Understanding the Response to Fesoterodine Through Genetic Evaluation in the Elderly (URGE)

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT01786967
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 61
• Location: 1
• Arm: 1
• Actual Duration (Months): 64
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Urge Urinary Incontinence	Drug: Fesoterodine Fumarate	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Understanding the Response to Fesoterodine Through Genetic Evaluation in the Elderly
• Actual Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Dec 31, 2017
• Actual Study Completion Date: Dec 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fesoterodine Fumarate Participants will receive 4 mg of study drug for first 2 weeks, and then 8 mg of study drugs for 2 weeks.	Drug: Fesoterodine Fumarate; FDA approved anticholinergic medication used for treatment of urge urinary incontinence; Other Names: Toviaz

Outcome Measures

Primary Outcome Measures

1. Percentage With Treatment Success [4 weeks]

   Treatment Success (Yes/No) was defined by the Treatment Benefit Scale (TBS). TBS is a 4-point scale which was dichotomized into Yes/No for the Treatment Success outcome. The scale asks participants to rate "My condition has been improved: 1= greatly improved, 2=improved, 3=not changed, 4= worsened." If a participant responded 1 (greatly improved) or 2 (improved), they were considered as a "Yes" for Treatment Success. If a participant responded 3 (not changed) or 4 (worsened), then they were considered as a "No" for Treatment Success.

Secondary Outcome Measures

1. Percentage With Moderate to Severe Anticipated Drug Associated Adverse Events [4 weeks]

   Outcome was defined as moderate to severe anticipated adverse events (AE) based on the NCI Common Terminology Criteria for Adverse Events (CTCAE). Each AE is graded 1-5 with Grade 1=mild AE, Grade 2=moderate AE, Grade 3=severe AE, Grade 4=life-threatening or disabling AE, grade 5=Death-related to AE. Any side effect grade >= 2 considered a moderate to severe AE. Anticipated AEs included dizziness, somnolence, insomnia, confusion, cognitive impairment, dry eyes, blurry vision, dry mouth, constipation, nausea, dyspepsia and urinary retention. Example: dry mouth grades per CTCAE: Grade 1=symptomatic without significant dietary alteration; unstimulated saliva flow > 0.2 mL/min; Grade 2=symptomatic and significant oral intake alteration; unstimulated saliva flow 0.1 to 0.2 mL/min; Grade 3=symptoms leading to inability to adequately aliment orally; IV fluids, tube feedings or total parenteral nutrition indicated; unstimulated saliva < 0.1 mL/min.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

• Willingness to avoid off-protocol UUI therapy during the study period

• Post Void Residual (PVR) <150 mL

Exclusion Criteria:

• Contraindications to fesoterodine (e.g., bladder outlet obstruction, narrow angle glaucoma, myasthenia gravis, severe hepatic or renal impairment)

• Inability to complete study-related items and visits - i.e., cognitive impairment based on Mini-Cog test score (exclude if score of 0 or 1-2 (Abnormal))

• Urinary retention requiring catheterization

• Symptomatic, untreated urinary tract infection not resolved prior to starting fesoterodine

• Botulinum toxin injection for UUI in the last year

• Current therapy with peripheral or sacral neuromodulation

• Neurologic conditions that may affect urinary function (stroke, multiple sclerosis, spinal cord injury, Parkinson's disease)

• Women taking potent CYP3A4 inhibitors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UNC-Chapel Hill, Dept of Ob/Gyn	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Jennifer M Wu, MD, UNC-CH

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 1, 2017

More Information

Publications

None provided.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT01786967
• Other Study ID Numbers: 13-2066; 1R03AG042335-01; Pro00036147
• First Posted: Feb 8, 2013
• Last Update Posted: Mar 18, 2020
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of North Carolina, Chapel Hill: overactive bladder; urge urinary incontinence; pharmacogenetics
• Additional relevant MeSH terms: Urinary Incontinence; Enuresis; Urinary Incontinence, Urge; Fesoterodine

Study Results

Participant Flow

Arm/Group Title	Fesoterodine Fumarate
Arm/Group Description	Participants will receive 4 mg of study drug for first 2 weeks, and then 8 mg of study drugs for 2 weeks. Fesoterodine Fumarate: FDA approved anticholinergic medication used for treatment of urge urinary incontinence
Period Title: Overall Study
STARTED	61
Extensive Metabolizers	54
Poor Metabolizers	4
Metabolizer Status Undetermined	3
COMPLETED	61
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Fesoterodine Fumarate
Arm/Group Description	Women aged 50 and older received 4mg of fesoterodine fumarate for 2 weeks followed by 8mg fesoterodine for 2 weeks.
Overall Participants	61
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.2 (8.1)
Sex: Female, Male (Count of Participants)
Female	61 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.6%
Not Hispanic or Latino	60 98.4%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 11.5%
White	54 88.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Functional Comorbidity Index Score (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	3
Current smoker (Count of Participants)
Current smoker-Yes	2 3.3%
Current smoker-No	59 96.7%
Katz ADL (Activities of Daily Living) score (total) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	5
Lawton IADL (Instrumental Activities of Daily Living Scale) score (total) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	8
Overactive bladder questionnaire - symptom bother (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	68.1 (19.9)
Overactive bladder questionnaire - quality of life (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	48.0 (19.8)

Outcome Measures

1. Primary Outcome

Title	Percentage With Treatment Success
Description	Treatment Success (Yes/No) was defined by the Treatment Benefit Scale (TBS). TBS is a 4-point scale which was dichotomized into Yes/No for the Treatment Success outcome. The scale asks participants to rate "My condition has been improved: 1= greatly improved, 2=improved, 3=not changed, 4= worsened." If a participant responded 1 (greatly improved) or 2 (improved), they were considered as a "Yes" for Treatment Success. If a participant responded 3 (not changed) or 4 (worsened), then they were considered as a "No" for Treatment Success.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Extensive and poor metabolizers are the two cohorts being compared. These cohorts were determined based on their CYP2D6 sequence. Only 58 subjects have data as 3 participants' sequencing did not yield a definitive metabolizer status.

Arm/Group Title	Extensive Metabolizers	Poor Metabolizers
Arm/Group Description	Extensive metabolizer status was based on CYP2D6 sequence	Poor metabolizer status was based on CYP2D6 sequence
Measure Participants	54	4
Number [percentage of participants]	74.1 121.5%	75.0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Extensive Metabolizers, Poor Metabolizers
	Comments	Null hypothesis was that there will be no difference in treatment benefit scale between the two groups
	Type of Statistical Test	Superiority
	Comments	This was a pilot study to provide preliminary data to inform future sample size estimates for a larger more definitive trial
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage With Moderate to Severe Anticipated Drug Associated Adverse Events
Description	Outcome was defined as moderate to severe anticipated adverse events (AE) based on the NCI Common Terminology Criteria for Adverse Events (CTCAE). Each AE is graded 1-5 with Grade 1=mild AE, Grade 2=moderate AE, Grade 3=severe AE, Grade 4=life-threatening or disabling AE, grade 5=Death-related to AE. Any side effect grade >= 2 considered a moderate to severe AE. Anticipated AEs included dizziness, somnolence, insomnia, confusion, cognitive impairment, dry eyes, blurry vision, dry mouth, constipation, nausea, dyspepsia and urinary retention. Example: dry mouth grades per CTCAE: Grade 1=symptomatic without significant dietary alteration; unstimulated saliva flow > 0.2 mL/min; Grade 2=symptomatic and significant oral intake alteration; unstimulated saliva flow 0.1 to 0.2 mL/min; Grade 3=symptoms leading to inability to adequately aliment orally; IV fluids, tube feedings or total parenteral nutrition indicated; unstimulated saliva < 0.1 mL/min.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Extensive and poor metabolizers are the two cohorts being compared. These cohorts were determined based on their CYP2D6 sequence. Only 58 subjects have data as 3 participants' sequencing did not yield a definitive metabolizer status.

Arm/Group Title	Extensive Metabolizers	Poor Metabolizers
Arm/Group Description	Extensive metabolizer status is based on CYP2D6 sequence	Poor metabolizer status is based on CYP2D6 sequence
Measure Participants	54	4
Number [percentage of participants]	14.8 24.3%	0.0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Extensive Metabolizers, Poor Metabolizers
	Comments	Null hypothesis was that there was no difference in the rate of moderate to severe adverse events.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; .76 to .95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	4 weeks
Arm/Group Title	Extensive Metabolizers		Poor Metabolizers		Metabolizer Status Undetermined
Arm/Group Description	Extensive metabolizer status was based on CYP2D6 sequence		Poor metabolizer status was based on CYP2D6 sequence		Metabolizer status was not able to be determined
All Cause Mortality
	Extensive Metabolizers		Poor Metabolizers		Metabolizer Status Undetermined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/54 (0%)		0/4 (0%)		0/3 (0%)
Serious Adverse Events
	Extensive Metabolizers		Poor Metabolizers		Metabolizer Status Undetermined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/54 (0%)		0/4 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Extensive Metabolizers		Poor Metabolizers		Metabolizer Status Undetermined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/54 (9.3%)		0/4 (0%)		0/3 (0%)
Eye disorders
Anticholinergic adverse events	5/54 (9.3%)	5	0/4 (0%)	0	0/3 (0%)	0

Limitations/Caveats

This is a pilot study. Given the smaller size of the study population in this pilot trial, the number of poor metabolizers is low.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.