Myrbetriq™ (Mirabegron) to Reduce Pain and Discomfort Following Ureteral Stent Placement
Phase: PHASE2
Conditions: Urinary Bladder, Overactive, Pain, Lower Urinary Tract Symptoms
Sponsor: Southern Illinois University

Version 1.4 / 20 April 2016 
 
Myrbetriq™ (Mirabegron) to Reduce Pain and Discomfort Following Ureteral Stent Placement 
 
 
 
Principal Investigator:  
Ahmed El-Zawahry, MD 
NCT number:  
 
02462837 
 
 
Contact Information:   
Ahmed El-Zawahry, MD 
Assistant Professor of Urology 
Division of Urology, Department of Surgery 
301 N. 8th street, 4th floor 
Springfield, IL 62794-9665 
Administrative phone:  217-545-7362 
Fax:  217-545-7305 
Email: ael-zawahry@siumed.edu 
 
 
 
 
 
Danuta I. Dynda, MD 
 
 
 
 
Research Program Manager – Urology 
 
 
 
 
CCR 
301 N. 8th street, 4th floor 
Springfield, IL 62794-9665 
Administrative Phone:  217-545-7443 
Fax:  217-545-7305 
Email:  ddynda@siumed.edu 
 
 
 
 
 
 
 
 

Myrbetriq™ (Mirabegron) to improve ureteral stent related pain and discomfort. 
PI: Ahmed El-Zawahry, MD 
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Background 
Ureteral stents are used extensively in urologic patients suffering from stones, ureteral 
obstruction secondary to strictures and malignancy, as well as post-operatively in various 
urologic procedures that involve the ureters and/or kidneys.  These stents are a frequent source of 
pain and discomfort to urologic patients. 
 
Typically ureteral stents may cause a wide spectrum of lower urinary tract symptoms (LUTS). 
These include urinary frequency, urgency, dysuria, incomplete emptying, flank pain and 
suprapubic pain1. Patient discomfort may lead to increased need for narcotic or other pain 
medications and increase length of hospital stay. This may also result in greater patient anxiety 
and a reduced quality of life. A major source of discomfort in these scenarios is thought to result 
from a spastic response of the bladder and/or ureter in response to the indwelling foreign object.   
 
It has been shown that stimulation of β(3)-adrenoceptors (β-AR) causes relaxation of mammalian 
ureteral smooth muscle2.  β(3)-AR are expressed in human ureter smooth muscle at the mRNA 
level3,4.  β(3)-AR agonists can relax ureter smooth muscle, which results in reduction of both the 
frequency and force of contraction in the acutely obstructed ureter5.  
 
Myrbetriq™ has been approved for the treatment of overactive bladder symptoms such as 
urinary frequency, urgency and urgency urinary incontinence.  These symptoms are similar to 
the symptoms that patients usually suffer from with ureteral stent placement and are a source of 
extreme agony and discomfort to patients.  Utilizing the proven therapeutic effect of Myrbetriq™ 
on the detrusor smooth muscle and the possible reduction of ureter smooth muscle tone could be 
clinically and practically relevant in patients with ureteral pain associated with stent placement.    
 
We hypothesize that Myrbetriq™, as a β(3)-AR agonist6, could harbor a great therapeutic 
potential for controlling storage bladder symptoms (LUTS) and ureteral pain associated 
with ureteral stent placement. 
 
Study Objective and Endpoints 
The objective of this pilot study is to assess whether Myrbetriq™ will improve post-operative 
ureteral pain and discomfort, reduce bladder storage symptoms and increase quality of life 
following ureteral stenting. This study will be conducted as an exploratory pilot investigation. In 
doing so, we will confirm the potential effect size for reduction in associated pain following 
stenting within this study population.  Results from this pilot study will also be used to assess 
feasibility for the design and conduct of a larger, prospective study in this population. 
Primary Endpoints: 
• Improvement from baseline in the Incontinence Symptom Severity Index (ISSI) in 
the Myrbetriq™ group at the 1 week follow-up and 2 week follow-up compared 
to placebo group. 
• Improvement from baseline in the number micturition per 24 hours and the 
number of incontinence episodes in the Myrbetriq™  group at the 1 week follow-
up and 2 week follow-up compared to placebo group. 
Exploratory Endpoints: 
• Improvement in pain and discomfort perception using a 10 point Visual Analog 
Scale for pain assessment (VAS) at the 1 and 2 week follow-up. 
• Improvement from baseline on the Patient Global Impression of Severity (PGI-S) 
at the 2 week follow-up.  

Myrbetriq™ (Mirabegron) to improve ureteral stent related pain and discomfort. 
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• Reduction in pain medicine intake at the 2 week follow-up. 
 
Study Methods 
This study is a prospective, randomized, double-blind, placebo-controlled 2 week clinical trial to 
evaluate the efficacy of Myrbetriq™ to reduce ureteral stent related pain and bladder symptoms 
in subjects undergoing a urologic procedure involving ureteral stenting.  The study will be 
conducted at Southern Illinois University (SIU) School of Medicine, Department of Urology and 
its affiliated hospitals in Springfield, IL.   
Subjects will be enrolled per the inclusion/exclusion criteria.  Subjects will be screened and 
consented prior to their stent placement procedure for stone disease.  Patients will be formally 
enrolled and randomized post-operatively based on no severe complications intra-operatively, 
such as extensive extravasation, hematoma could confound the pain and compromise the results.    
All subjects will complete at baseline and all follow-up visits: 1) the Incontinence Symptoms 
Severity Index (ISSI), 2) American Urologic Association symptom score (AUASS) 3) the Visual 
Analog Scale (VAS) to represent change in acute pain 4) the Patient Global Impression of 
Severity (PGI-S) quality of life scale 5) a voiding diary for 1 to 3 days preceding day, 7, and 
stent removal visits, and then 14 days after the stent removal (if done by day 28) to obtain base 
line diary  and   6) a narcotic log starting after surgery through 14 days after stent removal (if 
done by day 28).  The ISSI will be used to assess any change in voiding symptoms.  This scale 
has been validated to efficiently capture and quantify urological symptoms7.  The voiding diary 
is used to capture the number of micturition per day, urgency and associated incontinence.  The 
VAS has been validated to measure changes in acute pain that are clinically significant8.  The 
PGI-S has been proven to efficiently summarize a patient’s perception to change in severity in 
regards to lower urinary tract symptoms (LUTS)9.  Subjects will undergo a blood draw prior to 
stent placement (complete blood count (CBC), comprehensive metabolic panel (CMP) and urine 
analysis (sugar, protein, WBC/RBC, bacteria)) to verify eligibility.  These laboratories will not 
be repeated if they were performed routinely as a part of preoperative work up. 100 subjects will 
be equally randomized into 1 of 2 study groups, active treatment with Myrbetriq™ or 
administration of a placebo.  A daily 50 mg dose of Myrbetriq™ will be administered in the 
treatment group for up to 4 weeks initiated on the day of stent placement.  A 50mg dose was 
chosen as the initial dose due to the acute nature of the symptoms which do not require long term 
therapy.  It has been shown that Myrbetriq™ 50 mg taken orally once daily has superior efficacy 
in treatment of LUTS when compared to placebo by week 4 (the duration of this study) and this 
effect was maintained.  A 50mg dose was proven to be safe and effective to patients in Phase III 
trials 10,11.  Both study groups will receive similar prescriptions of narcotics in dose and number.  
Patients will be given a log to record use of narcotics.  If a different form of narcotics is 
prescribed due to side effects or allergic reaction, a narcotic analgesia converter calculator will 
be used to adjust for the doses, for analysis purposes.  Post-operative symptoms and pain 
medicine intake will be assessed at days 1, 7 via telephone interview, and with a clinic visit the 
day of stent removal (or day 14 if stent removal postponed) and via phone 14 days after the stent 
is removed.  If patient is to have stent removed on day 28, or later, the patient will receive a day 
21 telephone call to obtain post-operative pain and pain medicine intake, as well as 
questionnaires.  They will remain on study drug until day 28.  Use of prescription, over-the-
counter and supplemental medications for pain control will be captured using self-report and 
direct observation/recording of medication labels by the study team.  These interviews will be 
conducted by study staff who will be blinded to the subject’s treatment.  Subjects will complete 

Myrbetriq™ (Mirabegron) to improve ureteral stent related pain and discomfort. 
PI: Ahmed El-Zawahry, MD 
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the ISSI, the AUASS, voiding diary, VAS, narcotic log, and PGI-S during these follow ups.  The 
day 14 assessments will be collected prior to their stent removal procedure. 
 
 
Study Subjects 
Patients will be identified and recruited through the SIU urology clinics and St. John’s Hospital 
during a 24 month enrollment period.  Participation in this study will be completely voluntary.   
Male and female subjects presenting with planned stent placement for ureteral obstruction or 
post-ureteroscopy procedures for stone, except for those undergoing uteropelvic junction 
obstruction, will be evaluated for participation.  Should the patient decline to participate, their 
choice will not change their prescribed course of standard urologic treatment.  After review and 
approval by the local Institutional Review Board, the study will enroll 100 patients that meet the 
inclusion criteria below and agree to participate.  Annually, the study investigators perform 
approximately 350 stenting procedures (based on 2 previous years of clinical data). 
 
Inclusion Criteria 
1. 
Age ≥ 18. 
2. 
Subject scheduled to undergo a ureteral stent placement for ureteral obstruction or post- 
ureteroscopy procedure. 
3. 
Otherwise healthy subjects who are able and willing to participate in the study.  
4. 
None of the planned interventions are documented in the labeled contraindications, 
warnings and precautions of the study drug. 
 
Exclusion Criteria  
1. 
Does NOT give consent. 
2. 
Subject is using prohibited medications which cannot be stopped safely at the screening 
visit. Subject is excluded if using restricted medications not meeting protocol-specified 
criteria:  
(i) 
Phytotherapy for BPH or a 5-alpha reductase inhibitor within 3 months, with 
persistent urinary symptoms and AUASS more than 7. 
(ii) 
Taken an oral alpha agonist, anticholinergic or cholinergic medication within 5 
days of the first screening visit with the following exception(s): a singular dose 
given in ER or on the hospital floor prior to procedure, topical anticholinergic eye 
drops used for glaucoma or inhaled anti-cholinergic used for COPD. 
(iii) 
Taken tricyclic antidepressants within 2 weeks of the first screening visit. 
(iv) 
Taken an estrogen, androgen, or any drug producing androgen suppression, or 
anabolic steroids within 3 months with the following exceptions: any topical 
creams for local treatment. 
3. 
Post void residual volume > 350 mL.  
4. 
Female subject is breastfeeding, pregnant, intends to become pregnant during the study, 
or of childbearing potential is sexually active and not practicing a highly reliable method 
of birth control. 
5. 
Subject has known neurogenic bladder. 
6. 
Subject with uncontrolled chronic pain problems or on chronic pain medications. 
7. 
Subject has significant stress incontinence or mixed stress/urgency incontinence where 
stress is the predominant factor as determined by the investigator (for female subjects 
confirmed by a cough provocation test). 
8. 
Subject has an indwelling catheter or practices intermittent self-catheterization. 

Myrbetriq™ (Mirabegron) to improve ureteral stent related pain and discomfort. 
PI: Ahmed El-Zawahry, MD 
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Version 1.4 / 20 April 2016 
9. 
Known primary neurologic conditions such as multiple sclerosis, Parkinson's disease, 
diabetic neuropathy or any neurological diseases known to affect bladder function. 
10. 
Subject has evidence of a symptomatic active urinary tract infection, chronic 
inflammation such as interstitial cystitis, previous pelvic radiation therapy or previous or 
current malignant disease of the pelvic organs, or bladder stones (which can be located in 
different anatomical location and can cause LUTS similar to bladder infection and pain 
related to their location in the bladder which could mask the treatment effect). 
11. 
Subject who is currently under active treatment with botulinum toxin (and all other 
bladder paralytics) intravesically. 
12. 
Subject has moderate to severe hepatic impairment [ALT (SGPT) or AST (SGOT) value 
greater than 3 times the upper limit of normal in the clinical center lab; confirmed on a 
second measurement]. 
13. 
Subject has severe renal impairment or End Stage Renal disease (i.e., creatinine greater 
than 2.0 mg/dl). 
14. 
Subject has severe uncontrolled hypertension (defined as systolic blood pressure 
≥180mmHg and /or diastolic pressure ≥ 110mmHg). 
15. 
Subject has a clinically significant abnormal ECG in their chart or has a known history of 
QT prolongation or currently taking medication known to prolong the QT interval. Any 
patient taking Digoxin. 
16. 
Subject has a known or suspected hypersensitivity to Mirabegron or any of the inactive 
ingredients. 
17. 
Subject has a concurrent genitourinary malignancy, or active cancer (except noninvasive 
skin cancer) within the last 5 years prior to screening.  Men with a history of prostate 
cancer regardless of curability are not eligible. 
18. 
Subject has been treated with an experimental device within 30 days or received an 
experimental agent within the longer of 30 days or five half-lives. 
19. 
Unable to follow protocol directions due to organic brain or psychiatric disease. 
20. 
Intra-operative complications that require hospital admissions.   
21. 
History of alcoholism or any other substance abuse, which, in the opinion of the  
investigator, would affect compliance with the protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Myrbetriq™ (Mirabegron) to improve ureteral stent related pain and discomfort. 
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Visit window for all visits are +/- 2 days 
 
 
Study Procedures 
 
Informed Consent 
All participants will be required to provide written informed consent.  The study staff will 
introduce the study after being informed the subject is potentially eligible.  The study coordinator 
and/or study staff will review the informed consent document with the subject.  The subject will 
be provided information related to the study purpose, procedures, potential risks and benefits to 
participation, voluntary nature of their potential participation and provide them an opportunity to 
ask and have answers to all questions prior to obtaining any signature.  A study investigator will 
be available to answer any questions.  Subjects will not be compensated for participation and 
there are no additional costs to subjects for participation in the study.   
 
Randomization Schema 
Assessment  
or Procedure 
Baseline/ 
Stent 
Placement 
Post-Op 
Day 1 
(phone) 
Post-Op 
Day 7 
(phone) 
Stent 
removal 
( Post-Op 
Day 14 if 
stent not 
removed) 
visit 
 
 
 
Post- Op 
Day 21 
(phone) 
(if stent 
not 
removed) 
 
 
2 weeks 
after 
stent 
removal 
or Day 42 
(phone) 
 
 
 
Early 
Withdrawal 
Informed Consent  
X 
 
 
 
 
 
 
Verify Eligibility 
X 
 
 
 
 
 
 
Review Medical & Surgical History 
X 
 
 
 
 
 
 
Physical Examination (H & P) 
X 
 
 
BP and 
HR only 
 
 
BP and HR 
only 
Review Prior & Current 
Medications 
X 
X 
X 
X 
X 
X 
X 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
ISSI 
X 
X 
X 
X 
X 
X 
X 
VAS 
X 
X 
X 
X 
X 
X 
X 
PGI-S Quality of Life Scale 
X 
X 
X 
X 
X 
X 
X 
AUASS 
X 
X 
X 
X 
X 
X 
X 
Voiding diary  
 
 
X 
X  
 
X 
 
Pain log 
 
X 
X 
X 
X 
X 
X 
Laboratory screening tests 
(hematology & chemistry) 
X 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
Study drug 
administration/Accountability 
X 
 
 
X 
 
X only if 
you have 
drug 
X 

Myrbetriq™ (Mirabegron) to improve ureteral stent related pain and discomfort. 
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The order of group assignment will be randomized using a simple random numbers table.  Equal 
numbers of participants will be allocated to the two study groups: Group 1: daily Myrbetriq™ 
(50mg) or Group 2: placebo.  The randomization procedure is concealed to the participating 
Urologists, residents and study coordinators.  The random assignment schedule will be 
maintained by the pharmacist at St. John’s Hospital. After the patient has provided consent to 
participate in the study and all inclusion/exclusion criteria have been met, the study coordinator 
will obtain the subject’s identification (ID) number. 
 
Data Management and Confidentiality 
Study coordinators will be responsible for data collection and will ensure that forms are 
completed and signed.  Data will be entered into an excel spreadsheet for subsequent analysis.  
Each subject will be assigned a study identification code (ID codes).  Data collection forms and 
consent forms will be maintained for the duration of the study in a locked file cabinet.  Electronic 
data will be stored on a secure server accessible via password-protected computer.  Only 
authorized study personnel will have access to the study data.  Electronic data will be maintained 
until all analyses have been completed.   Study data will be kept for six years after study 
completion and then destroyed.   
 
Statistical Analyses 
Due to the exploratory nature of the efficacy endpoints within this study population, we have 
chosen to conduct this study as a pilot clinical trial. Descriptive summary statistics will be used 
primarily in the exploratory efficacy analysis. Summary statistics for these endpoints will also be 
provided by cohort, treatment group and visit. 
 
Data analysis will be concluded upon the completion of the study.  Subjects’ age, height, weight, 
and other continuous baseline variables will be summarized using descriptive statistics, while 
gender, race and other categorical variables will be provided using frequency tabulations. 
Medical history data will be summarized using frequency tabulations by system organ class and 
preferred term. Chi-square and t-tests will be used, as appropriate, to compare percent change 
and mean change from baseline in the ISSI, voiding diary, narcotic log, VAS score and PGI-S at 
the final study visit (14 days) or at any early termination visit.  A split-plot ANOVA with 
repeated measures will be used for each measure (ISSI, VAS and PGI-S) to compare groups 
(Myrbetriq™ and placebo) over time and to determine if there is an interaction between groups.  
Significance will be assumed when p < 0.05.  A preliminary power analysis based on previously 
published data, using an estimated SD for each study group of 4.17, a sample size of 50 in each 
study group (Myrbetriq™ and placebo) has an 80% power to detect an ISSI difference of 25% 
between the two groups with a significance level (alpha) of 0.05 (two-tailed)12. 
Pertinent to each Specific Aim are the following calculations: 
• Primary Endpoints:  Comparison of the change from baseline in ISSI and voiding diaries 
between Myrbetriq™ and placebo will be made using an independent t test for 
continuous scoring and a chi-squared test for ordinal scoring. Inferential analyses of 
changes from base line in micturition episodes per 24 hours and incontinence episodes 
per 24 hours will be performed using a stratified rank analysis to compare to baseline and 
as a covariance for each treatment. 
• Exploratory Endpoints:  Comparison of the change from baseline of total VAS between 
Myrbetriq™ and placebo will be made using an independent t test for continuous scoring 
and a chi-squared test for ordinal scoring.  Comparison of the change from baseline in 
PGI-S between Myrbetriq™ and placebo will be made using an independent t test for 

Myrbetriq™ (Mirabegron) to improve ureteral stent related pain and discomfort. 
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continuous scoring and a chi-squared test for ordinal scoring.  Comparison of pain 
medicine intake between Myrbetriq™ and placebo groups will be made using an 
independent t test. 
 
Safety Considerations 
Screening laboratory safety tests (hematology, chemistry), blood pressure, heart rate 
measurements, urinalysis, and liver function tests will be performed at the initial screening visit 
if they are not performed as the standard pre-operative work-up. Adverse event (AE) assessments 
will be reviewed by the PI and reported by study personnel as Myrbetriq™ is dispensed on a 
daily basis.  Any reported changes in patient symptoms will be reviewed again at the end of the 
study.  AEs will be summarized by treatment group according to the last treatment taken before 
the AE took place. 
 
Data Safety Monitoring Plan 
The investigators will be responsible for all study assessments and will monitor each 
participating subject for any adverse events.  An adverse event log has been created for this study 
and side effects of study subjects will be collected, tabulated and reviewed.  Regularly scheduled 
meetings of study personnel will take place (at least monthly) to review study progress and 
procedures. Real time management of AEs will be done per standard of care by the subjects’ 
health care providers.   Any serious AE or unanticipated problems will be reported to the 
Springfield Committee for Research Involving Human Subjects (SCRIHS) within 24 hours in 
accordance with SCRIHS policy. 
 
Institution and Investigator Interests 
SIU School of Medicine and the Principal Investigator, Ahmed El-Zawahry, MD received a 
grant from Astellas to support the costs of conducting this clinical trial.  Astellas is the 
manufacturer of the drug (Mirabegron) being used in this study.  Astellas is also providing the 
drug free of charge to subjects while participating in this study. 
 

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