Reduced-dose Botox for Urgency Incontinence Among Elder Females

Overactive Bladder Clinical Trial

— RELIEF  

Official title:

Reduced-dose onabotuLinumtoxinA for Urgency Incontinence Among Elder Females (RELIEF): A Randomized Controlled Comparative Effectiveness Trial With Embedded Qualitative and Costing Analyses

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05512039
• Other study ID #: STUDY02001338
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 12, 2023
• Est. completion date: January 1, 2027

Study information

• Verified date: August 2023
• Source: Dartmouth-Hitchcock Medical Center
• Contact: Morgan T Mazanec, MPH
• Phone: (603) 308-9233
• Email: morgan.t.mazanec[@]hitchcock.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to study the treatment of urgency urinary incontinence (UUI), specifically among women 70 years and older, by comparing reduced versus standard dose of onabotulinumtoxinA (BTX; trade name BOTOX(c)) injection in the bladder.

Description:

The purpose of this quadruple-masked, randomized-controlled study is to study the treatment of urgency urinary incontinence (UUI) specifically among older women with low- versus standard-dose of onabotulinumtoxinA (BTX) via: symptom-specific and health-related quality of life (QOL; Aim 1), patient-reported and clinical outcome measures including adverse events (Aim 2), qualitative experience with focused interviews (Aim 3) and cost burden and economic impact (Aim 4). This study is an active collaboration between researchers in Gynecology, Urology, and Geriatrics at Dartmouth Hitchcock Medical Center (DHMC) and at 5 other centers; University of Alabama (UAB), University of Pittsburgh (U Pitt), University of Texas Southwestern (UTSW), Kaiser Permanente of Southern California (KPSCP), and Oregon Health & Sciences University (OHSU). The investigators also have collaborators at Stanford University and University of Connecticut, though those sites are not recruiting participants.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 376
• Est. completion date: January 1, 2027
• Est. primary completion date: September 1, 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 70 Years and older

Eligibility

Inclusion Criteria:

1. Adult female at least 70 years old at date of enrollment

2. Urge-predominant mixed urinary incontinence (urge>stress per the MESA questionnaire)

3. On average 2 or more urgency or insensible incontinence episodes per day per patient report

4. Refractory urinary urgency incontinence, defined as

1. Persistent symptoms despite trial of one or more conservative treatments (e.g. behavioral therapy, physical therapy, home Kegel exercises); participants not required to have attempted first line therapies if deemed not feasible or appropriate by provider with input of participant/caregiver.

2. Persistent symptoms despite the use of anticholinergic and/or beta-3 agonist medication; or inability to tolerate medication due to side effects, or has a contraindication to taking medication, or is unable to afford the cost of the medication.

5. Currently not on an anticholinergic or beta-3 agonist medication or is willing to stop medication for 3 weeks prior to completing baseline bladder tally, with plan to remain off medication through duration of the study. Currently not actively using sacral neuromodulation therapy (either has not tried, or unit has been off for 4 weeks prior to baseline bladder tally and will remain turned off for the duration of the study). It is permissible for participants to continue self-led conservative therapies during participation in the study, including Kegel exercises, avoidance of bladder irritants, and urge suppression.

6. Willing and able to complete all study-related items, with assistance of caregiver(s) if needed.

7. Demonstrates awareness of possible need for catheterization in event of post-injection urinary retention & acknowledges risks of catheterization. Participant does not need to demonstrate ability to perform self-catheterization.

8. Grossly neurologically normal on exam and no gross systemic neurologic conditions believed to affect urinary function. Patients with a diagnosis of Parkinson's disease or diabetes may be eligible provided they have a grossly normal neurologic exam and otherwise fulfill the inclusion/exclusion criteria.

Exclusion Criteria:

1. Lack of capacity to provide consent. Will be assessed if needed per judgment of the site PI and study staff, with use of optional questionnaire.

2. Baseline persistently elevated post-void residual [PVR] (>150mL on 2 occasions in the 6 weeks prior to enrollment). If the PVR was obtained via bladder scanner with measurements differing by more than 100mL, or if there is concern about the accuracy of the scanner, it will be confirmed via catheterization which will be considered the gold standard.

3. Need for BTX injection to take place in the Operating Room or under sedation. (Of note, for repeat injection under the protocol, patients may have OR injection if indicated due to pain with initial BTX injection.)

4. Previous treatment with intravesical BTX in the last 12 months or use of sacral neuromodulation therapy within the past 4 weeks (unit may remain implanted, but should remain off for duration of the study).

5. Untreated symptomatic urinary tract infection (UTI). Eligible once UTI treatment complete and symptoms resolved.

6. Known bladder abnormality, including current or prior bladder malignancy, carcinoma in situ or untreatable cystitis (e.g. eosinophilic cystitis); prior major bladder surgery that would alter the detrusor muscle, such as augmentation cystoplasty; or hematuria that has not been evaluated.

7. Neurogenic detrusor overactivity or neurologic disease that may impact bladder function, including stroke, multiple sclerosis, peripheral neuropathy, spinal cord injury. Conditions such as Parkinson's disease and diabetes are acceptable provided normal bladder emptying and grossly normal neurologic function.

8. Concurrent BTX use for other indication, participants cannot exceed 300 units BTX in a 3 month period. Participants who may have conflict between study BTX administration and administration for other purposes may be excluded from participation if there is concern that study drug administration will be compromised. Concurrent use of BTX for another indication that would not exceed 300 units in a 3 month period, or that can have time of administration of the other BTX adjusted to avoid excessive dose, is acceptable; for instance, for migraines.

9. Greater than stage 2 pelvic floor prolapse, uncorrected or persistent despite pessary use (leading edge of prolapse not greater than 1cm beyond the hymen). Ongoing pessary use is permissible. Patients may have had a prior repair for pelvic organ prolapse. (see chart review of recent exam or perform brief exam while collecting post-void residual)

10. Planned prolapse or stress incontinence surgery; would defer enrollment to >3 months post-operative.

11. Allergy or intolerance to lidocaine or BTX.

12. Participation in another research study that could conflict with the RELIEF study, in estimation of the site PI.

Related Conditions & MeSH terms

• Enuresis
• Overactive Bladder
• Urgency Urinary Incontinence
• Urinary Bladder, Overactive
• Urinary Incontinence
• Urinary Incontinence in Old Age

Intervention

Drug:
• Botox 50 Unit Injection
Participants will be randomized to either receive a standard dose (100 units) or low dose (50 units) of onabotulinumtoxinA. If a participant has decreased symptom relief, after 3 months post injection, they may receive repeat injection up to twice during the 12 month follow-up period.
• Botox 100 Unit Injection
Participants will be randomized to either receive a standard does (100 units) or low dose (50 units) of botox one time.If a particParticipants will be randomized to either receive a standard dose (100 units) or low dose (50 units) of onabotulinumtoxinA. If a participant has decreased symptom relief, after 3 months post injection, they may receive repeat injection up to twice during the 12 month follow-up period.

Locations

Country	Name	City	State
United States	University of Alabama - Birmingham	Birmingham	Alabama
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Kaiser Permanente Medical Group	San Diego	California

Sponsors (10)

Lead Sponsor	Collaborator
Dartmouth-Hitchcock Medical Center	Dartmouth College, Kaiser Permanente, Oregon Health and Science University, Patient-Centered Outcomes Research Institute, Stanford University, University of Alabama at Birmingham, University of Connecticut, University of Pittsburgh, University of Texas

Country where clinical trial is conducted

United States, 

References & Publications (8)

Amundsen CL, Komesu YM, Chermansky C, Gregory WT, Myers DL, Honeycutt EF, Vasavada SP, Nguyen JN, Wilson TS, Harvie HS, Wallace D; Pelvic Floor Disorders Network. Two-Year Outcomes of Sacral Neuromodulation Versus OnabotulinumtoxinA for Refractory Urgency Urinary Incontinence: A Randomized Trial. Eur Urol. 2018 Jul;74(1):66-73. doi: 10.1016/j.eururo.2018.02.011. Epub 2018 Feb 24. — View Citation

Coyne KS, Payne C, Bhattacharyya SK, Revicki DA, Thompson C, Corey R, Hunt TL. The impact of urinary urgency and frequency on health-related quality of life in overactive bladder: results from a national community survey. Value Health. 2004 Jul-Aug;7(4):455-63. doi: 10.1111/j.1524-4733.2004.74008.x. — View Citation

Drake MJ, Nitti VW, Ginsberg DA, Brucker BM, Hepp Z, McCool R, Glanville JM, Fleetwood K, James D, Chapple CR. Comparative assessment of the efficacy of onabotulinumtoxinA and oral therapies (anticholinergics and mirabegron) for overactive bladder: a systematic review and network meta-analysis. BJU Int. 2017 Nov;120(5):611-622. doi: 10.1111/bju.13945. Epub 2017 Aug 2. — View Citation

Furlong WJ, Feeny DH, Torrance GW, Barr RD. The Health Utilities Index (HUI) system for assessing health-related quality of life in clinical studies. Ann Med. 2001 Jul;33(5):375-84. doi: 10.3109/07853890109002092. — View Citation

Gormley EA, Lightner DJ, Faraday M, Vasavada SP; American Urological Association; Society of Urodynamics, Female Pelvic Medicine. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015 May;193(5):1572-80. doi: 10.1016/j.juro.2015.01.087. Epub 2015 Jan 23. — View Citation

Horsman J, Furlong W, Feeny D, Torrance G. The Health Utilities Index (HUI): concepts, measurement properties and applications. Health Qual Life Outcomes. 2003 Oct 16;1:54. doi: 10.1186/1477-7525-1-54. — View Citation

Monz B, Pons ME, Hampel C, Hunskaar S, Quail D, Samsioe G, Sykes D, Wagg A, Papanicolaou S. Patient-reported impact of urinary incontinence--results from treatment seeking women in 14 European countries. Maturitas. 2005 Nov 30;52 Suppl 2:S24-34. doi: 10.1016/j.maturitas.2005.09.005. Epub 2005 Nov 16. — View Citation

Yalcin I, Bump RC. Validation of two global impression questionnaires for incontinence. Am J Obstet Gynecol. 2003 Jul;189(1):98-101. doi: 10.1067/mob.2003.379. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in symptom specific quality of life and bother over time.	The Overactive bladder questionnaire (OABq-SF), is a validated and reliable patient-centered quality of life questionnaire. The OABq-SF is based on a continuous sore of 0-100, with higher score translating to greater bother.	Baseline, monthly post-injection through 12 months post-injection; primary outcome is at 3 months post-injection.
Secondary	Symptom severity	Urogential Distress Inventory (UDI-6). The UDI-6 has a cut off score of 33.33 to distinguish women who are symptomatic versus asymptomatic. UDI-6 scores that are greater than 33.33 indicated higher distress caused by urinary incontinence symptoms.	Baseline, 3, 6, & 12 months post injection. Results will be compared at the end of the 12 months.
Secondary	Symptom bother	Incontinence impact questionnaire (IIQ). The IIQ has a cut off score of 9.52. This score distinguish women who are symptomatic and asymptomatic.	Baseline, 3, 6, & 12 months post injection. Results will be compared at the end of the 12 months.
Secondary	Change in number of urgency urinary incontinence (UUI) episodes per day.	Participants will keep a bladder tally for 3 days and results will be compared from baseline to 1, 3, and 6 months post injected to determine if there has been a change in the number of urgency urinary incontinence episodes.	Baseline, and 1, 3, and 6 months post injection
Secondary	Change in Global Symptom Improvement	Participants will be asked to complete the Patient Global Impression of Improvement (PGI-I) scale. The PGI-I scale is a one item assessment with responses ranging from "very much better" to "very much worse".	Baseline,3, 6, & 12 months post injection
Secondary	Goal setting and attainment	Participants will express 3-5 goals and goal attainment will be assessed with the Patient Global Impression of Improvement Survey (PGI-I Scale). The PGI-I scale is a one item assessment with responses ranging from "very much better" to "very much worse".	Baseline & 3 months post injection.
Secondary	Change in general health-related quality of life as measure by the Health Utility Index-3	Participants will complete the Health Utilities Index (HUI). The HUI measure health status, reporting health-related quality of life, and producing utility scores. The score ranges from 0.00 (dead) to 1.00 (perfect health).	Baseline, 3 6 and 12 months
Secondary	Depression	Patient Health Questionnaire-9 (PHQ-9) is a 10 item scale with scores ranging from 1(minimal depression) to 27 (severe depression).	Baseline, 3, 6 and 12 months post injection. Results will be compared at the end of the 3 month post injection.
Secondary	Procedural discomfort and adverse events	Urinary retention, post-void residual & duration of voiding dysfunction; urinary tract infection, unscheduled clinic/emergency department visits and any adverse events assessed using the Clavien-Dindo scale,which has been validated for use in urology setting.	Day of injection and monthly through 12 months
Secondary	Qualitative experience of BTX treatment and adverse events	Using novel focused interview for a subset of participants. Participants will be interviewed before injection and 3 months post injection.	Baseline & 3 months post injection
Secondary	Survey of economic burden	Incontinence Resource Use Questionnaire measures the amount of use of various incontinence products. Questions include the number of incontinence protection items used per week.	Baseline, 3 & 12 months. Results will be compared at the end of the 12 months.