Clinical trial NCT01786967
Conditions: Urge Urinary Incontinence
Keywords: overactive bladder urge urinary incontinence pharmacogenetics
Sponsor: University of North Carolina, Chapel Hill
Start date: 2012-09-01; Completion date: 2017-12-31
Enrollment: 61 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Urge urinary incontinence, characterized by unpredictable and embarrassing large volume urine leakage, is a major health issue for elderly women, as it is incredibly common and significantly impairs quality of life. Although anticholinergic medications are the most common therapy, the investigators are unable to predict an individual's response to a particular drug in terms of both effectiveness and side effects. Through genetic evaluation, the investigators have the potential to personalize and optimize drug therapy for millions of elderly women suffering from urge incontinence.

Detailed description:
Urge urinary incontinence (UUI), characterized by unpredictable and embarrassing large volume urine leakage, is a major public health burden to elderly women, given its high prevalence, impairment of quality of life, associated caregiver burden, and substantial economic costs. UUI is significantly more prevalent in older adults and disproportionately affects women, with a prevalence of 19% in community-dwelling women over 65 and 60-78% in long-term care female residents.

Anticholinergic medications are the most common first-line therapy for UUI. Although numerous trials have demonstrated that anticholinergics are efficacious for UUI, the response to these medications is variable, as their effectiveness is often limited by poor response or adverse events (AEs), such as cognitive impairment or constipation, which are particularly problematic in older adults. Furthermore, a comprehensive systematic review concluded that no one drug is definitively superior, leaving clinicians without any evidence to guide decision-making regarding drug choice. As a result, UUI pharmacotherapy is empiric and not personalized, even though it is clear that individual variations exist in both response and toxicity. The treatment of UUI is especially challenging in the geriatric population, given their higher risk for AEs, polypharmacy, and pharmacokinetic changes that occur with age. The ability to predict which elderly women with UUI will experience low efficacy or develop significant adverse events from anticholinergic medications would be a paradigm shift in the therapeutic practice to this highly prevalent and bothersome condition.

Pharmacogenetics may provide insight into how to predict response to anticholinergic UUI therapy. Research has already shown that genetic differences in drug metabolism impact a patient's drug response. For example, "fast metabolizers" may metabolize the drug so rapidly that therapeutic levels are never reached, limiting effectiveness. In contrast, "slow metabolizers" may develop high drug concentrations, resulting in significantly more AEs. While pharmacogenetic research exists for numerous classes of drugs, including anticoagulants, selective serotonin-reuptake inhibitors,14 beta-blockers, immunosuppressants and opioids, this type of translational research does not exist for anticholinergics for UUI. Thus, this proposed project represents a novel concept and unique opportunity to dramatically change UUI pharmacotherapy.

Fesoterodine is an ideal anticholinergic medication to launch a pharmacogenetic study in this field. Fesoterodine's active metabolite, 5-hydroxymethyl tolterodine (5-HMT), is metabolized by a well-characterized cytochrome P450 (CYP) enzyme, CYP2D6. The CYP2D6 gene has several genetic variants, which result in different metabolizer statuses ranging from poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), to ultrarapid metabolizers (UM). These different CYP2D6 profiles may be clinically important, as they may contribute to the variability in efficacy and AEs. In fact, pharmaceutical company data for fesoterodine demonstrated that PMs have a two-fold higher plasma concentration than EMs; however, no published data exist on how CYP2D6 metabolizer status correlates with clinical outcomes such as efficacy or AEs. The ability to use CYP2D6 metabolizer status to predict which individuals will experience low efficacy or develop AEs to fesoterodine, and to utilize alternative therapies in these women, would challenge existing therapeutic paradigms and would significantly advance clinical practice via a pharmacogenetic approach.

Specific Aim 1: To explore whether CYP2D6 metabolizer status can predict efficacy during 4 weeks of fesoterodine fumarate therapy in elderly women with UUI. All subjects will be started on fesoterodine 4mg for 2 weeks followed by 8mg for 2 weeks. The primary outcome will be patient-reported treatment response based on a 4-point scale utilized in phase III clinical trials.8,9 We hypothesize that women who rapidly metabolize fesoterodine based on CYP2D6 metabolizer status are more likely to have low efficacy.

Specific Aim 2: To explore whether CYP2D6 metabolizer status can predict moderate to severe adverse events during 4 weeks of fesoterodine fumarate therapy in elderly women with UUI. In the same study design as Aim #1, we will identify subjects with moderate to severe fesoterodine-related AEs. We hypothesize that women who are CYP2D6 poor metabolizers are more likely to have moderate to severe AEs.

Specific Aim 3: To utilize preliminary data from this pilot, proof-of-concept study to plan a future large-scale trial to predict outcomes of anticholinergic UUI therapy based on CYP2D6 metabolizer status. Data regarding efficacy rates, risk of moderate-severe AEs, and the impact of CYP2D6 metabolizer status on efficacy and AEs, in addition to information regarding recruitment, drop-out, and questionnaire burden, will critically inform the study design, outcome measures and sample size of future, definitive trials.

This proposal represents an innovative approach to pharmacotherapy for UUI, a highly prevalent condition with significant morbidity. Pharmacogenetics has tremendous potential to identify ideal candidates for anticholinergic UUI therapy and to distinguish individuals who may benefit from alternative treatment options. This pioneering pharmacogenetic research has the potential to lay the necessary groundwork for future long-term research which would optimize and personalize UUI therapy for millions of elderly women.

Design \& Procedures:

Patient Population: All women aged 50 years or older who desire treatment for bothersome UUI will be approached for enrollment. Women with ≥ 3 UUI episodes on a 3-day voiding diary will be included. Although women who have previously failed fesoterodine will be excluded, those who have failed other UUI anticholinergics remain eligible after a 2-week washout period.

Subjects with auditory or visual sensory impairment will be included. If visual impairment exists, the research coordinator will provide assistance to complete the necessary documents. However, those who are unable to complete the study-related items and visits, such as women with cognitive impairment, based on the Mini-Cog validated questionnaire will be excluded.

Arms: arm 1: Participants will receive 4 mg of study drug for first 2 weeks, and then 8 mg of study drugs for 2 weeks.
Interventions: intervention 1: Fesoterodine Fumarate
Intervention descriptions: intervention 1: FDA approved anticholinergic medication used for treatment of urge urinary incontinence

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Understanding the Response to Fesoterodine Through Genetic Evaluation  
in the Elderly (URGE) 
 
 
NCT Number:  NCT01786967 
 
Document Date: 09-01-17 
 
 
 


 
URGE Study Protocol 
 
IRB #: 13-2066 
Clinicaltrials.gov: NCT01786967 
Last updated: 09-01-17 
 
Study Population  
 
Inclusion Criteria: 
• 
Women ≥ 50 years 
• 
≥ 3 UUI episodes on a 3-day voiding diary 
• 
Urge-predominant incontinence, >50% of total incontinence episodes 
• 
No history of failure to fesoterodine 
• 
2-week washout period if currently on an anticholinergic for UUI 
 
Exclusion Criteria: 
• 
Contraindications to fesoterodine (e.g. bladder outlet obstruction, narrow angle glaucoma [open angle is OK 
if pt. knows], myasthenia gravis, severe hepatic or renal impairment) 
• 
Urinary retention requiring catheterization 
• 
Bladder outlet obstruction 
• 
Symptomatic, untreated UTI not resolved prior to starting fesoterodine 
• 
Recurrent UTI’s (>3 in one year), current UTI needs to be treated before pt. is enrolled 
• 
Botulinum toxin injection for UUI in the last year 
• 
Current therapy with PTNS or Interstim 
• 
Neurologic conditions that may affect urinary function (any history of stroke, multiple sclerosis, spinal cord 
injury, Parkinson’s disease) 
• 
Women taking potent CYP3A4 inhibitors  
• 
Pelvic Organ Prolapse, pessary use OK  
 
 
Recruitment 
 
Phone Screening 
1. Complete a telephone screen for interested patients that contact research staff from CDWH mailings or flyers 
2. If pt. is eligible, enter pt. into enrollment log on Interested tab with appropriate notes and add to CRMS as 
Interested 
3. Go over study with pt. and answer any questions 
4. Mail a consent and an URGE BD to pt. and instruct her to call to go over BD when completed to confirm 
eligibility (≥3 leaks in 3 days, >50% of leaks UUI related) 
• 
If pt. is taking an anticholinergic and willing to do 2 week washout have her begin BD after 1 week and 
then schedule for BL/week 0 visit after the 2 week washout ends 
• 
Pt. can skip a day on BD if needed due to plans/convenience 
5. If pt. is eligible after BD is completed, schedule to come in for baseline/week 0 visit per steps below and have 
her bring completed BD to visit  
6. If pt. is ineligible per phone screen or BD, add pt. to Ineligible tab in the enrollment log and add/change in CRMS 
as Ineligible then screen for ACE study if eligible 
 
Recruiting in Clinic 
1. Pre-screen all scheduled patients in EPIC before appointments according to inclusion and exclusion criteria  
2. If pt. is eligible, note on your copy of printed clinic schedule and let MD know which pts. may be eligible, include 
any new patients who are presenting for UI symptoms as well  


 
3. If pt. is interested, briefly describe the study and administer the in-clinic screen, give pt. an Urge consent to take 
home and look over  
4. If pt. does not have a recent UDS BD, give pt. an URGE BD and voiding hat, ask her to call when BD completed to 
go over on the phone to confirm eligibility 
• 
If pt. is taking an anticholinergic and willing to do 2 week washout have her begin BD after 1 week and 
then schedule for BL/week 0 visit after the 2 week washout ends 
• 
Pt. can skip a day on BD if needed due to plans/convenience 
5. If pt. has UTI based on urine dip, have pt. wait until antibiotics are done before starting BD 
• 
Note: If pt. calls in about possible UTI while not in clinic RNs can perform a 'Test to Cure', message RN to 
call pt. to come in for urine dip and if positive can get a Rx for antibiotics 
6. Enter subject into enrollment log on the Interested tab and add to CRMS as Interested  
7. Once BD is complete, go over to insure eligibility and schedule all study visits 
• 
Ask pt. to bring completed BD to study visit 
• 
Make a copy of BD and add pt. labels, place in medical records bin to be scanned 
• 
Update on the enrollment log and in CRMS as enrolled (pt. has to be active to be linked to study 
timeline) 
8. If pt. ineligible add to Ineligible tab in enrollment log and change to Ineligible in CRMS, then refer to ACE if 
eligible 
 
 
Study Visits 
 
Before the study visit:  
1. Give pt. a reminder call with date/time of appt. and remind her to bring completed BD to appt.  
2. Have previously completed pt. screen to confirm eligibility and to complete page 2 at visit (de-identify and keep 
in study folder) 
3. Obtain 4mg dose of study drug from Rex/HBO IDS supply  
 
Baseline/Week 0 Visit  
1. Read through consent/HIPAA with pt. and have pt. sign and date, research staff person to sign and date as 
witness 
a) Make a copy for the patient and a copy to scan to medical records keep the original and file at Rex 
b) Complete Documentation of Informed Consent and make a copy for medical records, staple the original 
to the original consent/HIPAA to be filed at Rex  
c) Place stapled and patient labeled copies in medical records bin to be scanned and give other copy to pt.  
2. Print out patient medication list from EPIC (filter with View Active and Unverified Meds) and confirm with 
patient, have patient note any other meds not on the list or mark through meds pt. is no longer taking 
3. Administer the following measures: 
a) Functional Comorbidity Index  
4. Have pt. complete the following: 
a) Demographics form 
b) OABq-SF  
5. Complete the following: 
a) P450 Drug Interactions form (exclude if patient is taking a strong/potent CYPD34A inhibitor)  
b) Physical Exam Form (with data from medical records) 
c) Bladder Diary Evaluation (based on BD pt. filled out for inclusion in study) 
6. Complete the Medication Dispensing form  
a) Dispense 4mg dosage: 4mg = light blue, 8mg = dark blue 
b) Instruct pt. to take medication whole and with a liquid, can be taken with or without food 
c) Tell pt. she can take it at same time every day w/other daily meds to help her remember to take it and 
to bring back unused pill at next visit 
7. Go over Medication/AE Diary with pt. and instruct her to bring back to go over at every study visit 


 
a) Tell pt. to contact you if any moderate to severe AEs occur, this will be immediately reported to the 
PI/physician and serious AEs reported to the IRB 
8. Give patient BD to complete 3 days before next visit (or as close to it as possible), record the dates on BD before 
handing to pt. and tell her to bring to next visit  
9. Obtain two 10mL lavender top EDTA tubes of blood via intravenous phlebotomy (Note: blood draw can be done 
at any visit) 
a) Label each tube with BSP label, date, and time of blood draw 
b) Place tubes in sample refrigerator (samples need to be stored at 4 degrees Celsius) 
10. Remind pt. of Week 2 and Week 4 visits, or schedule if needed 
11. Dispense two $20 gift cards (for Baseline and Visit 0) 
a) Fill out the Gift Card Form and staple to inside of pt. study folder 
b) Track cards on the Gift Card Reconciliation Log 
12. Update enrollment log  
13. Make a copy of the BD with labels to be scanned in to medical records and create a telephone encounter for the 
pt. that states that a BD has been completed and scanned in to medical records 
14. Transport blood to BSP in a biohazard cooler with ice packs within 2 days 
15. NOTE: If pt withdraws from study via phone prior to the end of the study please complete: 
a) AE form for all AEs reported (start/stop dates and severity)  
b) Med Diary: how many days they took the medication (start/stop dates) 
 
Before Week 2 Visit: 
1. Before the study visit, obtain 8mg dose of study drug from IDS or from Rex/HBO supply following instructions 
above for the 4mg dose 
2. Give pt. reminder call and remind her to bring unused pills, completed BD, and Med/AE diary 
 
Week 2 Visit: 
1. Ask if patient has had any med changes since last visit and notes changes on med printout 
2. Have pt. complete the following:  
• 
OABq-SF  
• 
Treatment Benefit Scale 
3. Complete the following:  
• 
Bladder Diary Evaluation 
• 
P450 Drug Interactions  
• 
Medication Dispensing Form 
4. Go over Medication/AE diary with pt. and record any AEs on the Adverse Event form 
• 
Discuss with pt. whether AEs are mild, moderate, or severe using the AE definitions and criteria 
• 
Report to PI any AEs and to get rating for un/expectedness and causality 
• 
Report any serious AEs to the IRB as an unanticipated problem on IRB immediately 
• 
Study drug-related AEs: dizziness, somnolence/sedation, insomnia, confusion, cognitive impairment, dry 
mouth/throat, constipation, dyspepsia, nausea, dry eyes, blurry vision, and urinary retention 
• 
If pt. wants to discontinue study drug, have the patient follow-up with their provider to discuss other 
options for management of their UUI symptoms, log as drop-out in enrollment log and CRMS, then 
message PI 
5. Give patient BD to complete 3 before Week 4 visit (or as close to it as possible), record the dates on BD before 
handing to pt. and tell her to bring to next visit 
6. Dispense one $20 gift card 
10. Dispense 8mg study medication and return any unused pills to IDS (write date pt. returned meds on bottle) 
11. Make a copy of the BD with labels to be scanned in to medical records 
12. NOTE: If pt withdraws from study via phone prior to the end of the study please complete: 
• 
AE form for all AEs reported (start/stop dates and severity)  
• 
Med Diary: how many days they took the medication (start/stop dates) 
 
 


 
Before Week 4 Visit: 
1. Give pt. reminder call and remind her to bring unused pills, completed BD, and Med/AE diary 
 
Week 4 Visit: 
1. Ask if patient has had any med changes since last visit and notes changes on med printout 
2. Have pt. complete the following:  
• 
OABq-SF  
• 
Treatment Benefit Scale 
3. Complete the following:  
• 
Bladder Diary Evaluation 
• 
P450 Drug Interactions  
• 
Medication Dispensing Form 
4. Go over Medication/AE diary with pt. and record any AEs on the Adverse Event form 
• 
Discuss with pt. whether AEs are mild, moderate, or severe using the AE definitions and criteria 
• 
Report to PI any AEs and to get rating for un/expectedness and causality 
• 
Report any serious AEs to the IRB as an unanticipated problem on IRBis immediately 
• 
Study drug-related AEs: dizziness, somnolence/sedation, insomnia, confusion, cognitive impairment, dry 
mouth/throat, constipation, dyspepsia, nausea, dry eyes, blurry vision, and urinary retention 
5. Dispense one $20 gift card 
13. Ask pt. to let MD know whether she would like a Rx to study drug, and if so which dosage she felt she responded 
better to, or to let MD know if she wants to try another Tx option 
14. Update enrollment log and change to completed in CRMS 
15. Make a copy of the BD with labels to be scanned in to medical records 
16. Return any unused pills to IDS (write date pt. returned meds on bottle) 
17. File pt. study folder at Rex clinic 
 
 
Statistical Analysis Plan 
Data-cleaning efforts and assessment of overall population and two cohorts 
Univariate statistics to check each variable, distribution, outliers 
• Follow-up on any questionable data points, outliers 
 
Compare sociodemographics of two cohorts 
• Bivariate analysis with chi-square, Fisher’s exact, Student’s t-test, Mann-Whitney U as appropriate 
• Variables include: age, race, education 
 
Compare health, ADLs between cohorts using bivariate analysis 
• Variables include: functional comorbidity index (FCI), current smoking status, Katz ADL, Lawton IADL scores 
 
Evaluate urinary incontinence information between two cohorts using bivariate analysis 
• OABq questionnaires (symptom bother and health-related QoL) 
 
 
Primary outcome analysis 
Primary outcome of effectiveness (Treatment benefit scale, dichotomized) 
• 
Compare rate of effectiveness between two cohorts, Fisher Exact, Risk Ratio (95% CI) 
 
Secondary outcome analysis 
Secondary outcome of moderate to severe AEs (Dichotomous response – Yes/No to mod-severe AEs per CTCAE grading) 
• 
Compare rate of moderate to severe AEs between two cohorts, Fisher exact, Risk Ratio (95% CI)