Role of Combination Therapy in Women With Refractory Overactive Bladder

NCT ID: NCT06438861

Last Updated: 2025-12-15

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: NA
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-31
• Study Completion Date: 2026-01-31

Brief Summary

Defined by the International Continence Society (ICS) as urinary "urgency, with or without urge incontinence, usually with frequency and nocturia", overactive bladder (OAB) presents as challenging syndrome to treat. OAB is a very prevalent condition, affecting between 11.8% to 16% of the population with equal impact on women and men and growing prevalence with age. OAB is associated with a significant financial burden to both patients and the health care system with a estimated cost of US $82.6 billion in 2020. Traditionally, a stepwise approach has been taken in managing OAB; starting first with lifestyle modifications, followed by anticholinergic or beta-3-agonist medications as the second line, and lastly, intradetrusor onabotulinumtoxinA injections, percutaneous tibial nerve stimulation (PTNS), and sacral neuromodulation (SNM) as third line options. Given the limitations of this stepwise approach in patients with refractory OAB, combination therapy offers patients an increasing number of treatment options but the literature surrounding the efficacy of combination therapy is somewhat limited. A 2019 systematic review revealed there were only 32 studies in the current OAB literature that explored the role of combination therapy, and the majority of these studies examined the effect of lifestyle modifications with another intervention strategy, highlighting an untapped area of research5.

To date, there has only been a single pilot study conducted in Taiwan examining the effect of intradetrusor onabotulinumtoxinA injections with the addition of mirabegron for patients with refractory OAB. This study by Wang et al. explored the therapeutic impact of adding either an anticholinergic, solifenacin, or a beta-3 agonist, mirabegron, to intradetrusor onabotulinumtoxinA injections as compared to each other as well as patients receiving onabotulinumtoxinA alone. Ninety patients were enrolled with 30 patients allocated to the solifenacin arm, 31 to the mirabegron arm, and 29 to the control group. While the baseline data among the three arms was comparable, the percentage of OAB wet in the mirabegron plus onabotulinumtoxinA group was significantly less at 3-, 6-, 9-, and 12-month intervals than the solifenacin plus onabotulinumtoxinA and the onabotulinumtoxinA alone groups. While this pilot study reveals the potential additive benefit of a beta-3 agonist to intradetrusor onabotulinumtoxinA, no further studies have been performed to date and there are no studies regarding the additive benefit of vibegron, which has a more tolerable side effect profile and is not as limited by as many contraindications as mirabegron. If vibegron can potentiate the effect of intradetrusor onabotulinumtoxinA, this presents a new treatment strategy for OAB and could offer patients an additional line of therapy before having to pursue more invasive and costly management option of sacral neuro modulation.

Detailed Description

The study will be a prospective double-blinded randomized control trial to examine the effect of administering vibegron versus placebo in conjunction with intradetrusor onabotulinumtoxinA injections for the management of refractory OAB. Patients who present to the University of Alabama at Birmingham urogynecology practice with refractory OAB undergoing the standard 100U intradetrusor onabotulinumtoxinA will be offered enrollment to either the onabotulinumtoxinA plus vibegron or the onabotulinumtoxinA plus placebo groups. Prior to onabotulinumtoxinA injections, patients' baseline demographics will be documented and their genitourinary symptoms will be assessed using the previously validated Urinary Distress Inventory Short Form (UDI-6), the Incontinence Impact Questionnaire Short Form (IIQ-7), the Overactive Bladder Questionnaire (The OAB-q), and a 3 day voiding diary. Patients will be blinded to which cohort they are randomized to. Each patient will undergo intradetrusor onabotulinumtoxinA injections of 100U either in the office or in the operating room depending on patient and provider preference. Patients will begin taking vibegron or a placebo pill daily starting the day of their procedure. At 12 weeks, patients will complete a 3 day voiding diary as well as the UDI-6, IIQ-7, and OAB-q questionnaires. Patient charts will be queried for timing of repeat onabotulinumtoxinA injection as another secondary outcome.

Primary outcome: Change in mean urinary urgency incontinence episodes at 12 weeks based on 3 day voiding diary

Secondary outcomes: Mean change in UDI-6 responses at 12 weeks, mean change in IIQ-7 responses at 12 weeks, mean change in OAB-q responses at 12 weeks, duration to repeat onabotulinumtoxinA injection

Sample Size Calculation:

It is anticipated that women randomized to the 100U intradetrusor onabotulinumtoxinA plus vibegron arm will experience a greater improvement in UUI episodes compared to the 100U intradetrusor onabotulinumtoxinA plus placebo cohort. A recent study comparing the PTNS plus mirabegron to PTNS plus placebo performed a sample size calculation using existing data 7,8. In that calculation, a 2-sided alpha=0.05, the estimate for that difference in improvement had been estimated to be 2.5 UUI episodes over a 3-day bladder diary pre-vs. post-treatment with a standard deviation of 3 and a power of 0.80 and given the assumed attrition rate of 10%, the total N per arm was estimated to be 27 subjects for the study. Given the similarities between this study and our proposed study, the sample size calculation was felt be applicable to this study.

Conditions

Overactive Bladder Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

100U intradetrusor onabotulinumtoxinA plus vibegron

Each patient will undergo intradetrusor onabotulinumtoxinA injections of 100U either in the office or in the operating room depending on patient and provider preference. Patients randomized to this arm will begin taking vibegron 75mg daily, which is the standard dose, starting the day of their procedure and continue for 3 months.

Group Type: ACTIVE_COMPARATOR

Vibegron 75mg

Intervention Type: DRUG

Each patient will undergo intradetrusor onabotulinumtoxinA injections of 100U either in the office or in the operating room depending on patient and provider preference. Patients will begin taking vibegron 75mg daily or a placebo pill daily starting the day of their procedure and continue for 3 months.

100U intradetrusor onabotulinumtoxinA plus placebo

Each patient will undergo intradetrusor onabotulinumtoxinA injections of 100U either in the office or in the operating room depending on patient and provider preference. Patients randomized to this arm will begin taking a placebo pill daily starting the day of their procedure and continue for 3 months.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Each patient will undergo intradetrusor onabotulinumtoxinA injections of 100U either in the office or in the operating room depending on patient and provider preference. Patients will begin taking vibegron 75mg daily or a placebo pill daily starting the day of their procedure and continue for 3 months.

Interventions

Vibegron 75mg

Each patient will undergo intradetrusor onabotulinumtoxinA injections of 100U either in the office or in the operating room depending on patient and provider preference. Patients will begin taking vibegron 75mg daily or a placebo pill daily starting the day of their procedure and continue for 3 months.

Intervention Type: DRUG

Placebo

Each patient will undergo intradetrusor onabotulinumtoxinA injections of 100U either in the office or in the operating room depending on patient and provider preference. Patients will begin taking vibegron 75mg daily or a placebo pill daily starting the day of their procedure and continue for 3 months.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Women undergoing intradetrusor botulinum injections for refractory OAB

2. Age 18 years old or greater

3. Fluency and literacy in English

4. Capacity to provide consent

Exclusion Criteria

1. Allergy to Vibegron

2. Currently pregnant or planning to become pregnant

3. Breastfeeding

4. Current digoxin use

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Katelyn Donaldson, MD

Urogynecology Fellow

Responsibility Role: PRINCIPAL_INVESTIGATOR

References

Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, Van Kerrebroeck P, Victor A, Wein A; Standardisation Sub-Committee of the International Continence Society. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003 Jan;61(1):37-49. doi: 10.1016/s0090-4295(02)02243-4. No abstract available.

Reference Type: BACKGROUND

PMID: 12559262 (View on PubMed)

Coyne KS, Wein A, Nicholson S, Kvasz M, Chen CI, Milsom I. Economic burden of urgency urinary incontinence in the United States: a systematic review. J Manag Care Pharm. 2014 Feb;20(2):130-40. doi: 10.18553/jmcp.2014.20.2.130.

Reference Type: BACKGROUND

PMID: 24456314 (View on PubMed)

Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S, Coyne K, Kelleher C, Hampel C, Artibani W, Abrams P. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol. 2006 Dec;50(6):1306-14; discussion 1314-5. doi: 10.1016/j.eururo.2006.09.019. Epub 2006 Oct 2.

Reference Type: BACKGROUND

PMID: 17049716 (View on PubMed)

Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, Wein AJ. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003 May;20(6):327-36. doi: 10.1007/s00345-002-0301-4. Epub 2002 Nov 15.

Reference Type: BACKGROUND

PMID: 12811491 (View on PubMed)

Kasman A, Stave C, Elliott CS. Combination therapy in overactive bladder-untapped research opportunities: A systematic review of the literature. Neurourol Urodyn. 2019 Nov;38(8):2083-2092. doi: 10.1002/nau.24158. Epub 2019 Sep 4.

Reference Type: BACKGROUND

PMID: 31483070 (View on PubMed)

Wang CC, Lee CL, Hwang YT, Kuo HC. Adding mirabegron after intravesical onabotulinumtoxinA injection improves therapeutic effects in patients with refractory overactive bladder. Low Urin Tract Symptoms. 2021 Oct;13(4):440-447. doi: 10.1111/luts.12384. Epub 2021 May 6.

Reference Type: BACKGROUND

PMID: 33960119 (View on PubMed)

Sancaktar M, Ceyhan ST, Akyol I, Muhcu M, Alanbay I, Mutlu Ercan C, Atay V. The outcome of adding peripheral neuromodulation (Stoller afferent neuro-stimulation) to anti-muscarinic therapy in women with severe overactive bladder. Gynecol Endocrinol. 2010 Oct;26(10):729-32. doi: 10.3109/09513591003649815.

Reference Type: BACKGROUND

PMID: 20210697 (View on PubMed)

Stanley RF, Meyer I, Blanchard CT, Richter HE. Posterior Tibial Nerve Stimulation With versus Without Mirabegron: A Randomized Controlled Trial. Int Urogynecol J. 2024 Aug;35(8):1709-1717. doi: 10.1007/s00192-024-05835-y. Epub 2024 Aug 5.

Reference Type: BACKGROUND

PMID: 39101958 (View on PubMed)

Other Identifiers

Pending

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

IRB-300012698

Identifier Type: -

Identifier Source: org_study_id