A Double Blind Placebo Control Trial of Mirabegron for Medical Expulsive Therapy and to Manage Stent Pain for Ureteral Stones(Protocol # 01-16-20-02)
Phase: PHASE2
Conditions: Ureteral Obstruction, Flank Pain
Sponsor: Baylor College of Medicine

A DOUBLE BLIND PLACEBO CONTROL TRIAL OF MIRABEGRON FOR MEDICAL 
EXPULSIVE THERAPY AND TO MANAGE STENT PAIN FOR URETERAL STONES 
(Protocol # 01-16-20-02) 
 
 
Version: February 20, 2019 
 
 
 
PRINCIPAL INVESTIGATOR: 
Wesley A. Mayer, MD 
 
Assistant Professor  
 
Scott Department of Urology  
 
Baylor College of Medicine 
 
7200 Cambridge 10th Floor, Suite B 
 
Houston, TX 77030 
 
713-798 - 4001 
 
wesley.mayer@bcm.edu 
 
 
 
 
 
KEYWORDS: 
Medical expulsive therapy; ureteral stone; beta agonist; stent pain; 
 
 
 
IND#:  
131892 EXEMPT 
 
 
ClinicalTrials.gov: NCT02744430 
 
 
 
 
 
 
 
 
 
 
 
 
This clinical research protocol will be conducted in accordance with OHRP, FDA, ICH and IRB 
regulations and guidelines. The Scott Department of Urology complies fully with the HIPAA 
guidelines. 
 

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TABLE OF CONTENTS 
 
 
Abbreviations and Definitions of Terms ..........................................................................................3 
1. 
Background ..............................................................................................................................5 
2. 
Significance ..............................................................................................................................5 
3. 
Objectives .................................................................................................................................6 
4. 
Drug Information......................................................................................................................6 
5. 
Phase of Study ..........................................................................................................................6 
6. 
Eligibility Criteria ................................................................................................................ 6-7 
7. 
Design.......................................................................................................................................7 
8. 
Randomization .........................................................................................................................8 
9. 
Procedures ................................................................................................................................8 
10. Laboratory Considerations .....................................................................................................12 
11. Sample Size ............................................................................................................................12 
12. Statistical Considerations .......................................................................................................12 
13. Data Analysis .........................................................................................................................12 
14. End-points ..............................................................................................................................13 
15. Risks ................................................................................................................................. 13-16 
16. Assessment of Safety ....................................................................................................... 16-17 
17. Withdrawal of Subjects ..........................................................................................................17 
18. Benefits...................................................................................................................................17 
19. Alternatives ............................................................................................................................17 
20. Costs to Subject ......................................................................................................................17 
21. Payment to Subjects ...............................................................................................................18 
22. Confidentiality ........................................................................................................................18 
23. Ethics ................................................................................................................................ 18-19 
24. References ..............................................................................................................................20 
25. Investigator Statement ............................................................................................................21 
26. Appendices .............................................................................................................................22 
A. Schedule of Events ...........................................................................................................23 
B. Questionnaires ..................................................................................................................24 
i. 
Wong Baker FACES Pain Scale and Pain Score and Narcotic Diary, English ........25 
ii. Wong Baker FACES Pain Scale and Pain Score and Narcotic Diary, Spanish .......28 
iii. USSQ (English and Spanish versions) .....................................................................31 
iv. USSQ (English) .................................................................................................. 32-41 
v. USSQ (Spanish) .................................................................................................. 42-56 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse Event 
BCM 
Baylor College of Medicine 
BMP 
Basic Metabolic Panel 
BOO 
Bladder Outlet Obstruction 
C 
Celsius 
CBC 
Complete Blood Count 
CFU 
Colony Forming Units 
CT 
Computed Tomography 
CYP2D6 
Cytochrome P450 2D6 - an enzyme 
DPB 
Diastolic Blood Pressure 
ED 
Emergency Department 
EPIC 
Electronic Medical Record System 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
Hg 
Mercury 
HIPAA 
Health Insurance Portability and Accountability Act 
HPF 
High Powered field 
ICD 
Informed Consent Document 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IT 
Information Technology 
KUB 
Kidney, Ureters, Bladder Plain Film 
MET 
Medical Expulsive Therapy 
mg 
Milligrams 
mGy 
milligray 
MHRA 
Modern Humanities Research Association 
mm 
millimeter 
mSv 
millisieverts 
OAB 
Overactive Bladder 
OHRP 
Office of Human Research Protection 
OTC 
Over-The-Counter 

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PI 
Principal Investigator 
PT 
Prothrombin time 
PTT 
Prothrombin Time Test 
RUS 
Renal Ultrasound 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SDU 
Scott Department of Urology 
UAE 
Unanticipated Event 
USSQ 
Ureteric Stent Symptom Questionnaire 

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1. 
BACKGROUND 
 
Kidney stone passage down the ureter into the bladder often results in severe abdominal pain 
called ureteral colic. Ureteral colic is a common presenting symptom in emergency departments 
(ED). 
 
Approximately 550,000 episodes of ureteric colic are seen in ED in the United States per year 
costing nearly $3 billion.1 The current standard of care for ureteral stone passage involves 
hydration and pain control as approximately 47-80% of stones will pass within approximately 4 
weeks, depending on size and location.2 Patients who cannot achieve spontaneous stone passage 
or have a subsequent complication (including recurrent pain, compromised renal function, or 
infection) often require surgical therapy, typically either with extracorporeal shock wave 
lithotripsy or ureteroscopy. Two decades ago, the first randomized trial demonstrating the 
potential efficacy of a calcium channel blocker (nifedipine) for medical expulsive therapy of 
ureteral stones was performed.3 Subsequently, tamsulosin, a selective alpha-1a antagonist, has 
also been demonstrated as a potentially useful agent for medical expulsive therapy (MET) in 
randomized trials.4 Over the past decade, off-label MET has become more commonplace. 
However, the strength of findings from randomized trials is weak due to variability in quality and 
power of study design. 
 
In 2015, a large multi-center randomized placebo-controlled trial (SUSPEND Trial) included 
1167 patients and compared the efficacy of nifedipine and tamsulosin for the reduction in 
surgical therapy in patients passing ureteral stones within 4 weeks after randomization.5 This trial 
demonstrated that both nifedipine and tamsulosin were ineffective for MET and were associated 
with an increase in adverse effects (AE) compared to placebo. These findings suggest that 
current off-label therapy with calcium-channel blockers and alpha-blockers may be ineffective 
and inappropriate. Because ureteral stones remain an important and expensive medical problem, 
identification of other potential agents for MET may reduce the frequency of serious 
complications and necessity of surgical intervention as well as improve patient- centered 
outcomes. 
 
Mirabegron is a selective beta-3 adrenergic agonist that was approved for overactive bladder in 
the United States in 2012. Several human and animal studies have also shown the presence of 
beta-3 adrenergic receptors in the ureter and efficacy of agonists for the relaxation of the ureter.6, 
7 Stimulation of the beta-3 adrenergic receptors in the human ureter have been shown to promote 
urothelial relaxation in a pre-clinical model.6 We hypothesize that mirabegron may be useful as 
MET through beta-3 adrenergic-mediated ureteral relaxation which may enhance ureteral stone 
passage in patients who are expectantly managed. Because ureteral colic results from sustained 
ureteric smooth muscle contraction, we hypothesize that relaxation of the ureter may reduce pain 
associated with ureteral stones and ureteral stents that are placed after surgical intervention.8 As 
secondary endpoints, we will assess the efficacy of mirabegron for the reduction of pain during 
the expectant management period and during the post- surgical stent period. 
 
2. 
SIGNIFICANCE 
 
Ureteral obstruction due to kidney stones is a common and costly condition that requires surgical 
intervention in 20-50% of patients. It is associated with severe pain and discomfort along with 

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other serious adverse health outcomes such as renal failure and sepsis. If mirabegron can reduce 
either the need for surgical intervention or the pain associated with ureteral colic, this may alter 
standard of care for expectant stone management. Furthermore, stent pain is a major common 
adverse sequela of surgical intervention for kidney stones.9 If mirabegron can reduce stent pain, 
it would greatly improve quality of life for patients undergoing invasive surgical therapy for 
urolithiasis. 
 
3. 
OBJECTIVES 
 
A. 
Primary Objective 
 
The primary objective of this study is to determine whether the use of mirabegron 
can improve the spontaneous passage rate of patients with ureteral single ureteral 
calculi within 30 days of presentation. 
 
B. 
Secondary Objectives 
 
The secondary objectives of the study are to evaluate the effects of mirabegron on the 
reduction of pain level during the expectant management as well as stent-associated 
pain of those patients who had surgery. 
 
4. 
DRUG INFORMATION 
 
Mirabegron is a FDA-approved medication used in the treatment of overactive bladder (OAB) 
with symptoms of urgency, frequency, and leakage in adults. Both Mirabegron and placebo will 
be formulated and provided by Astellas Pharma US, Inc. The FDA-approved Mirabegron (50mg) 
product will be used without manipulation or reformulation (Mirabegron package insert; Rev. 
Jun 2012).10 
 
The efficacy and safety of mirabegron have been evaluated in three 12-week studies and one 
long-term (12-month) safety study. 
 
In clinical trials, mirabegron was shown to be effective in treating symptoms of OAB within the 
first several weeks. Those taking mirabegron made fewer trips to the bathroom and had fewer 
leaks than those not taking mirabegron. Results may vary. 
 
5. 
PHASE OF STUDY: Phase 2 
 
6. 
ELIGIBILITY CRITERIA 
 
A. Inclusion 
Subjects are eligible to be included in the study only if they meet all of the following 
criteria and provide signed informed consent at Visit 1. 
1) 
Males and females age 18-70 years of age 
2) 
Resident of Harris County 
3) 
Single unilateral ureteral calculus 4 to 10 mm visible on CT scan or 

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Ultrasound/KUB within the ureter 
4) 
Ability to tolerate oral fluids and oral pain medication 
5) 
Able to make informed medical decisions regarding consent 
6) 
Willingness to follow-up in the Urology Clinic in approximately 30 days 
7) 
Willing to undergo ureteroscopic extraction should the stone not pass in this 
time period 
B. 
Exclusion 
Subjects will be excluded from the study if they meet any of the following criteria: 
1) 
Adults unable to consent 
2) 
Age less than 18 
3) 
Solitary kidney 
4) 
Horseshoe kidney 
5) 
On immunosuppressant therapy 
6) 
On digoxin 
7) 
Uncontrolled hypertension (SBP > 170, DBP > 110) 
8) 
Allergy to mirabegron 
9) 
Current calcium antagonist or corticosteroid or alpha-adrenergic antagonist 
usage 
10) Patients already taking a beta-adrenergic agonist medication 
11) Patients taking thoridazine, flecainide, or propefenone (narrow CYP2D6 
therapeutic index) 
12) Renal insufficiency (GFR less than 45) 
13) Patients with Childs B and C liver failure 
14) Signs of infection 
i. Temperature greater than 38C 
ii. Circulating white blood count >15,000 x 109/L 
iii. Urinalysis with any of the following positive: 
a) 
Positive nitrites 
b) 
Positive urine culture (defined as a single isolated bacterial species 
population of greater than 100,000 CFU) 
 
15) Patients with chronic pain already undergoing treatment with narcotic medications 
16) Pregnant women and nursing mothers 
17) Prisoners 
18) No working phone number  
 
7. 
DESIGN 
 
The study will be a prospective randomized double-blind placebo-controlled trial of mirabegron 
for MET in patients with a CT scan or Ultrasound/KUB-proven ureteral stone between 4 to 10 
mm undergoing expectant management. Subjects will be distributed at a 1:1 ratio between the 
control and treatment groups. The treatment group will receive mirabegron and the control 
groups will receive a placebo. Both groups will receive analgesics and hydration will be 
recommended. All subjects will then be followed for 30 days to determine the proportion of 
subjects with spontaneous passage. Patients will record narcotic usage and pain scores during 

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this time. If there is stone persistence in the ureter based on imaging (CT scan or 
Ultrasound/KUB of the abdomen and pelvic, then the patient will undergo ureteroscopy with 
stent placement. In these patients, treatment will continue while the stent is in place and patients 
will fill out a validated questionnaire regarding stent pain. 
 
8. 
RANDOMIZATION 
 
Study participants will be randomized to the treated arm (mirabegron 50 mg orally once every 24 
hours starting immediately) or placebo in a 1:1 ratio using a randomized block design, stratified 
by stone size (≤5 mm versus >5 mm) and location (upper versus lower ureter). The 
randomization will be implemented through a database with software designed by the Director of 
Research Informatics at the Baylor College of Medicine’s (BCM) Dan Duncan Institute of 
Clinical and Translational Research. It will be a HIPPA-compliant secure database accessible via 
internet. 
 
Each randomly assigned participant will be given 60 capsules of trial medication (over-
encapsulated mirabegron or placebo) supplied by Astellas Pharm US, Inc. and dispensed by the 
Harris Health System Pharmacy. Both Astellas Pharm US, Inc. and Harris Health Pharmacy will 
have no further involvement in the trial, ensuring that participants, clinicians, and trial personnel 
remained unaware of the allocated group. 
 
 
Justification: 
Two decades ago, the first randomized trial demonstrating the potential efficacy of a calcium 
channel blocker (nifedipine) for medical expulsive therapy of ureteral stones was performed.3 
Subsequently, tamsulosin, a selective alpha-1a antagonist, has also been demonstrated as a 
potentially useful agent for MET in randomized trials.4 Over the past decade, off-label MET has 
become more commonplace. However, the strength of findings from randomized trials is weak 
due to variability in quality and power of study design. 
 
In 2015, a large multi-center randomized placebo-controlled trial (SUSPEND Trial) included 
1167 patients and compared the efficacy of nifedipine and tamsulosin for the reduction in 
surgical therapy in patients passing ureteral stones within 4 weeks after randomization.5 This trial 
demonstrated that both nifedipine and tamsulosin were ineffective for MET and were associated 
with an increase in adverse effects compared to placebo. These findings suggest that current off-
label therapy with calcium-channel blockers and alpha-blockers may be ineffective and 
inappropriate. Because ureteral stones remain an important and expensive medical problem, 
identification of other potential agents for MET may reduce the frequency of serious 
complications and necessity of surgical intervention as well as improve patient- centered 
outcomes. 
 
9. 
PROCEDURES 
 
Visit 1 – Emergency Department 
In the ED, the subjects will receive a full history and physical, blood tests (including CBC and 
BMP), urinalysis and culture, urine pregnancy test, CT scan or Ultrasound/KUB of the abdomen 

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and pelvis, and KUB as part of standard of care for ureteral colic. The radiology department will 
note on all imaging the largest diameter of the stone and the Hounsfield units. Research study 
staff will screen potential subjects in the ED by reviewing their charts and will obtain written and 
verbal consent (in Spanish when necessary) from subjects who meet all inclusion and exclusion 
criteria. Baseline data, including demographics, medical and surgical history, and current 
medications, will be collected before randomization. 
 
Each subject will be assigned a unique, consecutive three-digit identification number (i.e., 001, 
002…). The study number will be utilized for identification of the subject throughout the study. 
The clinical study coordinator of the trial will maintain the code that links the name of the 
participant to their study identification number. The study coordinator will maintain the code in a 
secured cabinet and the code will be kept confidential. Only the clinical study coordinator and 
Principal Investigator (PI) can access and view the codes. 
 
Subjects will be asked to complete the Wong-Baker FACES pain scale (available with validated 
Spanish translation as well). Subjects will be discharged from the ED with a (1) 60 day 
prescription for the study drug (mirabegron or placebo) (2) urine strainer (3) 60 day log for 
recording medication adherence, narcotic/analgesic usage, and ureteral pain. Subjects will be 
instructed to take one pill per day beginning immediately and continuing until they have 
completed all pills or until they have been instructed to discontinue by the study staff.  
 
Subjects will be provided instructions for use of the urine strainer and collection of any stone or 
stones that may be passed.  They will be instructed to bring any stones that have been passed to 
the next clinic visit. 
 
Subjects will be informed that they may also discontinue the study drug at any time if they would 
like to drop out of the trial and they may do so by contacting Dr. Mayer or designee. Subjects 
will be informed to contact Dr. Mayer or designee if they believe that they have passed their 
ureteral stone before discontinuing therapy. Subjects will be told to bring their medication bottles 
when they return to the clinic.  
 
In the event that a subject has additional pain, discomfort, or other symptoms that may be related 
to their ureteral stone they may follow-up for an unscheduled visit to either the emergency 
department or the Urology clinic. The subject will be treated according to standard of care and 
information regarding their visit will be collected. If the subject must undergo an emergent 
procedure for their stone they will be determined to have failed therapy but will remain in the 
study to evaluate the study drug to reduce stent pain. Subjects that fail therapy early will undergo 
Visit 3 and will be evaluated at Visit 4 for the removal of their stent. Subjects will remain in the 
study for all outcome measurements if they do not require surgical intervention. 
 
Interim Phone Follow-up #1 – (7 Days ± 3 days post-Visit 1) 
The research study staff will contact the subject by phone approximately 7 days after Visit 1. 
Research staff will assess ureteral pain, medication/strainer compliance, and adverse events. 
Research staff will also identify whether or not the subject subjectively or objectively has passed 
their ureteral stone. The research staff will also answer any questions that the subject may have 
during this follow-up event. 

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Interim Phone Follow-up #2 – (21 Days ± 3 days post-Visit 1) 
The research study staff will contact the subject by phone approximately 21 days after Visit 1. 
Research staff will assess ureteral pain, medication/strainer compliance, and adverse events. 
Research staff will also identify whether or not the subject subjectively or objectively has passed 
their ureteral stone. The research staff will also answer any questions that the subject may have 
during this follow-up event. The research staff will also remind the subjects to bring in their 
medication bottles to Visit 2 (see below). 
 
Visit 2 – Urology Clinic (30 days ± 5 days post-Visit 1) 
Subjects will follow-up in the Harris Health Urology Clinic approximately 30 days after Visit 1. 
Subjects will provide a blood sample for a CBC, BMP, coagulation studies (PT/INR/PTT), a 
urine sample for a urinalysis and culture, urine pregnancy test, and have their blood pressure 
taken, as per standard of care. Subjects will also undergo a CT or KUB plus renal ultrasound at 
the Harris Health Radiology Department to radiologically identify the status of their ureteral 
stone, as per standard of care. 
 
In the Urology Clinic, staff will perform a brief history and physical, review clinical imaging, 
observe any stones that the subject has collected, and determine whether or not the subject has 
passed their ureteral stone. Clinical and research staff will assess blood pressure, ureteral pain, 
pain medication and pain score log compliance, medication/strainer compliance, and adverse 
events using the adverse event checklist. Subjects will be asked to bring in their medication 
bottles at this visit to assess medication compliance. Subjects with persistent ureteral stones will 
be scheduled for ureteroscopy with laser lithotripsy and ureteral stent placement. These subjects 
will continue the study drug and strain their urine. Subjects will be provided additional study 
drug if necessary and instructed to continue until Visit 4, regardless of if they believe they passed 
their stone or not.  They will be asked to bring the study drug bottle and any collected stones 
upon their return to Visit 3. 
 
Subjects who have passed their stone will discontinue the study drug and exit the study. 
 
Visit 3 – Ureteroscopy (14 days ± 5 days post-Visit 2) 
Subjects who have failed the expectant management period as determined on Visit 2 will 
undergo ureteroscopy with laser lithotripsy approximately 14 days after Visit 2.  
Blood pressure will be checked prior to the procedure. Stone fragments will be collected for 
composition analysis. All subjects will be stented using the preferred 6-French Boston Scientific 
Contour Injection Ureteral Stent Set that has been appropriately sized for each patient. If this 
particular catheter cannot be used, any 6-French catheter is preferred, but any ureteral catheter 
may be utilized during this visit. The string will not be removed from the ureteral stent to 
facilitate easier removal later. In subjects for whom the ureteroscope cannot successfully be 
passed into the ureter after reasonable attempts, the surgeon will place a ureteral stent and the 
subject will remain on the trial until their ureteral stent has been in 1 week or until Visit 4. 
Subjects will receive 10 days of ciprofloxacin, Tylenol #3, phenazopyridine, per standard of 
care. Subjects will not be prescribed alpha-adrenergic blockers or anticholinergics. 
 
Clinical and research staff will assess blood pressure, ureteral pain, pain medication and pain 

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score log compliance, medication/strainer compliance, and adverse events using the adverse 
event checklist. 
 
They will be asked to bring the study drug bottle upon their return to the clinic at Visit 4. It is 
possible that some patients will pass their stone between visit 2 and visit 3. If the patient has 
physically seen the stone pass or has collected the stone, they will exit the study; otherwise, they 
will proceed with a diagnostic versus therapeutic ureteroscopy with stent placement. 
 
Visit 4 – Removal of Ureteral Stent (7 days ± 3 days post- Visit 3) 
Subjects will return the Harris Health Urology Clinic approximately 7 days after ureteroscopy to 
remove their ureteral stent. In the Urology Clinic, staff will perform a brief history and physical, 
including blood pressure, per standard of care.  Subjects will complete the USSQ. Stent pain, 
medication compliance, and medication-related adverse events, if any, will be assessed. Subjects 
will be asked to return any unused study drug and the study drug bottle at this visit. For subjects 
in whom the ureteroscope could not be passed and a stent was left in place, this visit will be a 
return to the operating room for completion ureteroscopy or stent removal, as clinically 
indicated. 
 
Early Completion of the Trial Period 
Subjects will be asked to call the study staff if they believe that they have passed their ureteral 
stone during the expectant management period or before ureteroscopy. Subjects that have 
objectively passed their stone will be asked to bring stone fragments for composition analysis. 
Subjects that have subjectively passed their stones will be asked to continue on their study 
medication until they can undergo a CT or KUB plus renal ultrasound and be interviewed in 
person by the clinical staff to determine stone passage. If a subject completes the trial before 
Visit 4, they will be asked to return any unused study drug. 
 
Protocol Exceptions 
Under the circumstance that any clinic visit cannot be made within the given timeframe due to 
system or subject issues unrelated to the study staff, the PI can review each case on an individual 
basis. If the PI determines that standard of care is ongoing, the subject may remain on the study. 
Under the circumstance that this may delay time to completion, the PI may extend study drug 
until completion of the trial. Extension of the study drug may continue in continuation with the 
initial 60 day dose or may be restarted after a period of drug cessation. This extension is not to 
exceed 60 additional days. 
 
Monitoring of Adverse Events 
Safety outcomes will be reported when they happened (via the case report form, patient 
questionnaires, and patient and clinician report). Suspected serious adverse events will be graded 
at site by the principal investigator. Safety events will be monitored by Astellas research ethics 
committee, and MHRA. Reporting of unanticipated problems will be in accordance to the current 
IRB guidelines and FDA regulations. An adverse event log will be maintained at the clinical site.  
The logs will be tabulated into a master log and submitted with each annual IRB renewal report. 
 

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10. 
LABORATORY CONSIDERATIONS 
 
Blood and urine samples will be obtained at the first visit in the ED and during the 30 day 
follow-up visit in the Urology clinic. Up to 10 ml of blood will be drawn for laboratory 
assessment of CBC, BMP, and the coagulation panel. 
 
The samples for standard of care testing will be sent to the laboratory at Ben Taub General 
Hospital. After tests are completed, any remaining samples will destroyed per laboratory's 
Standard Operating Procedures. 
 
No cell lines will be developed. If a subject withdraws, the samples will have already been 
destroyed; therefore, the subject will not be able to have the samples returned to them. 
 
Subjects may see and get a copy of their research related health information. The research doctor 
may be able to provide subjects with part of their information while the study is in progress and 
the rest of their information at the end of the study. 
 
11. 
SAMPLE SIZE 
 
The primary outcome measure is spontaneous stone passage. The proportion of patients who 
spontaneously pass the stone within 30 days will be compared between the mirabegron and 
placebo groups using Fisher’s exact test. Previous research suggests that about 50% of subjects 
in the placebo group will have a spontaneous stone passage. A sample size of 45 subjects per 
group will provide 80% power to detect a 0.30 unit difference in proportions using Fisher’s exact 
test assuming alpha=0.05 and half of the patients in the placebo group have spontaneous stone 
passage. Therefore, a total of 104 subjects will be enrolled into this study to allow for 15% 
attrition. 
 
12. 
STATISTICAL CONSIDERATIONS 
 
The primary analysis will evaluate the difference in the proportion of subjects who successfully 
pass their ureteral stone between subjects who received mirabegron and placebo. This analysis 
will provide information regarding the efficacy of mirabegron to improve stone passage rates for 
patients undergoing expectant stone management. 
 
The secondary analyses will involve a multivariable analysis to compare the difference in pain 
during passage and pain with a ureteral stent in place. This may include co-variates such as age, 
gender, location of ureteral stone, prior history of ureteral stones, pain medication used during 
expectant management, and stone size. 
 
13. 
DATA ANALYSIS 
 
Patient demographics and clinical characteristics will be summarized by means with standard 
deviations, medians with minimum and maximum values, or frequencies with percentages. 
Summary statistics will be stratified by treatment group. No univariable analysis will be 
completed in this randomized clinical trial. 

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The primary analysis will compare the proportion of subjects with spontaneous stone passage 
within 30 days between study groups using Fisher’s exact test. Statistical significance with be 
assessed at the 0.05 level (two-sided). A logistic regression model will also be used to estimate 
the odds ratio for spontaneous stone passage in the mirabegron group versus the placebo with a 
95% confidence interval. 
 
A multiple logistic regression model, adjusting for treatment group, will also be used to test for 
significant associations between spontaneous stone passage and patient demographics or clinical 
characteristics. Parameter estimates significant at the 0.05 level will be included in the final 
multiple regression model. No adjustments will be made for multiple hypothesis testing. 
A secondary objective of this study is to compare pain measures between treatment groups. The 
Wong Baker FACES pain scale will be measured daily for each patient. A general linear mixed 
model will be used to compare pain scores between treated and placebo groups. The model will 
include fixed effects for treatment group, time (discrete) and a group-time interaction term. The 
matrix of correlated residual terms will assume an unstructured format. This model will account 
for the correlation between repeated measures within the same subject and will allow for all 
available data to be included in the model. 
 
Missing data will not be imputed. Model fit will be assessed using influence diagnostics and 
residual analysis. Data transformations (e.g., natural logarithm) will be used if departure from 
model assumptions is evident. The model will also be used to explore associations between pain 
scores and demographic and clinical characteristics, adjusting for treatment group and time. 
 
The USSQ will be observed in patients who require surgical intervention, and will be observed 
during study visit 4. A general linear model will be used to compare USSQ pain scores between 
the treated and placebo groups. The model will also be used to explore associations between pain 
scores and demographic or clinical characteristics adjusting for treatment group. Secondary 
analyses will be assessed at the 0.05 level (two-sided) without adjusting for multiple 
comparisons. 
 
14. 
END-POINTS 
 
Endpoints will include spontaneous passage rate during the 30-day expectant management period 
or completion of the expectant management period without a requirement for surgery. Secondary 
endpoints will include ureteral pain during the expectant management period (Visit 1, Interim 
Follow-up #1 and #2, Visit 2) and pain with a ureteral stent in place (Visit 4). 
 
15. 
RISKS 
 
There are risks to any medication. However, mirabegron is a FDA-approved medication and has 
passed rigorous trials for safety. 
 
A. 
Mirabegron: Mirabegron is contraindicated in patients who have known 
hypersensitivity reactions to mirabegron or any component of the tablet. Mirabegron 
can increase blood pressure. Periodic blood pressure determinations are 

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recommended, especially in hypertensive patients. Mirabegron is not recommended 
for use in severe uncontrolled hypertensive patients (defined as systolic blood 
pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg). 
 
Urinary retention in patients with bladder outlet obstruction (BOO) and in patients 
taking antimuscarinic medications for the treatment of OAB has been reported in 
post-marketing experience in patients taking mirabegron. A controlled clinical safety 
study in patients with BOO did not demonstrate increased urinary retention in 
Mirabegron patients; however, Mirabegron should be administered with caution to 
patients with clinically significant BOO. Mirabegron should also be administered 
with caution to patients taking antimuscarinic medications for the treatment of OAB. 
 
Angioedema of the face, lips, tongue and/or larynx has been reported with 
Mirabegron. In some cases angioedema occurred after the first dose. Cases of 
angioedema have been reported to occur hours after the first dose or after multiple 
doses. Angioedema associated with upper airway swelling may be life threatening. If 
involvement of the tongue, hypopharynx, or larynx occurs, promptly discontinue 
Mirabegron and initiate appropriate therapy and/or measures necessary to ensure a 
patent airway. 
 
Since Mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to 
CYP2D6 substrates such as metoprolol and desipramine is increased when co-
administered with Mirabegron. Therefore, appropriate monitoring and dose 
adjustment may be necessary, especially with narrow therapeutic index drugs 
metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone. 
 
Most commonly reported adverse reactions over 2% and greater than with placebo) 
were hypertension, nasopharyngitis, urinary tract infection and headache. 
 
Subjects will be monitored carefully for such side effects and should the subject feel 
uncomfortable continuing treatment, he will be allowed to discontinue participation 
in the study. 
 
PREGNANCY: It is possible that the medicines used in this study could injure a fetus 
if the subject or partner becomes pregnant while taking them. Because of the 
potential risks involved, the subject or partner should not become pregnant while you 
are participating in this study.  
 
If subject is sexually active or become sexually active and can get pregnant or can get 
the partner pregnant, the subject must agree to use one of the following forms of birth 
control every time the subject has sex from now until 3 months after stopping the 
study drug: 
 
* oral contraceptives ("the pill"),  
* intrauterine devices (IUDs),  
* contraceptive implants under the skin, or contraceptive injections,  

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* condoms with foam.  
 
Should pregnancy occur while on this study, the subject must immediately notify the 
study personnel. 
 
The investigator will assist in finding appropriate medical care. The investigator also 
may ask to be allowed to continue getting information about the pregnancy. The 
subject can choose not to provide this information. 
 
B. 
Blood Draw: Inserting needles into veins for collecting blood may be uncomfortable. 
Risks include slight bruising at the puncture site, fainting, the formation of a small 
blood clot or swelling of the vein and surrounding tissue, bleeding from the site, and 
the remote possibility of infection at the site of the needle puncture. Fainting is 
usually harmless, of short duration, and typically produces feelings of weakness, 
sweating, slowing of the heart rate and an abnormal decrease in blood pressure. Care 
will be taken to avoid these complications. 
 
C. 
Blood Pressure: Subjects may feel a slight discomfort while the band on the arm is 
tightened in order to take the reading. 
 
D. 
Scans: CT scans, ultrasounds, and plain x-rays do not cause any physical discomfort. 
Anxiety in anticipating these procedures might be experienced. CT scans and plain x-
rays subject patients to small amounts of radiation. In the field of radiation 
protection, it is commonly assumed that the risk for adverse health effects from 
cancer is proportional to the amount of radiation dose absorbed and the amount of 
dose depends on the type of x-ray examination. A CT examination with an effective 
dose of 10 millisieverts (abbreviated mSv; 1 mSv = 1 mGy in the case of x rays) may 
be associated with an increase in the possibility of fatal cancer of approximately 1 
chance in 2000. This increase in the possibility of a fatal cancer from radiation can be 
compared to the natural incidence of fatal cancer in the U.S. population, about 1 
chance in 5. In other words, for any one person the risk of radiation-induced cancer is 
much smaller than the natural risk of cancer. Nevertheless, this small increase in 
radiation- associated cancer risk for an individual can become a public health concern 
if large numbers of the population undergo increased numbers of CT screening 
procedures of uncertain benefit. It must be noted that there is uncertainty regarding 
the risk estimates for low levels of radiation exposure as commonly experienced in 
diagnostic radiology procedures. 
 
E. 
Loss of Confidentiality: The loss of confidentiality regarding research information is 
a possibility, although, the risk is extremely small. The investigator and his/her 
research staff will make every effort to maintain the confidentiality. 
 
F. 
Ureteroscopy with stent placement: Patients will have a small camera placed in their 
bladder. A smaller camera will be placed in the kidney which will be used to find the 
stone. If unable to introduce this smaller camera in the kidney a stent will be left to 
open up the ureter, the tube that drains the kidney and another attempt will be made 

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in a few weeks. The stone will be broken apart by a laser. The small fragments may 
be individually removed. An x-ray will be used for the procedure. A stent will be left 
in the kidney after the procedure and will be removed in clinic. 
 
G. Questionnaires: Completing the questionnaires may cause some level of emotional 
discomfort due to the personal nature of the questions. The study doctor and staff will 
maintain a professional and caring attitude while administering the questionnaires. 
 
16. 
ASSESSMENT OF SAFETY 
 
A. Adverse Events Reporting 
 
All adverse event (Severe Adverse Event (SAE), Unanticipated Event (UAE), or 
Adverse Event (AE) will be assessed by the Principal Investigator using the BCM PI 
Determination form.  The IRB will be notified according to current rules, regulations, 
and procedures. 
 
B. 
Serious Adverse Event Reporting 
 
Within 24 hours of awareness of a serious adverse event, whether or not related to the 
study drug, the Investigator will complete and submit a Medwatch 3500A Form to 
FDA, containing all required information (reference 21 CFR 312.32).  The 
Investigator will submit a copy of this MedWatch 3500A form to Astellas by either e-
mail or fax, within the same timeframe.  If submission of this SAE to FDA or Astellas 
or is not possible within 24 hours, the Investigator’s local drug safety contact (IRB, 
etc.) should be informed by phone. 
 
The SAE documentation, including the Medwatch 3500A Form and available source 
records should be emailed or faxed to: 
 
 Astellas Pharma Global Pharmacovigilance – United States 
 Email: Safety-us@us.astellas.com 
 Fax number: (847) 317-1241 
 
The following minimum information is required: 
 
•        Study number/IIT regulatory identifier 
 
•        Subject number, sex and age 
 
•        The date of report 
 
•        A description of the SAE (event, seriousness of the event) 
 
•        Causal relationship to the study drug 
 

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Follow-up information for the event should be sent promptly (within 7 days) as 
necessary. 
 
C. Additional safety analyses will be conducted in the safety population, defined as all 
subjects who receive at least one treatment with study drug. 
 
Safety and tolerability will be assessed by evaluating physical, clinical laboratory 
tests, and reported AEs. 
 
17. 
WITHDRAWAL OF SUBJECTS 
 
Subjects for the study will be selected during screening based on the inclusion and exclusion 
criteria and clinical assessment listed below.  Subjects will be discontinued from the study 
prematurely if: 
 
A. Unacceptable AEs considered by the investigator to be associated with use of the 
study drug occur 
B. 
The subject requests to be withdrawn from the study 
C. A need for concomitant medication prohibited by the protocol arises 
D. The Principal Investigator decides that it is in the subject’s best interest 
E. 
The subject is significantly non-compliant with the protocol 
 
18. 
BENEFITS 
 
Subjects assigned to the mirabegron group may experience a reduction in their risk for surgical 
intervention or may experience reduced pain associated with ureteral colic or ureteral stenting. 
 
Should mirabegron prove beneficial in reducing the need for surgical stone extraction or reduce 
the pain associated with ureteral colic or ureteral stenting this medication may be used during the 
expectant management period for ureteral stones. This may decrease the adverse effects and 
morbidity associated with ureteral stones. Preventing the need for surgical intervention may 
reduce healthcare costs and reduce complications and morbidity associated with surgery. 
 
The anticipated benefits outweigh potential risks. The study medication used in this study has 
been approved as safe by the FDA. 
 
19. 
ALTERNATIVES 
 
Patients may choose not to participate in this study. Other treatment for small ureteral stones 
includes nifedepine or tamsulosin (off-label) in addition to hydration and NSAIDs. 
 
20. 
COSTS TO SUBJECTS 
 
The subjects and/or their insurance will cover the emergency department visit as well as follow-
up office visits, blood tests, diagnostic imaging, and surgical intervention that are standard of 
diagnosing and managing ureteral stones. 

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2/20/19 
 
The study medication, mirabegron, and the placebo are not considered standard of care. Astellas 
will provide these study drugs. 
 
21. 
PAYMENT TO SUBJECTS 
 
Subjects will receive $50 ClinCard for their participation in this study.  It will be provided to the 
subject at the follow-up visit. 
 
22. 
CONFIDENTIALITY 
 
Research data will be maintained and stored in the PI's office located at McNair Campus Medical 
Office Building, 7200 Cambridge, 10th floor, Suite B.  Entry to this location is by electronic 
badge scanner. All computers are password protected and data is stored on encrypted servers that 
are managed by BCM IT. At times of analysis, all computers for analysis will also be password 
protected/encrypted. 
 
Research data will also be accessible via a database designed by the Director of Research 
Informatics at the BCM’s Dan Duncan Institute of Clinical and Translational Research. It is a 
HIPPA-compliant secure database accessible via internet. 
 
Regulatory documents will be managed by Research Administration of the Scott Department of 
Urology located at Main Baylor, Rooms 502D and 506D. The Main Baylor offices have keyed 
entries. All computers are password protected and stored on encrypted BCM servers that are 
managed by IT. 
 
The Scott Department of Urology complies fully with the HIPAA Privacy Rule. 
 
23. 
ETHICS 
 
A. Informed Consent Process: 
 
Subjects will be identified from those visiting in the Emergency Room of Ben Taub 
General Hospital, a BCM-Affiliated Institution. Patients will be informed both 
verbally and in written form of the study and procedures involved and be given 
adequate opportunity to read it and discuss with family before it is signed. The PI 
and/or the study coordinator will obtain a signed/dated Informed Consent Document 
(ICD) before enrolling each subject and prior to the occurrence of any study events 
procedures. The original signed/dated ICD will be kept with the research study 
documents, a copy will be given to the subject, and a copy will be scanned to the 
subject’s EPIC record. 
 
Spanish speaking participants will be consented using a Spanish language consent 
form and subjects will be provided Spanish translated questionnaires. 
 
 
 

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B. 
Institutional Review Board 
 
The PI will provide the IRB with all requisite material, including a copy of the 
informed consent. The study will not be initiated until the IRB provides written 
approval of the protocol and the informed consent and until approved documents 
have been obtained by the PI. Appropriate reports on the progress of this study by the 
PI will be made to the IRB in accordance with the applicable government regulations. 
 
C. 
Study Monitoring 
 
The BCM, SDU, Quality Assurance Program Guidelines protocol will be in effect for 
monitoring and auditing of this study. 
 
D. Monitoring Case Report Forms 
 
The principal investigator or their designee will monitor all aspects of the study with 
respect to current GCP and standard operating procedures for compliance with 
applicable federal regulations.  These individuals will have access to all records 
necessary to ensure integrity of the data and will periodically review progress of the 
study with the Principal Investigator. 
 
E. 
Study Record Retention 
 
In accordance with FDA regulations and GCP guidelines, all study-related 
documentation shall be retained by the Principal Investigator as required. 
 
F. 
Changes to the Protocol 
 
Study procedures will not be changed without the approval of the BCM IRB. The 
revised informed consent document must be approved by the BCM IRB prior to it 
being used to enroll patients. 
 
 
 

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24. 
REFERENCES 
 
1. 
Ghani KR, Roghmann F, Sammon JD, et al. Emergency department visits in the United 
States for upper urinary tract stones: trends in hospitalization and charges. J Urology. 
2014;191:90-96. 
2. 
Preminger et al G. MANAGEMENT OF URETERAL CALCULI: EAU/AUA 
NEPHROLITHIASIS PANEL (2007). Vol 2016: American Urological Association; 
2007. 
3. 
Borghi L, Meschi T, Amato F, et al. Nifedipine and methylprednisolone in facilitating 
ureteral stone passage: a randomized, double-blind, placebo-controlled study. The J 
Urology. 1994;152:1095-1098. 
4. 
Porpiglia F, Ghignone G, Fiori C, Fontana D, Scarpa RM. Nifedipine versus tamsulosin 
for the management of lower ureteral stones. J Urology. 2004;172:568-571. 
5. 
Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric 
colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349. 
6. 
Matsumoto R, Otsuka A, Suzuki T, et al. Expression and functional role of beta3 -
adrenoceptors in the human ureter. International journal of urology : official journal of 
the Japanese Urological Association. 2013;20:1007-1014. 
7. 
Wanajo I, Tomiyama Y, Yamazaki Y, Kojima M, Shibata N. Pharmacological 
characterization of beta-adrenoceptor subtypes mediating relaxation in porcine isolated 
ureteral smooth muscle. J Urology. 2004;172:1155-1159. 
8. 
Bultitude M, Rees J. Management of renal colic. BMJ. 2012;345:e5499. 
9. 
Joshi HB, Okeke A, Newns N, Keeley FX, Jr., Timoney AG. Characterization of urinary 
symptoms in patients with ureteral stents. Urology. 2002;59:511-516. 
10. 
Astellas Pharm US, Inc. Mirabegron package insert 2012. 

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APPENDICES 
A. Schedule of Events  
B. Questionnaires: 
i. 
Wong Baker FACES Pain Scale and Narcotic Usage Diary 
ii. 
Wong Baker FACES Pain Scale, and Narcotic Usage Diary, Spanish 
iii. 
USSQ 
iv. 
USSQ, Spanish 
v. 
Adverse Event Checklist 
 

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APPENDIX A: SCHEDULE OF EVENTS 
Highlighted events are considered standard of care. 
Events/Time 
Visit 1 
Screening/ 
Randomization 
(D1) 
Interim 
Follow-up #1 
(D7 ± 3 days) 
Phone Call 
Interim 
Follow-up #2 
(D21 ± 3 days) 
 Phone Call 
Visit 2 
Urology Clinic 
(D30 ± 5 days) 
Visit 3 
Ureteroscopy 
(D44 ± 3 days) 
Visit 4 Removal 
of Ureteral Stent 
(D51 ± 3 days) 
Complete History/Physical 
X1 
Office Visit w/brief H&P 
X 
X 
Blood Pressure 
X1 
X 
X 
X 
Ureteroscopy, laser lithotripsy, 
stent placement 
X 
Phlebotomy 
X1 
X 
CBC 
X1 
X 
BMP 
X1 
X 
Coagulation Panel 
X 
Urine Collection 
Urinalysis 
X1 
X 
Culture 
X1 
X 
          Pregnancy test 
X1 
X
CT 
X1 
X2 
KUB 
X1 
KUB plus ultrasound 
X2
Stone Analysis 
X 
Randomization 
X 
Mirabegron/Placebo Dispense 
X 
Urine Strainer 
X1 
Ciprofloxacin, Tyleynol3, 
phenazopyridine 
 
 
 
 
X 
 
Medication Accountability 
X 
X 
X 
X 
Straining Accountability 
X 
X 
X 
Wong-Baker FACES Pain 
Rating Scale, Narcotics Diary 
X 
X 
X 
X 
X 
USSQ 
X 
Informed Consent 
X 
Adverse Events 
X 
X 
X 
X 
X 
Review Concomitant Meds 
X 
X 
1May be done prior to enrollment into study       
2May be used instead of CT 

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APPENDIX B: QUESTIONAIRES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Subject ID#   
 
Visit #   
 
Page 1 of 3 
 
 
A DOUBLE BLIND PLACEBO CONTROL TRIAL OF MIRABEGRON FOR 
MEDICAL EXPULSIVE THERAPY AND TO MANAGE STENT PAIN FOR 
URETERAL STONES (Protocol # 01-16-20-02) 
 
 
 
You have agreed to participate in the clinical research study conducted by Dr. W. A. Mayer. As 
part of that study, we need to review your pain levels while you are in the study. Please 
complete the follow diary once a day until you return to the clinic. 
 
Example of completed row: 
 
Day 
DATE 
Time of Day 
Pain Scale 
Medication for Pain (if needed) 
5 
2/5/16 
9:30 AM 
6 
Aspirins x 2 
 
 
Please complete the follow diary once a day until you return to the clinic. 
 
Day 
DATE 
Time of Day 
Pain Scale 
Medication for Pain (if needed) 
1 
2 
3 
4 
5 
6 
7 
8 
 

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Subject ID#   
 
Visit #   
 
Page 2 of 3 
 
 
Day 
DATE 
Time of Day 
Pain Scale 
Medication for Pain (if needed) 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
29 
 
 
 
 
30 
 
 
 
 
31 
 
 
 
 
32 
 
 
 
 
33 
 
 
 
 
34 
 
 
 
 
35 
 
 
 
 
36 
 
 
 
 

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Subject ID#   
 
Visit #   
 
Page 3 of 3 
 
 
 
Day 
DATE 
Time of Day 
Pain Scale 
Medication for Pain (if needed) 
37 
 
 
 
 
38 
 
 
 
 
39 
 
 
 
 
40 
 
 
 
 
41 
 
 
 
 
42 
 
 
 
 
43 
 
 
 
 
44 
 
 
 
 
45 
 
 
 
 
46 
 
 
 
 
47 
 
 
 
 
48 
 
 
 
 
49 
 
 
 
 
50 
 
 
 
 
51 
 
 
 
 
52 
 
 
 
 
53 
 
 
 
 
54 
 
 
 
 
55 
 
 
 
 
56 
 
 
 
 
57 
 
 
 
 
58 
 
 
 
 
59 
 
 
 
 
60 
 
 
 
 

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Subjeto ID#   
 
Visita #   
 
Pagina 1 de 3 
 
 
 
 
 
A DOBLE CIEGO PLACEBO CONTROL ESTUDIO DE MIRABEGRON PARA 
TERAPIA MEDICA DEL MANEJO DEL DOLOR Y EXPULSION DE PIEDRAS DE 
LOS URETERS (Protocol # 01-16-20-02) 
 
 
Usted acepto participar en un estudio de investigación clinica conducido por el Dr. W. A. 
Mayer. Como parte del studio, necesitamos revisar su nivel de dolor mientras usted esta en el 
estudio. 
Por favor complete el siguiente diario una vez al día hasta que usted regrese a la clinica. 
Ejemplo de como completer la tabla: 
Dia 
Fecha 
# Hora Del 
Dia 
Escala del 
Dolor 
Medicina para el dolor (si necesita) 
5 
2/5/16 
9:30 AM 
6 
Aspirina x 2 
 
 
Please complete the follow diary once a day until you return to the clinic. 
 
Dia 
Fecha 
# Hora Del 
Dia 
Escala del 
Dolor 
Medicina para el dolor (si necesita) 
1 
2 

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Subjeto ID#   
 
Visita #   
 
Pagina 2 de 3 
 
 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 

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Subjeto ID#   
 
Visita #   
 
Pagina 3 de 3 
 
 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
60 

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8/26/16 
 
URETERIC STEMT SYMPTOMS QUESTIONNAIRE 
 
 
The English and Spanish versions of this questionnaire are provided in the PDF version 
only.