxins, medicinal cannabis, or placement of external or indwelling 
catheters.8,9,10,11,12,13,14,15 Mirabegron (MBG) is the first beta-3 adrenergic agonist drug 
indicated for OAB treatment with symptoms of urge urinary incontinence, urgency and 
urinary frequency (see prescribing information).  This was based on studies conducted in 
general populations having OAB symptoms and not stress incontinence.16,17,18  MBG has 
not been studied in MS.   
Pelvic floor rehabilitation has a well-established role in the management of stress 
incontinence and idiopathic OAB.19  There is some evidence that pelvic floor exercise taught 
by physiotherapists over multiple sessions improves OAB in MS.20,21.  However, access to 
pelvic floor physical therapy is limited by third-party payer coverage, availability of 
therapists with the necessary expertise and incurred expenses and time requirements for the 
patients.  Behavioral modification, including pelvic floor exercise (BM-PFE) may be 
provided in a clinical setting using relevant educational materials.  The BM-PFE component 
will offer an important educational benefit to all subjects interested in this study.  Our center 
has a strong pelvic rehabilitation program with three therapists who are well-suited to 
produce the educational component of this study. 
Adding MGB may yield greater results than BM-PFE alone.  The standard starting dose is 
25mg daily.  An optional up-titration to 50mg is proposed, since some patients may respond 
better to the higher dosage, based on a Phase III trial including 25mg and 50mg daily 
treatment arms.  This titration will occur at visit 3; 32-40 days post Baseline Visit, to allow a 
balanced period of time for recording response to the two dosages.  Both dosages have been 
reported to be effective in treating OAB within 12 weeks.  
This study explores the benefits of combining a brief BM-PFE educational program with a 
pharmacotherapy, MBG for OAB due to MS. Our objective is to determine the effect of BM-
PFE with and without MBG in reducing the OAB Symptom Composite Score (OAB SCS).  
The OAB SCS is a validated measure that incorporates urinary frequency, urgency and 
incontinence episodes.22,23  The study design will also test differences in efficacy and 
tolerability between 25mg and 50mg doses of MBG. 
Methodology 
We propose a parallel-group, randomized, double-blind placebo-controlled trial of MBG as 
add-on therapy to an educational pelvic floor exercise (BM-PFE) intervention to a cohort of 
40 MS subjects with overactive bladder (OAB).     
Active drug will be MBG 25mg daily with optional up-titration to 50mg daily at Titration 
(visit 3).  Subjects will be enrolled at Baseline (visit 2) based upon scores for urinary urgency 
and micturition frequency in subject diary recorded during screening period.  
Voiding diaries of a 72 hour period each will be utilized during the screening period, between 
Phone Visit 1 and Titration and between Phone Visit 2 and Final Visit. Subjects will record 
the time of each micturition and/or urgency episode, urine volume with each void, any 
episode of incontinence, and the severity of urgency using the OAB-SCS.  This score 
accounts for frequency and the urgency components of OAB, including incontinence 
episodes.  
 
Number of centers & patients 
Multicenter study with subject number = 40 
 


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Population 
  Inclusion criteria 
 Confirmed diagnosis of MS (no sub-type restrictions) 
 Age ≥18 
 No change in disease modifying therapy in 60 days 
 Patient willing and able to complete micturition diary 
 Urinary urgency  (8 or more entries of bladder urgency score ≥2) in 72hr voiding 
diary recorded during screening period 
 Micturition frequency ≥ 8 / day or incontinence ≥ 2 episodes in 72hr voiding diary 
recorded during screening period 
 At least 36 hours of voiding activity recorded in 72 hour voiding diary recorded 
during screening period 
 Non-antimuscarinics medications that are likely to influence bladder function may 
not be initiated between screening and study completion.  They may be continued 
with no dose changes during the study.  
 Discontinued use of antimuscarinics at least two weeks prior to screening 
 Able to give informed consent 
 
 
  Exclusion criteria 
 Females who are breast-feeding, pregnant or have potential to become pregnant 
during the course of the study (fertile and unwilling/unable to use effective 
contraceptive measures). 
 MS exacerbation within 30 days of screening 
 Cognitive deficits that would interfere with the subject’s ability to give informed 
consent or perform study testing. 
 Screening blood pressure > 165 systolic or 100 diastolic 
 History of allergy to Mirabegron.   
 Screening post-void residual > 200ml 
 Evidence of urinary tract infection at screening 
 Evidence of chronic inflammation such as interstitial cystitis, bladder stones, 
previous pelvic radiation therapy, or previous or current malignant disease of the 
pelvic organs 
 Intravesical botulinum toxin treatment within the previous six months of 
screening. 
 Presence of InterStim device 
 Use of indwelling catheter or self-catheterization 
 Concurrent use of thioridizine, flecainide, propafenone or Digoxin 
 Concurrent use of antimuscarinics: oxybutynin (Ditropan®, Ditropan XL ®), 
tolterodine (Detrol®, Detrol LA®), fesoterodine extended-release (Toviaz®), 
solifenacin (Vesicare®), trospium (Sanctura®, Sanctura XR®), darifenacin 
extended release (Enablex®) 
 Screening estimated glomerular filtration rate (eGFR) < 60, AST  or ALT > 2x 
upper limit of normal 
 Any other serious and/or unstable medical condition 
 
Behavioral Modification with Pelvic Floor Exercise (BM-PFE) Educational Material 
We will utilize a 20 minute presentation, written by a physical therapist, utilizing a power 
point presentation.  Slides will include images such as pelvic floor anatomy as well as 


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outlines of key points.  Participants will be given a paper copy of the power point 
presentation to take home for reference and to help them with a home bladder exercise 
regimen.  
The following topics are part of this power point presentation:   
 
 Bladder health: What’s normal?  
 Bladder dietary irritants 
 Bladder retraining and urge delay techniques 
 Pelvic floor anatomy and function 
 How to perform a “Kegel” 
 “Kegel” home exercise program 
 Pelvic floor exercises with functional activities 
 Maintaining your home exercise program 
Subjects will have the opportunity to ask the study physician follow-up questions as needed.   
 
Investigational drug  
The study medication and matching placebo will be provided by Astellas Pharma Inc.  The 
active medication will be mirabegron (MBG) 25mg po daily from Baseline Visit to Titration 
Visit. At the Titration Visit subjects will be asked to choose to up-titrate to 50mg (or 
matching placebo) or to continue at 25mg dose (or matching placebo), while remaining 
blinded to treatment.  The research pharmacist will dispense the active or placebo medication 
at randomization and again at the Titration Visit.  An extra 5 day supply of medication will be 
provided for each study period to allow a window for scheduling of appointments.   
 
Randomization 
 Randomization will occur at the research pharmacy of EvergreenHealth (EH).  
 Non-EH research sites will submit a randomization request to the EH Research 
Pharmacist. 
 EH Research Pharmacist will assign randomization to placebo vs. active drug and 
record in randomization code book. 
 EH Research Pharmacist will send the randomization assignment (placebo or active 
drug assignment) back to un-blinded staff at the enrolling site.   
 Un-blinded staff at the enrolling site will dispense medication based on EH provided 
randomization assignment.   
 The investigating physician, nurse and research coordinator will be blinded as to 
treatment arm until the code is broken.  The randomization code may be broken by the 
investigator only in a medical emergency. The reasons for this have to be documented 
carefully. 
 
Concomitant therapy 
All concomitant therapy will be documented.  Prohibited will be concurrent use of 
antimuscarinics listed in Appendix 3: oxybutynin (Ditropan®, Ditropan XL ®), tolterodine 
(Detrol®, Detrol LA®), fesoterodine extended-release (Toviaz®), solifenacin (Vesicare®), 
trospium (Sanctura®, Sanctura XR®), and darifenacin extended release (Enablex®) within 
the previous 2 weeks of screening. Also prohibited will be concurrent use of thioridizine, 
flecainide, propafenone or Digoxin and intravesical botulinum toxin treatment within the 


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previous six months.  Medications that are likely to influence bladder function may not be 
initiated between screening and study completion.  They may be continued with no dose 
changes during the study.  This is listed as Appendix 3 and includes anticholinergic 
medications and drugs used in treatment of benign prostatic hypertrophy. 
 
Interruption or discontinuation of treatment 
Every patient has the right to discontinue study participation at any time, and every patient 
may be discontinued from the study by the PI for any reason beneficial to his/her wellbeing 
or any other reason. All data generated up to the time of discontinuation from the study will 
be analyzed and the reason(s) for discontinuation will be recorded.  
 
Treatment Compliance 
Patients will be asked to return all unused medication and all medication bottles, including 
empty bottles, at each visit and at the end of the study and the quantity of returned medication 
will be documented. 
 
Blinding 
The subjects will receive identical appearing active or placebo study medication tablets, with 
identification known only to the research pharmacist.   
Visit schedule and assessments  
See schedule of assessments, Appendix 2 
 
Enrollment 
Subjects who may qualify for this study will be identified in the context of clinical care at the 
participating centers.  Such eligible patients may receive a copy of the informed consent form 
at the time of their clinic visit.  Recruitment may also occur through local promotional 
opportunities (doctor’s programs, patient education programs).  Patients may contact the 
participating centers without clinic visitation after reading a notice about the study on the 
centers’ websites or other online postings, or after referral from an outside medical 
practitioner for study consideration.  Such subjects will be offered the chance to undergo a 
telephone screening using an institutional review board (IRB) approved telephone screening 
text.  Subjects will be requested to send pertinent outside medical records for chart review by 
the principal investigator and be scheduled for a screening visit.   
 
Screening Visit 
At this visit, subjects will be given ample time to read, review and ask questions about the 
study and the content of the informed consent form.  After subjects have signed the informed 
consent form, they will undergo the following assessments: 
 Review of  Medical History 
 Review of MS History  
 Study Eligibility (Inclusion/Exclusion) 
 Review of Concomitant Medications 
 Physical Examination 
 Vital Signs: Blood Pressure, Heart Rate and Temperature 
 General and Neurological Evaluation  
 Expanded Disability Status Scale (EDSS)  
 Laboratory Testing: Complete Blood Count and Comprehensive Metabolic Panel 
 Urine Pregnancy Testing for Female Subjects of Childbearing Potential  


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 Urine Analysis, including Culture and Sensitivity for Subjects Reporting Dysuria, 
Fever and/or Abdominal Pain (at the discretion of the principal investigator) 
 Post-void Residual Urine Volume Using Ultrasound Scanner  
 Subject Diary Training 
 Void Volume Measurement Training 
 
Subjects who meet all inclusion criteria will receive a diary with instructions to record 
information in their diaries for 72 continuous hours prior to Baseline Visit, during the 
screening period. Subjects will receive a urine receptacle (“hat” or hand-held urinal, patient 
preference) and will be trained on how to measure urine volume and record in diary 
whenever possible during the 72 hour diary period.   
 
Baseline Visit 
This visit will be scheduled 7 to 14 days post Screening Visit.  The following assessments 
will be performed: 
 Study Eligibility (Inclusion/Exclusion) 
 Review of Concomitant Medications 
 Adverse Event Assessment  
 Vital Signs: Blood Pressure, Heart Rate and Temperature 
 Physical Examination (if deemed necessary by investigator)  
 Subject Diary Review  
 
Subjects who meet all inclusion criteria will complete the following assessments: 
 Qualiveen Questionnaire - pages #1-6 & #9-10 (pages #7-8 are N/A) 
 Subject Global Impression 
 Bladder Management Difficulties Questionnaire – Short Form (SCI-QOL v1.0) 
 Bowel Management Difficulties Questionnaire – Short Form (SCI-QOL v1.0)  
 Pelvic Floor Exercise Adherence Question 
 Pelvic Floor Exercise Presentation 
 Randomization to Group A or Group B  
 Drug Dispensing and Training 
 Subject Diary Training (if needed) 
 Void Volume Measurement Training (if needed) 
 
Phone Visit 1 
Study staff will contact each subject 28-32 days post Randomization Visit. The following 
assessments will be performed: 
 Adverse Event Assessment   
 Prompting to Resume Subject Diary  
 Subject Diary Training (if needed) 
 Void Volume Measurement Training (if needed) 
 
Subjects will be instructed to complete the 72 continuous hours of diary entries prior to the 
Titration Visit. Study staff will reconfirm scheduled dates for follow-up study visits. 
 
Titration Visit 
This visit will be scheduled 35-40 days post Randomization Visit. The following assessments 
will be performed:  


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 Review of Concomitant Medications 
 Adverse Event Assessment  
 Vital Signs: Blood Pressure, Heart Rate and Temperature 
 Physical Examination (if deemed necessary by investigator) 
 Urine Pregnancy Testing for Female Subjects of Childbearing Potential (if deemed 
necessary by investigator) 
 Subject Diary Review  
 Qualiveen Questionnaire - pages #1-6 only 
 Subject Global Impression 
 Bladder Management Difficulties Questionnaire – Short Form (SCI-QOL v1.0) 
 Bowel Management Difficulties Questionnaire – Short Form (SCI-QOL v1.0)  
 Pelvic Floor Exercise Adherence Question 
 Subject Diary Training (if needed) 
 Void Volume Measurement Training (if needed) 
 Drug Dispensing and Training 
 Drug Return and Accountability 
 Up-Titration Option Question 
Subjects may receive increased dose of 50mg of MBG or matching placebo, or remain at 
25mg of MBG or placebo, at their discretion and in consultation with the investigator.  
 
Phone Visit 2 
Study staff will contact each subject 70-74 days post Randomization Visit. The following 
assessments will be performed: 
 Adverse Event Assessment   
 Prompting to Resume Subject Diary  
 Subject Diary Training (if needed) 
 Void Volume Measurement Training (if needed) 
Subjects will be instructed to complete the 72 continuous hours of diary entries prior to the 
Final Visit. Study staff will reconfirm scheduled dates for follow-up study visits. 
 
Final Visit 
This visit will be scheduled 74-82 days post Randomization Visit. The following assessments 
will be performed:  
 Review of Concomitant Medications 
 Adverse Event Assessment  
 Vital Signs: Blood Pressure, Heart Rate and Temperature 
 Physical Examination (if deemed necessary by investigator) 
 Urine Pregnancy Testing for Female Subjects of Childbearing Potential (if deemed 
necessary by investigator) 
 Subject Diary Review  
 Qualiveen Questionnaire - pages #1-6 only 
 Subject Global Impression 
 Bladder Management Difficulties Questionnaire – Short Form (SCI-QOL v1.0) 
 Bowel Management Difficulties Questionnaire – Short Form (SCI-QOL v1.0)  
 Pelvic Floor Exercise Adherence Question 
 Drug Return and Accountability 
 
 


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Unscheduled Visits 
Subjects may return to the clinic for safety evaluation or to receive additional study 
medication as needed.   
 
Laboratory tests  
Screening blood testing will include complete blood count and comprehensive metabolic 
panel.  At screening, subjects reporting dysuria, fever or abdominal pain will undergo urine 
analysis, culture and sensitivity at the discretion of the principal investigator.  Urine 
pregnancy testing will be performed at Screening Visit and office visits thereafter, as 
indicated by female fertility status and as deemed necessary by investigator. 
 
Screen failures / Rescreening  
Subjects who screen fail due to not meeting inclusion criteria or due to certain exclusions, 
e.g. presence of urinary tract infection, may rescreen in 30 days at the discretion of the 
investigator.  
 
Early Termination 
Criteria for early termination include, but are not limited to < 36 hours of time covered in a 
bladder diary, poor adherence to study medication (less than 70% of study medication 
consumed), safety issues related to study-related or non-study related adverse events, and at 
the request of the subject or at the discretion of the investigator. 
 
Efficacy Assessment  
Primary Outcome Measure  
Average daily OAB-SCS total score based on OAB SCS at Final Visit vs. Baseline Visit.  
Every toilet void or incontinence episode will be recorded in a diary based on the OAB-SCS 
system: 1 = no urgency (normal voiding); 2 = mild (could postpone voiding for as long as 
necessary without fear of incontinence); 3 = moderate (could postpone voiding for a short 
while without fear of leakage); 4= severe (could not postpone, had to rush to the toilet); 5= 
urgency incontinence (could not make it to the toilet without some leakage).  Every 
incontinence episode is scored as 5.  Each voiding event is multiplied by the score for the 
event and then all events are summed to generate a total daily OAB-SCS cumulative score.   
Each daily total score is averaged to generate the Average daily OAB-SCS total score.  For 
incomplete days (e.g. went out for 6 hours and forgot to record voids) the sum score will be 
adjusted as follows: total score over 24 hours X 24 / actual # of hours included in 
documentation (see reference Zinner et al).   
 
Secondary Outcome Measures based on diaries compared to Baseline Visit: 
 Average daily OAB-SCS total score based on OAB SCS reviewed at Titration Visit  
 Titration Visit and Final Visit mean number of micturition/day* 
 Titration Visit and Final Visit mean number of incontinence episodes/day* 
 Titration Visit and Final Visit mean volume voided/micturition*  
*missing blocks of time will not be included in the scoring  
 
Secondary Outcome Measures based on Titration Visit and Final Visit compared to 
Baseline Visit: 
 Qualiveen Questionnaire  
 The English version of the Qualiveen has been found to be a valid and 
responsive measure of bladder function in MS.24. Site will use pages 


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#1-6 & #9-10 at baseline and only pages #1-6 at other visits. Pages #7-
8 will not be used as they are not applicable. 
 
 Subject Global Impression  
 This is a single question: “How would you rate your level of bladder 
control during the past week?”  Please circle your choice:   
o Extremely good, Quite good, Better than average, 
Average, Below Average, Quite bad, Extremely bad”   
 
 Pelvic Floor Exercise Adherence Question 
 This is a single question: “How many days did you perform pelvic 
floor exercises during the past two weeks? Please circle your choice:   
o Never, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 
days, more than once a day” 
 
 Bladder Management Difficulties Questionnaire – Short Form (SCI-QOL v1.0) 
 8 multiple choice questions  
 
Exploratory Outcome Measures based on Titration Visit and Final Visit compared to 
Baseline Visit: 
 Bowel Management Difficulties Questionnaire – Short Form (SCI-QOL v1.0)25  
 9 multiple choice questions  
 
Questionnaires will be administered by the research coordinator or study nurse.  See Schedule 
of Assessments above for timing of testing. 
 
Safety Measures 
All subjects will undergo baseline blood testing, CBC and CMP.  Subjects with screening 
estimated glomerular filtration rate (eGFR) < 60, or AST or ALT > 2x upper limit of normal 
will be excluded.  At screening, subjects reporting dysuria, fever or abdominal pain will 
undergo urine analysis, culture and sensitivity at the discretion of the principal investigator.  
Subjects with blood pressure > 165 systolic or 100 diastolic will be excluded at screening or 
discontinue study medication if this occurs while on study medication.  However, they may 
complete other elements of the study.  Subjects with screening post-void residual > 200ml 
will be excluded.  Symptoms of urinary retention will be monitored throughout the study and 
may lead to early discontinuation of study medication; however, such subjects may complete 
other elements of the study.  Subjects with a range of health conditions that may put the 
patient at risk for adverse outcomes will be excluded, as listed under Exclusion Criteria.  
Female subjects will undergo urine pregnancy testing if they are deemed to have any risk of 
being pregnant or becoming pregnant during the study.   
 
Subjects will be monitored for adverse events throughout the trial. The occurrence of adverse 
events will be ascertained by observation, telephone monitoring and questioning by the 
investigator. Safety assessments will consist of monitoring and recording all adverse events, 
including serious adverse events.  
 
Adverse events include adverse drug reactions, illness with onset during the study, 
exacerbations of pre-existing conditions or clinically significant changes in physical 
examination or significantly abnormal objective test findings.  Medical conditions/diseases 


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present before starting study treatment are only considered adverse events if they worsen 
after starting study treatment.  All adverse events will be recorded and graded as mild, 
moderate or severe by the principal investigator in accordance with general guidelines of 
clinical research.  The principal investigator and all other research staff will be blinded 
towards randomization of active drug versus placebo until after completion of study.   
 
Adverse events that arise between the Baseline Visit and Final Visit will be classified as 
acute therapy phase adverse events.   
 
A serious adverse event is an undesirable sign, symptom or medical condition which: 1. is 
fatal or life-threatening, 2. required or prolonged hospitalization, 3. results in persistent or 
significant disability/incapacity, 4. constitutes a congenital anomaly or a birth defect, 5. is 
medically significant, in that it may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. If any serious adverse 
events occur, the treatment status of the subject(s) may be revealed, as clinically indicated.  
Subjects who discontinue medication use will be followed for adverse events until reaching 
the termination of adverse events.  No interim analysis of safety data is planned because the 
entire study will be conducted over 2 months.  However, the frequency of adverse events 
(AE) will be under continuous scrutiny during the observation with comparison to AE rates 
that have been recorded in published MS fatigue drug trials.   
 
Serious Adverse Events Reporting 
The FDA will be informed of serious unexpected adverse reactions (SAEs) as soon as 
possible or within 15 calendar days. In addition, the Investigator will notify the FDA of any 
unexpected, fatal or life-threatening experience associated with the use of the drug as soon as 
possible, or within 7 calendar days, by telephone or facsimile. When the principal 
investigator has determined that a Serious Adverse Event requires reporting to the FDA 
(unexpected and possibly related to study drug), the following actions will be taken: 
 
1. Telephone the FDA immediately (day of awareness), in the case of reportable death or life 
threatening events. 
2. Complete FDA Form 3500. 
3. Send the completed Form 3500 to the FDA (preferably by fax at 1-800-FDA-0178) within 
the timelines mentioned above. 
4. Attach the photocopy of all examinations, medical notes and records related to the Serious 
Adverse Event and document the dates these were made. For laboratory results, include the 
laboratory normal ranges. For hospitalizations, Admission H&P, Discharge Summary, 
Consultative reports, etc. could be very helpful. In the case of a fatal event, provide an 
autopsy report, when it becomes available. 
 
Any symptoms or signs that could be due to an MS exacerbation will prompt an unscheduled 
visit with the investigating physician to confirm or refute an MS exacerbation.  Any 
confirmed exacerbations will be noted in the results, but will not lead to removal from the 
study unless it is deemed by the subject or the investigating physician to be in the subjects’ 
best interest to do so.  Treatment of exacerbation with IV methylprednisolone 1gm daily for 
three days with oral steroid taper may be provided at the investigator’s discretion.   
 
 
 


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Sample Size Considerations 
This is a prospective double-blinded, controlled pilot study.  The purpose is to test a 
hypothesis in a preliminary fashion and to assess for safety in this population with a specific 
neurological disease.  As such, a power calculation may be irrelevant.  However, a small 
number of subjects (e.g.) less than 10, may cause significant sampling error to miss a 
treatment effect or common safety issue.  Some entities that establish criteria for level of 
evidence consider a sample size of 20 subjects in each arm to be a minimum representative 
population to be considered for Class III or better classification of Level of Evidence.  
Therefore, a sample size of 40 subjects is a reasonable number for a pilot study of this nature.   
 
Statistical Analysis 
Demographics and baseline disease characteristics, including age, gender, MS type and 
duration of disease, level of disability (EDSS), and disease modifying therapy status will be 
compared between study groups. 
Summary and analysis of primary and secondary outcome measures will include  
1. Summary statistics (n, mean, standard deviation, median, minimum and maximum) at 
baseline and week 5 and week 10 by treatment 
2. Summary of % change from baseline to week 5 and 10. 
3. Significance testing 
For the primary outcome measure, Average daily OAB-SCS, each voiding event is multiplied 
by the score for the event and then all events are summed to generate a total daily OAB-SCS 
cumulative score.   Each daily total score is averaged to generate the Average daily OAB-
SCS total score.  For incomplete days (e.g. went out for 6 hours and forgot to record voids) 
the sum score will be adjusted as follows: total score over 24 hours X 24 / actual # of hours 
included in documentation (see reference Zinner et al). 
 
Mean OAB-SCS score at Baseline Visit will be included in the model as an independent 
variable. The primary time points for all comparative measures will be Baseline Visit, 
Titration Visit and Final Visit. Outcome measures will be compared between groups using 
analysis of covariance (ANCOVA) or other method.  Demonstration of superiority will 
depend on achieving statistical significance for the primary endpoint.  Level of significance 
will be defined as p=0.05.  All statistical tests will be two-sided.  Statistical assistance will be 
provided by a statistician consultant whose company is contracted with EvergreenHealth and 
whose services we have used on two recent MS studies. 
 
Aggregate, de-identified data from the Bladder and Bowel Management Difficulties Short 
Form Questionnaires (SCI-QOL v1.0) will be shared with the University of Washington in 
Seattle, WA. This will be done as a courtesy for giving the investigator permission to use 
these questionnaires in this protocol.  
 
Ethics and Good Clinical Practice 
This study will be performed according to the principles of Good Clinical Practice [Chapter 2 
of the ICH Harmonized Tripartite Guideline for Good Clinical Practice (GCP)], the 
declaration of Helsinki, and national laws and regulations about clinical studies. The study 
may not start without written Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board approval and the written informed consent of the patient. 
                                                 
 


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1 National MS Society website, accessed June 19, 2013. 
http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-
ms/symptoms/bladder-dysfunction/index.aspx 
 
2 Fowler CJ. The cause and management of bladder, sexual and bowel symptoms in multiple 
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5 Ciancio, SJ, Mutchnik SE, Rivera VM, et al. Urodynamic pattern changes in multiple 
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11 Freeman RM, Adekanmi O, Waterfield MR, et al. The effect of cannabis on urge 
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12 Schulte-Baukloh H, Schobert J, Stolze T, et al. Efficacy of botulinum –A toxin bladder 
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