Mirabegron and Urinary Urgency Incontinence: The Clinical Response and the Female Urinary Microbiome
Phase: PHASE4
Conditions: Overactive Bladder
Sponsor: Loyola University

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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 
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A., Petri, E., Rizk, D.E., Sand, P.K., et al. (2010a). An International Urogynecological 
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A., Petri, E., Rizk, D.E., Sand, P.K., et al. (2010b). An International Urogynecological 
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Hilt, E.E., McKinley, K., Pearce, M.M., Rosenfeld, A.B., Zilliox, M.J., Mueller, E.R., 
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Irwin, D.E., Kopp, Z.S., Agatep, B., Milsom, I., and Abrams, P. (2011). Worldwide 
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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. 
 
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Kliethermes, S., Schreckenberger, P.C., Brubaker, L., Gai, X., et al. (2014). The female 
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Sajadi, K.P., and Vasavada, S.P. (2010). Overactive bladder after sling surgery. Curr 
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Siddiqui, H., Nederbragt, A.J., Lagesen, K., Jeansson, S.L., and Jakobsen, K.S. (2011). 
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Stapleton, A., and Stamm, W.E. (1997). Antecedent antimicrobial use increases the risk 
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