Clinical trial NCT02495389
Conditions: Overactive Bladder
Keywords: Urinary Urgency Incontinence Mirabegron Myrbetriq Betmiga
Sponsor: Loyola University
Start date: 2015-01-28; Completion date: 2019-01-29
Enrollment: 84 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is for women diagnosed with urinary urgency incontinence (UUI) or overactive bladder (OAB). Some patients continue to have symptoms even while taking medication for OAB. The purpose of this study is to estimate the number of women who respond to a medication called mirabegron and estimate change in symptom severity over 12 weeks of therapy. A secondary goal is to correlate the female urinary microbiome (FUM) with response to treatment and change in symptom severity over 12 weeks of therapy.

Detailed description:
Mirabegron is an FDA-approved medication for urgency incontinence. Evaluation of mirabegron's influence on clinical symptoms may need to take into account the effect of the female urinary microbiome (FUM) on a patient's response to treatment. Compared to asymptomatic patients, several bacterial species are more common in patients with overactive bladder.

Currently, physicians have limited ability to personalize a patient's urinary urgency incontinence treatment and, consequently, the prescribed medication may provide minimal symptom relief. Since the FUM can be assessed prior to treatment, this study proposes to determine if baseline FUM assessment can provide insight into future symptom relief with mirabegron treatment.

Arms: arm 1: Participants received mirabegron (Myrbetriq) daily for 12 weeks
Interventions: intervention 1: Mirabegron
Intervention descriptions: intervention 1: Mirabegron is a medication for the treatment of overactive bladder. It was developed by Astellas Pharma and was approved by the United States Food and Drug Administration (FDA) in July 2012.

Protocol documents:
ICF_000.pdf: 
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Document ID#:207102ar3.011718 
Version Date: 01/17/2018  
IRB NUMBER:   207102012815 
 
LOYOLA UNIVERSITY CHICAGO 
HEALTH SCIENCES DIVISION 
MAYWOOD, ILLINOIS 
DEPARTMENT OF OBSTETRICS & GYNECOLOGY 
DIVISION OF FEMALE PELVIC MEDICAINE AND RECONSTRUCTIVE SURGERY 
 
INFORMED CONSENT 
 
Participant’s Name: _________________________________________________________ 
 
Medical Record Number: _____________________________________________________ 
 
PROJECT TITLE:  Mirabegron and Urinary Urgency Incontinence: The Clinical Response and 
the Female Urinary Microbiome 
 
THE APPROVAL FOR THIS PROJECT EXPIRES ON 01/17/2019. 
 
Participant Information 
 
PRINCIPLES CONCERNING RESEARCH:  You are being asked to take part in a research 
project.  It is important that you read and understand the principles that apply to all individuals 
who agree to participate in the research project described below: 
 
1. Taking part in the research is entirely voluntary. 
 
2. We do not know if you will benefit from taking part in the research but the knowledge 
obtained may help others. 
 
3. You may withdraw from the study at any time without anyone objecting and without 
penalty or loss of any benefits to which you are otherwise entitled. 
 
4. If during your participation in the research project new information becomes available 
which would affect your being in the research project (such as better treatments or the 
side effects of the treatments), your doctor will discuss this new information with you and 
will help you make a decision about your continuing in the research. 
 
The purpose of the research, how it is to be done, and what your part in the research will be is 
described below.  Also described are the risks, inconveniences, discomforts and other important 
information which you need to make a decision about whether or not you wish to participate.  
You are urged to discuss any questions you have about this research with the staff members. 
 
PURPOSE OF RESEARCH:  You are being asked to participate in this study because  
you have been diagnosed with urgency incontinence or overactive bladder (OAB). 


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This purpose of this study is to see why so many patients with OAB symptoms have persistent 
symptoms while taking medications for OAB. We believe that bladder bacteria plays a role in 
women not responding to OAB treatment. Although it is not well known, most women have 
bacteria in their bladders. These bacteria live in the bladder without causing symptoms. When 
women get symptoms of overactive bladder, they only improve with medications about 50% of 
the time 
 
Mirabegron is an FDA-approved medication for urgency incontinence. Mirabegron is a 
medication that works on receptors in the bladder wall muscle. When these receptors are filled 
and activated, the bladder actively relaxes and is less likely to develop overactive bladder 
contractions that result in urgency incontinence.  
 
The purpose of this study is to see if women who respond to mirabegron have different bladder 
bacteria than women who do not respond. Our hope is that by studying the interaction between 
mirabegron and bladder bacteria we will better understand the cause of urgency incontinence.  
 
This research is sponsored by Astellas Pharma US 
 
Approximately 120 women with OAB people will participate in this research.   
 
DESCRIPTION AND EXPLANATION OF PROCEDURES:  If you agree to participate in 
this study, you will be asked to sign this consent document.  
 
If you are currently are taking an anticholinergic medication for overactive bladder symptoms 
you will need to stop taking the medication for 2 weeks before you can start the study.  Stopping 
the medication may temporarily worsen your overactive bladder symptoms.   
 
Mirabegron is used for the treatment of overactive bladder.   Stopping your current medication 
allows us to better understand how mirabegron (once you start taking it) is helping your 
symptoms. 
 
You will be required to come to the clinic for 4 visits: baseline, 4 weeks, 8 weeks & 12 weeks 
total participation time will be 12 to 14 weeks. 
 
At each visit your urine will be tested to see if you have a urinary tract infection. The urine 
sample will be collected by passing a catheter (a small rubber tube) through your urethra and into 
your bladder. This is called a catheterized urine samples. You will also need to complete 5 
questionnaires (USIQ, PFDI, OABq and UDI-6, PGI-S, and PPBC).  You will then be given 
mirabegron (Myrbetriq) to start treatment. This visit should take about 45-60 minutes. 
 
We will collect urine at each visit and the urine will be sent to the research laboratory for special 
tests done on the bacteria in the urine.  Since these are research tests and the meaning of the 
results not known, you and your doctor will not be notified of the results of any research tests 
done on your bacteria and your urine. 
 


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If you have an active urinary tract infection at 4 or 8 weeks or 12 weeks, we will collect a 
catheterized sample and then treat appropriately with antibiotics. This visit would be part of your 
usual care. One week after completion of antibiotic therapy, we will obtain another catheterized 
sample and complete the questionnaires. 
 
You will take a daily 25 mg dose by mouth of Mirabegron.   You will take this medication by 
mouth once a day for twelve weeks.   If after 4 weeks you do not feel that your symptoms are 
adequately improved you will have the option of increasing the Mirabegron dose to 50 mg per 
day for the remaining 8 weeks of the study.  
 
The data collected is being used solely for research purposes and will be given a study 
identification number in order to insure your privacy. 
 
We will also review your medical record to collect additional information that is normally 
collected as part of your routine care. Again, no personal identifiers will be used in collecting 
this information. As above, your study identification number will be used. 
 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time. 
 
RISKS/DISCOMFORTS:  It is possible that the study treatment you receive may not be 
effective in treating your overactive bladder symptoms.    
 
If you are currently taking an anticholinergic medication for overactive bladder symptoms and 
stop taking it for the washout period of 2 weeks, there is the chance that your symptoms may 
temporarily worsen until you start taking mirabegron. 
 
You may experience slight discomfort when the catheter (rubber tube) is placed into the opening 
of the bladder (urethra). There is a small risk (less than a 1% chance) of a urinary tract infection 
with the placement of the catheter (rubber tube) into the opening of the bladder (urethra). 
 
The medication used for this study is Mybetriq (mirabegron). It is approved for the treatment of 
urge incontinence. 
 
Uncommon side effects of mirabegron (1-5%) reported include:  
• high blood pressure,  
• difficulty emptying the bladder,  
• fatigue 
 
Rare events have been reported. These include:  
• swelling,  
• skin rash,  
• allergic reactions (including very severe reactions that require hospitalization),  
• headache,  


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• confusion,  
• hallucinations,  
• heart palpitations,  
• changes in the electrical pattern of the heart  
 
As mentioned above you will not be identified by name or by any other identifying information 
on the questionnaires. A study identification number will be listed on each questionnaire and 
data collection sheets. 
 
REPRODUCTIVE AND SEXUAL ACTIVITY INFORMATION: The intervention in this 
study could affect a developing baby. Therefore, you cannot participate in this research project if 
you are pregnant or breast feeding.  
 
If you are a woman of childbearing potential, a pregnancy test will be done to make certain that 
you are not pregnant before beginning the study.  Women who are able to have children must use 
an effective method of preventing pregnancy while participating in this study.  
 
In addition, as study medications may remain in the body for a period beyond their 
administration, you will be asked to continue to employ an effective method of preventing 
pregnancy for 4 weeks after you have finished taking the study medication.   You are encouraged 
to discuss your preferred method with the study physician Dr. Mueller.  She will answer any 
questions you have regarding effective methods of preventing pregnancy. It is important that you 
consult with your physician because some study medications may affect the effectiveness of 
various methods of preventing pregnancy. 
 
If you become pregnant, suspect that you have become pregnant, notify Dr. Mueller 
immediately.  
 
BENEFITS:   We do not know if you will benefit from participating in this study.  The 
information learned may help others in the future.   
 
ALTERNATIVE TREATMENTS:  You do not have to participate in this research project to 
receive care and treatment at Loyola University Medical Center.  
 
You can choose the treatment, mirabegron in this project without participating in the project.   
 
Your doctor has discussed other options with you along with their risks and benefits. 
 
FINANCIAL INFORMATION:  Some health plans will not pay the costs for people taking 
part in studies. Check with your health plan or insurance company to find out what they will pay 
for. Taking part in this study may or may not cost your insurance company more than the cost of 
getting treatment without being in this study.  Depending on your health insurance, there may be 
a co-payment for the standard visits.  You will be responsible for any usual out-of-pocket 
expenses such as co pays, coinsurance or deductibles.   
 
As part of your normal clinical care, a catheterized urine culture will be obtained. The clinic will 


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also obtain a catheterized specimen for any urinary symptoms that suggest a urinary tract 
infection. This is part of the clinic routine of care and as such will be charged to your health 
insurance plan just as they would if you were not participating in a research study.  
 
Costs for procedures not included in the standard care will be covered by the research study.  
 
The medication used in this study will be provided at no cost to you. There will be no costs to 
you for participating in this research. You will be responsible for all other costs associated with 
your care. 
 
Neither you nor your insurance provider will be billed for any procedures that are performed 
exclusively for this research study. Those procedures that are being performed for research 
purposes only include 4, 8, and 12 week catheterized urine culture, research tests done on the 
urine and expanded quantitative urine culture. The study will pay for the 4, 8, and 12 week office 
visits. 
 
You will be given a parking sticker for the day of your visit. 
 
RESEARCH RELATED INJURY: In the event that you are injured or have side effects as a 
result of participating in this research project, your doctor will take the necessary steps to treat 
the problem.  There are no funds available from Loyola University Medical Center, Loyola 
University Health System or Loyola University Chicago to pay for the cost of care of the 
problem. You will be financially responsible for the cost of care of any problems.  By signing 
this form, you are not giving up any legal rights to seek to obtain compensation of injury. 
 
INFORMATION COLLECTED AND WHAT WILL HAPPEN TO IT:  In order to meet the 
goals of the research study (see Purpose of Research section of this consent), we will collect 
information on you, your test results, and how you do from you and your Loyola University 
Medical Center (LUMC) medical records. The information will be collected by the Principal 
Investigator Dr. Wolfe, the study physician(s), the research nurses, data administrators and 
secretaries.   
 
Information about you will be provided to Loyola University Chicago; Astellas Pharma US, the 
research sponsor; data collection and study verification agencies; and/or government regulatory 
agencies such as the Food and Drug Administration. 
 
In this way, we will learn why so many patients with overactive bladder still have symptoms 
after treatment with Myrbetriq. We believe that bladder bacteria play a role in OAB symptom 
persistence.  
 
The information we will collect and send includes:  
 
__X__ DEMOGRAPHIC INFORMATION (e.g., name, address, phone number,) 
__X__ MEDICAL RECORD (including, but not limited to, history and physical exam notes, 
progress notes, consultation reports, laboratory test results, AND/OR operative reports) 


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We will collect and provide this information about you for as long as you are in the study, 
Once the information is disclosed outside of LUMC, it may no longer be protected by federal 
privacy laws.  This authorization does not expire.  
 
It is possible that the sponsor, Astellas Pharma US, , research nurses, data collection and/or study 
verification agencies, data administrators or staff,  or the Food and Drug Administration will 
come to LUMC and view the medical record (see above for description of content) and the 
research records.  They may take notes or copy pages of the medical record.  This is done to 
verify the accuracy of the information LUMC is sending to them. 
 
The results of this research study may be published in a journal for the purpose of advancing 
medical knowledge.  You will not be identified by name or by any other identifying information 
in any publication or report about this research. 
 
Consent for LUMC to use and disclose your medical information is required in order for you to 
participate in the study.   
 
WITHDRAWAL OF CONSENT: Your consent to use and disclose your medical information 
for the purpose of this research study is completely voluntary.  You can withdraw your consent 
for LUMC to use and disclose your information and your consent to participate in this study at 
any time without affecting your ability to receive care and treatment at LUMC unrelated to the 
research study.  Withdrawal means that all study procedures and follow-up will stop and we will 
not send any more information about you to the sponsor of this research or its designees.  
However, information already used and disclosed to the research sponsor prior to the time of 
your withdrawal from this study may continue to be used and disclosed by LUMC and the 
sponsor. 
 
For your safety, we may ask that you return to clinic one more time for follow-up.  We will also 
ask that you return any unused study medication.  If you withdraw from the study, you will need 
to contact your physician(s) to discuss what other options may be available. 
 
If you withdraw from the study, we will ask that you sign the form attached to this consent and 
send it to or give it to the study staff. Your withdrawal from the study will not have any effect on 
any actions by LUMC taken before the attached form is received by LUMC. 
 
Your study doctor, the Institutional Review Board, the regulatory authorities, or the sponsor, 
Astellas Pharma US, may terminate the study at any time with or without your consent. 
 
Your study doctor may choose to take you out of the study because of unexpected or serious side 
effects, treatment non-compliance, or because you are not taking the medication as you were 
instructed. You may also be removed from the study if your study doctor feels that you are not 
benefiting from the study treatment.   


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CONSENT 
 
I have fully explained to ____________________________ the nature and purpose of the above- 
described procedure and the risks that are involved in its performance.  I have answered and will 
answer all questions to the best of my ability.  I may be reached at 708-216-2067.  
 
________________________________________________Date:____/_____/____ 
Signature 
 
Alan Wolfe, Ph.D., is the principal investigator for this study.   Elizabeth Mueller, M.D., is the 
clinical principal investigator for this research project.  Dr. Mueller can answer any questions 
you have about the treatments, procedures and side effects or complications that can be 
associated with the study.  Alan Wolfe, Ph.D., can answer any questions you may have about the 
relationship between bacteria in the bladder and response to treatments.  Alan Wolfe, Ph.D., can 
be reached at: 708- 216-5814.  Dr. Mueller can be reached at:  708-216-2170. 
 
If you ever feel that you have been injured by participating in this study or if you have any 
questions concerning your rights as a research participant, you may contact either Kenneth 
Micetich, MD, Chair of the Institutional Review Board for the Protection of Human Subjects-
Loyola University Chicago Health Sciences Division, at 708-216-2633 or the Director of the 
Human Research Subjects Protection Program at 708-216-4608.   
 
Although you have the right to revoke this authorization, you accept that such revocation will 
not apply to any uses and disclosures of your information that are described in the Loyola 
University Health System Notice of Privacy Practices or otherwise allowable under any Federal 
or State laws.   
 
You will receive a signed copy of this informed consent document. 
 
You have been fully informed of the above-described research program with its possible benefits 
and risks.  Your signature below indicates that you are willing to participate in this research 
study and agree to the use and disclosure of information about you as described above.  You do 
not give up any of your legal rights by signing this consent document.   
 
________________________________________________Date:____/_____/____ 
Signature:   Participant 
 
________________________________________________Date:____/_____/____ 
Signature:   Witness 
 
 
 
 


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PROJECT TITLE:  Mirabegron and Urinary Urgency Incontinence: The Clinical Response and 
the Female Urinary Microbiome 
 
 
REVOCATION OF AUTHORIZATION TO 
RELEASE PROTECTED HEALTH INFORMATION (PHI) 
 
 
I, _____________________________________, hereby revoke my consent to participate 
in the study titled, “Mirabegron and Urinary Urgency Incontinence: The Clinical Response and 
the Female Urinary Microbiome”, at Loyola University Medical Center (“LUMC”).  I also 
revoke my consent to release information I provided to LUMC that allowed LUMC to use and 
disclose my medical information to Astellas Pharma US as outlined on the consent form, which I 
signed on ____/_____/____ (INSERT DATE CONSENT WAS SIGNED ORIGINALLY).  I 
understand that this revocation does not apply to any action LUMC has taken in reliance on the 
consent I signed earlier.   
 
 
________________________________________________Date:____/_____/____ 
Signature:  Participant 
 
 
 
 
Please return this form to: 
 
Dr. Alan Wolfe 
Loyola University Medical Center 
2160 South First Avenue 
Maywood, Illinois 60153 

Prot_001.pdf: 
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MIRABEGRON AND URINARY URGENCY INCONTINENCE:  
THE CLINICAL RESPONSE AND THE FEMALE URINARY MICROBIOME 
 
P.I. Alan Wolfe PhD 
Clinical P.I. Elizabeth Mueller M.D. 
 
 
 
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1. Background 
Overactive bladder syndrome (OAB) is defined by the International Continence 
Society (ICS) as “urinary urgency, usually accompanied by frequency and nocturia, with 
or without urinary urge incontinence, in the absence of urinary tract infection (UTI) or 
other obvious pathology (Haylen et al., 2010a, b). OAB affects at least 15% of adult 
women, with higher incidence with aging (Hartmann et al., 2009). By 2018, the 
prevalence of OAB worldwide is estimated to rise to over 20% (Irwin et al., 2011). Rates 
of OAB in urogynecologic patients with pelvic organ prolapse (POP) or urinary 
incontinence (UI) are as high as 88% (de Boer et al., 2010; Sajadi and Vasavada, 2010). 
OAB symptoms can be caused by multiple etiologies, including bladder infection, 
malignancy, or neurological disease, e.g. multiple sclerosis or spinal cord injury 
(Mostwin, 2002). For most patients with OAB, however, the exact cause is unknown. 
One current theory is that OAB results from dysregulation in the neural pathways 
controlling micturition. Thus, the current medications for OAB are anticholinergic 
medications that target the muscarinic receptors in the detrusor muscle of the bladder 
(Michel and Chapple, 2009).  
Mirabegron is an exciting new oral medication marketed by Astellas for OAB. It is a 
3-adrenergic receptor agonist that relaxes the detrusor smooth muscle during the urine 
storage phase, increasing bladder capacity. At usual clinical doses, mirabegron is 
believed to display selectivity for the 3-adrenergic receptor subtype compared to its 
affinity for the 1- and 2-adrenoceptor subtypes. Data support that -adrenoceptors, 
predominately the 3 subtype, mediate detrusor smooth muscle tone and promote the 
storage function of the human bladder. Efficacy is seen within 8 weeks; steady state 
achieved within 7 days. Mirabegron can be effective for some patients, providing good 
symptom relief. Most studies, however, have documented that many patients (~50%) do 
not experience these preferred results (Chapple et al., 2014a; Chapple et al., 2014b).  
Any attempt to understand mirabegron’s influence on clinical symptoms should take 
into account our recent discovery of the female urinary microbiome (FUM) (Brubaker et 
al., 2014; Hilt et al., 2014; Pearce et al., 2014; Wolfe et al., 2012). The following 
observations support our hypothesis that the FUM exists and that it contributes to OAB 
and patient response to treatment. First, the bladders of women with and without lower 
urinary tract symptoms contain a FUM (Brubaker et al., 2014; Fouts et al., 2012; Hilt et 
al., 2014; Khasriya et al., 2013; Pearce et al., 2014; Siddiqui et al., 2011; Wolfe et al., 
2012). Second, the bacteria that comprise the FUM are clearly distinct from those that 
cause overt clinical urinary tract infection (UTI) (Hilt et al., 2014; Pearce et al., 2014; 
Wolfe et al., 2012). Third, the FUM is associated with pre-treatment OAB symptoms and 
protection against UTI (Brubaker et al., 2014). Fourth, several bacterial species are more 
common in OAB patients than in asymptomatic controls (Pearce et al., 2014). Finally, 
response to an Astellas OAB anti-cholinergic treatment (solifenacin) varies according to 
FUM status (see Preliminary Data). These exciting findings open previously 
unappreciated opportunities for scientific inquiry concerning prevention, etiology and 
treatment of OAB. 
These exciting findings with solifenacin should be replicated in clinically relevant 
populations treated with mirabegron, as it would be advantageous to identify affected 
individuals who are likely to respond prior to prescription. Currently, physicians have 
limited ability to meaningfully personalize UUI pharmacologic treatment and thus broadly 
prescribe too many affected individuals, including those who are likely to have minimal 
symptom relief. Since the FUM can be assessed prior to treatment, we propose to 
determine if baseline FUM assessment can provide insight into future symptom relief 


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with mirabegron treatment. 
 
We propose the following hypothesis:  
In UUI-affected women treated with mirabegron, changes in urinary urgency 
incontinence are associated with changes to the FUM. 
 
2. Objectives:  
A. In UUI-affected women treated with mirabegron, correlate patterns of urinary 
urgency relief with FUM characteristics. 
B. To develop clinically useful predictors for treatment response. 
 
3. Materials and Methods:  
 
Following IRB approval, we will enroll 120 women with OAB. Human-research 
certified researchers will approach potentially eligible Loyola patients seeking care at the 
women’s health or urogynecology clinics.  
 
Inclusion criteria:  
 
Bothersome idiopathic (non-neurologic) UUI who recall > 5 urgency predominant 
urinary incontinence episodes in the prior week (urgency urinary incontinence or 
mixed urinary incontinence-urgency predominant) (Kenton et al., 2006); and  
 
No contraindications to taking mirabegron.  
 
Drug-naïve patients will account for at least 50% of enrolled participants. Patients on 
current OAB therapy will undergo a two-week drug washout period prior to baseline 
assessment in this study. 
Exclusion criteria:  
 
Neurologic disease known to affect the lower urinary tract,  
 
Systemic immunologic deficiency,  
 
Current UTI (based on dipstick assessment) or recurrent culture-proven UTIs,  
 
History or current pelvic malignancy or radiation,  
 
Untreated symptomatic POP > POP-Q Stage II, or  
 
A contraindication to receiving mirabegron.  
We also will exclude women of childbearing potential who are pregnant or nursing, or 
intend to become pregnant during the study, or who are not practicing a reliable method 
of contraception. Finally, patients must have not taken any antibiotics, for any reason, in 
the 4 weeks prior to enrollment (Smith et al., 1997). 
Rescreening Opportunities: 
 
Patients who had POP/UI surgery during the prior 12 weeks are ineligible, but may 
be rescreened at a later time.  
  
 
Patients on current OAB therapy can participate after undergoing a two-week drug 
washout period.   
 
 
 


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Procedures: Eligible woman will undergo an informed research consent process, 
which will be documented in their medication record. Participants who provide 
consent and sign the IRB-approved research consent form will complete a series of 
questionnaires that will be used to quantify symptoms. Symptom quantification will 
permit patient stratification based on phenotype. Stratification will be used to assess 
symptom-based correlates of response status. To quantify symptoms, we will use the 
following validated questionnaires: Urgency Severity and Life Impact Questionnaire 
(USIQ) (Lowenstein et al., 2012), Overactive Bladder Questionnaire (OAB-q) (Coyne 
et al., 2002), Urinary Distress Inventory (UDI-6) Pelvic Floor Distress Inventory 
(PFDI) (Barber et al., 2011), and Patient Global Impression of Severity (PGI-S) 
(Tincello et al., 2013).  
From each patient-participant, a urine sample will be obtained by transurethral 
catheter and cultured (by standard clinical microbiology protocol) as part of their normal 
clinical evaluation. A portion of this urine will be saved for purposes of this study, but will 
be discarded if the patient declines study participation.   
Once the research team confirms that the clinical culture is negative and the patient 
accepts the clinical recommendation for OAB oral medication, the patient-participant will 
be supplied with 25 mg daily of free mirabegron. Per the study protocol, the patient will 
be provided the free medication for the 12-week duration of the study. 
Consistent with clinical follow-up for OAB treatment, the OAB patient-participants on 
mirabegron will return at 4, 8 and 12 weeks. In addition to their care, at each visit, each 
patient-participant will have her symptoms assessed by the questionnaires listed above 
and undergo catheterization for collection of urine specimen. To determine medication 
response, we will use the validated Patient Perception of Bladder Control (PPBC) 
(Coyne et al., 2006). If a subject's symptoms are adequately controlled with mirabegron 
25 mg daily (based on a PPBC score of 4 or 5), she will continue at that study 
medication dose for the entirety of the study (an additional 8 weeks for a total of 12 
weeks) and she will be considered a member of the 25-mg responder cohort. If a subject 
does not feel that they have adequate symptom control at 4 weeks (based on a PPBC 
score of 1, 2 or 3), she will be offered a dosage increase to 50 mg. At 12 weeks, if she 
feels that her symptoms are adequately controlled (based on a PPBC score of 4 or 5), 
then she will be considered to be a member of the 50-mg responder cohort. If, at 12 
weeks, she feels that she does not have adequate symptom control, she will be 
considered a member of the non-responder cohort. The primary outcome, medication 
response, will be obtained at the end of the study (i.e., 12 weeks). 
Consistent with clinical care, any patient with an active UTI will undergo 
catheterization for collection of a urine specimen with subsequent appropriate antibiotics, 
as indicated and consistent with the patient’s allergy profile. For patient-participants who 
have a UTI at the time of a study visit, we will defer the completion of questionnaires and 
repeat catheterized urine specimen to the subsequent week in order to ensure 
appropriate clinical care of the UTI. 
 
Urine specimens handling:  
All urine samples obtained will be split into two aliquots. One aliquot will be sent to 
the clinical microbiology laboratory to undergo the normal clinical urine culture. The other 
aliquot, without any patient identifiers, will be sent to the laboratory of Alan Wolfe, PhD to 
undergo processing for expanded quantitative urine culture (EQUC) and 16S rRNA gene 
sequencing. These complementary assays will allow us to identify the bacterial species 
present in the urines of these women. 
 


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HUMAN SUBJECTS 
Protection of Human Subjects   
Recruitment & Informed Consent. Participants will be counseled by study personnel 
(Drs. Brubaker or our experienced study coordinator, Mary Tulke, RN) prior to their 
signing of the Loyola-IRB approved informed consent for study participation.  
Participant Safety. Urinary catheterization for baseline assessment is part of normal 
clinical care.  Participants will have two catheterizations that are not part of their normal 
clinical care.  There is a possibility of an increase in UTI that would be readily identified 
and treated with conventional antibiotic therapy.  We do not anticipate any other 
increased risks to participants as a result of their participation in this study as there are 
no research interventions & the participant’s normal clinical care will proceed at the 
discretion of her individual physician.  This protocol will comply with all prevailing 
regulations that govern human subject research. Dr. Brubaker will oversee the safety 
and confidentiality of study participants. Any adverse events, including unintentional 
breaches of confidentiality, will be documented & reported to the Loyola IRB. 
Protection Against Risk. In compliance with regulations that govern human subject 
research, we will safeguard protected health information by using an assigned study ID 
number for participants. Documents linking patient identifiers & study ID will be kept in 
an appropriately secured location. 
Potential benefits of research to subjects and importance of knowledge gained by 
participation in this study will have no direct benefit to individual subjects, as clinical care 
will be performed independently of study findings. However, the data obtained has the 
potential to improve the clinical ability to prevent and treat OAB, to advance our 
understanding of the urinary microbiota in the subset of women with OAB, and to 
generate important hypothesis regarding changes in the urinary microbiota in women 
who have bothersome OAB symptoms.   
 
4.  Adverse Event Reporting: 
As with all clinical protocols, a variety of adverse events could occur.  The risk of serious 
adverse event from study participation in this protocol is low.  Reportable adverse events 
would include allergic reactions, heart palpitations and changes in EKG’s... 
There is also an unlikely risk of privacy violation despite diligent adherence to protection 
of all identified human data, using the Loyola secure server and in compliance with our 
institutional policies. 
 
 
5.  Data Collection: 
 
We will collect demographic data (age, race, BMI, medical co-morbidities, tobacco 
use, medical history including estrogen status, and surgical history) on all participants.  
We will also collect the responses of the USIQ, PFDI, OABq and UDI-6, PGI-S, and 
PPBC. The urine specimens will be split into two specimens, one will be sent to the 
clinical microbiology laboratory for routine culture while the other de-identified specimen 
will be sent to the Wolfe laboratory for EQUC and sequencing. 
 
6. Plan to protect the identifiers from improper use and disclosure:  
In compliance with regulations that govern human subject research, we will 
safeguard protected health information by using an assigned study ID number for 


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participants. Documents linking patient identifiers and study ID will be kept in an 
appropriately secured location. Data will be maintained on the secure Loyola Research 
server.   
 
7. Access to protected health information:  
Clinical study investigators will have access to the information for data entry only.  All 
identifiers will be removed from the samples submitted for laboratory analysis. Following 
completion of data entry, the data will be de-identified for analysis. HIPAA-compliant, 
anonymous data from this project will be available for sharing with interested 
researchers. 
 
8. Use of data/Statistical Analysis Plan: 
There is no statistical analysis plan.  The data are intended to add to available 
information on the understanding of the female urinary microbiome, mirabegron and 
OAB in order to better treat our patients. 
 
9. Bibliography:  
 
Barber, M.D., Chen, Z., Lukacz, E., Markland, A., Wai, C., Brubaker, L., Nygaard, I., 
Weidner, A., Janz, N.K., and Spino, C. (2011). Further validation of the short form 
versions of the Pelvic Floor Distress Inventory (PFDI) and Pelvic Floor Impact 
Questionnaire (PFIQ). Neurourol Urodyn 30, 541-546. 
 
Brubaker, L., Nager, C.W., Richter, H.E., Visco, A., Nygaard, I., Barber, M.D., Schaffer, 
J., Meikle, S., Wallace, D., Shibata, N., et al. (2014). Urinary bacteria in adult women 
with urgency urinary incontinence. Int Urogynecol J. 
 
Chapple, C.R., Cardozo, L., Nitti, V.W., Siddiqui, E., and Michel, M.C. (2014a). 
Mirabegron in overactive bladder: a review of efficacy, safety, and tolerability. Neurourol 
Urodyn 33, 17-30. 
 
Chapple, C.R., Nitti, V.W., Khullar, V., Wyndaele, J.J., Herschorn, S., van Kerrebroeck, 
P., Blauwet, M.B., and Siddiqui, E. (2014b). Onset of action of the beta3-adrenoceptor 
agonist, mirabegron, in Phase II and III clinical trials in patients with overactive bladder. 
World J Urol. 
 
Coyne, K., Revicki, D., Hunt, T., Corey, R., Stewart, W., Bentkover, J., Kurth, H., and 
Abrams, P. (2002). Psychometric validation of an overactive bladder symptom and 
health-related quality of life questionnaire: the OAB-q. Qual Life Res 11, 563-574. 
 
Coyne, K.S., Matza, L.S., Kopp, Z., and Abrams, P. (2006). The validation of the patient 
perception of bladder condition (PPBC): a single-item global measure for patients with 
overactive bladder. Eur Urol 49, 1079-1086. 
 
de Boer, T.A., Salvatore, S., Cardozo, L., Chapple, C., Kelleher, C., van Kerrebroeck, P., 
Kirby, M.G., Koelbl, H., Espuna-Pons, M., Milsom, I., et al. (2010). Pelvic organ prolapse 
and overactive bladder. Neurourol Urodyn 29, 30-39. 
 
Fouts, D.E., Pieper, R., Szpakowski, S., Pohl, H., Knoblach, S., Suh, M.J., Huang, S.T., 
Ljungberg, I., Sprague, B.M., Lucas, S.K., et al. (2012). Integrated next-generation 
sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome 


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from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. 
J Transl Med 10, 174. 
 
Hartmann, K.E., McPheeters, M.L., Biller, D.H., Ward, R.M., McKoy, J.N., Jerome, R.N., 
Micucci, S.R., Meints, L., Fisher, J.A., Scott, T.A., et al. (2009). Treatment of overactive 
bladder in women. Evid Rep Technol Assess (Full Rep), 1-120, v. 
Haylen, B.T., de Ridder, D., Freeman, R.M., Swift, S.E., Berghmans, B., Lee, J., Monga, 
A., Petri, E., Rizk, D.E., Sand, P.K., et al. (2010a). An International Urogynecological 
Association (IUGA)/International Continence Society (ICS) joint report on the 
terminology for female pelvic floor dysfunction. Int Urogynecol J 21, 5-26. 
 
Haylen, B.T., de Ridder, D., Freeman, R.M., Swift, S.E., Berghmans, B., Lee, J., Monga, 
A., Petri, E., Rizk, D.E., Sand, P.K., et al. (2010b). An International Urogynecological 
Association (IUGA)/International Continence Society (ICS) joint report on the 
terminology for female pelvic floor dysfunction. Neurourol Urodyn 29, 4-20. 
 
Hilt, E.E., McKinley, K., Pearce, M.M., Rosenfeld, A.B., Zilliox, M.J., Mueller, E.R., 
Brubaker, L., Gai, X., Wolfe, A.J., and Schreckenberger, P.C. (2014). Urine is not sterile: 
use of enhanced urine culture techniques to detect resident bacterial flora in the adult 
female bladder. J Clin Microbiol 52, 871-876. 
 
Irwin, D.E., Kopp, Z.S., Agatep, B., Milsom, I., and Abrams, P. (2011). Worldwide 
prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary 
incontinence and bladder outlet obstruction. BJU Int 108, 1132-1138. 
 
Kenton, K., Fitzgerald, M.P., and Brubaker, L. (2006). What is a clinician to do-believe 
the patient or her urinary diary? J Urol 176, 633-635; discussion 635. 
 
Khasriya, R., Sathiananthamoorthy, S., Ismail, S., Kelsey, M., Wilson, M., Rohn, J.L., 
and Malone-Lee, J. (2013). Spectrum of bacterial colonization associated with urothelial 
cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol 51, 2054-
2062. 
 
Lowenstein, L., Rickey, L., Kenton, K., Fitzgerald, M.P., Brubaker, L., Tulke, M., 
Fordham, J., and Mueller, E.R. (2012). Reliability and responsiveness of the Urgency 
Severity and Life Impact Questionnaire (USIQ). Int Urogynecol J 23, 193-196. 
 
Michel, M.C., and Chapple, C.R. (2009). Basic mechanisms of urgency: roles and 
benefits of pharmacotherapy. World J Urol 27, 705-709. 
 
Mostwin, J.L. (2002). Pathophysiology: the varieties of bladder overactivity. Urology 60, 
22-26; discussion 27. 
 
Pearce, M.M., Hilt, E.E., Rosenfeld, A.B., Zilliox, M.J., Thomas-White, K., Fok, C., 
Kliethermes, S., Schreckenberger, P.C., Brubaker, L., Gai, X., et al. (2014). The female 
urinary microbiome: a comparison of women with and without urgency urinary 
incontinence. MBio 5, e01283-01214. 
 
Sajadi, K.P., and Vasavada, S.P. (2010). Overactive bladder after sling surgery. Curr 
Urol Rep 11, 366-371. 


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Siddiqui, H., Nederbragt, A.J., Lagesen, K., Jeansson, S.L., and Jakobsen, K.S. (2011). 
Assessing diversity of the female urine microbiota by high throughput sequencing of 16S 
rDNA amplicons. BMC Microbiol 11, 244. 
 
Smith, H.S., Hughes, J.P., Hooton, T.M., Roberts, P., Scholes, D., Stergachis, A., 
Stapleton, A., and Stamm, W.E. (1997). Antecedent antimicrobial use increases the risk 
of uncomplicated cystitis in young women. Clin Infect Dis 25, 63-68. 
 
Tincello, D.G., Owen, R.K., Slack, M.C., and Abrams, K.R. (2013). Validation of the 
Patient Global Impression scales for use in detrusor overactivity: secondary analysis of 
the RELAX study. BJOG 120, 212-216. 
 
Wolfe, A.J., Toh, E., Shibata, N., Rong, R., Kenton, K., Fitzgerald, M., Mueller, E.R., 
Schreckenberger, P., Dong, Q., Nelson, D.E., et al. (2012). Evidence of uncultivated 
bacteria in the adult female bladder. J Clin Microbiol 50, 1376-1383.