Trial Design for Mixed Urinary Incontinence: Mid-urethral Sling vs. Botulinum toxin A (MUSA)

Abstract

IMPORTANCE:

Mixed urinary incontinence (MUI) is common and can be challenging to manage.

OBJECTIVES:

We present the protocol design and rationale of a trial comparing the efficacy of two procedures for the treatment of women with MUI refractory to oral treatment. The Mid-urethral sling versus Botulinum toxin A (MUSA) trial compares the efficacy of intradetrusor injection of 100 units of onabotulinimtoxinA (an office-based procedure directed at the urgency component) versus mid-urethral sling (MUS) (a surgical procedure directed at the stress component).

STUDY DESIGN:

MUSA is a multi-center, randomized trial of women with MUI electing to undergo procedural treatment for MUI at 7 clinical centers in the NICHD Pelvic Floors Disorders network. Participants are randomized to either onabotulinumtoxinA 100 units or MUS. OnabotulinimtoxinA recipients may receive an additional injection between 3 and 6 months. Participants may receive additional treatment (including crossover to the alternative study intervention) between 6 and 12 months. The primary outcome is change from baseline in Urogenital Distress Inventory (UDI) at 6 months. Secondary outcomes include change in UDI at 3 and 12 months, irritative and stress sub-scores of the UDI, urinary incontinence episodes, predictors of poor treatment response, quality of life and global impression outcomes, adverse events, use of additional treatments, and cost effectiveness.

RESULTS:

Recruitment and randomization of 150 participants is complete and participants are currently in the follow-up phase.

CONCLUSIONS:

This trial will provide information to guide care for women with MUI refractory to oral treatment who seek surgical treatment with either onabotulinumtoxinA or MUS.

INTRODUCTION

Urinary incontinence (UI) is a common condition affecting up to 58% of women¹, and the prevalence and number of women undergoing UI treatment are expected to increase with our aging population.^2–4 The two most common forms of UI in women are stress urinary incontinence (SUI), defined as “involuntary loss of urine on effort or exertion, sneezing or coughing”, and urgency urinary incontinence (UUI), defined as “complaint of involuntary loss of urine associated with urgency” which is commonly part of overactive bladder (OAB), defined as “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence”.⁵ Up to 50% of women with UI have mixed urinary incontinence (MUI), a combination of both SUI and UUI.^6–8 Patients report that the urgency component is more bothersome than the stress component and the combination of both is more bothersome than either UUI or SUI alone.^9–13

It is often difficult to accurately distinguish between different subtypes of UI.¹ Many women with MUI do not report clear SUI or UUI but simply that “they leak”. In addition, MUI excludes both women who have detrusor overactivity in the absence of sensory urgency and women who may have significant urgency and/or frequency without UUI, which can add to the difficulty of diagnosis. Our current approach to defining UI does not adequately characterize the diverse phenotypes of MUI symptoms.¹ For this trial, the recommendations of Brubaker et al are utilized which suggest that the distinct descriptions of both urgency and stress subcomponents be used to characterize women with MUI.^14–15 This approach was utilized in the ESTEEM trial which compared mid-urethral sling (MUS) combined with behavioral treatment to MUS alone in women with MUI.^16,17

While some experts argue that SUI and UUI are separate and unrelated conditions¹⁸, increasing evidence suggests that common pathophysiologic processes may explain co-existing SUI and UUI in women with MUI.¹ It has long been known that anti-incontinence procedures of the bladder neck, such as colposuspension and bladder neck sling, improve SUI but can worsen UUI.¹⁹ By contrast, in the ESTEEM study, MUS alone, even without additional behavioral treatment, resulted in improvement of both SUI and UUI components of MUI.¹⁶ Also, in several onabotulinumtoxinA clinical trials, the majority of which were performed in women with urgency-predominant MUI, participants reported improvement not only of UUI episodes but also of overall UI episodes.^20,21 Taken together, these studies suggest that common pathophysiologic processes may contribute to co-existing symptoms and treatment response of SUI and UUI. Therapies directed at one component of MUI, either UUI or SUI, have the potential of affecting outcomes of the other component. In this trial, outcomes for SUI, UUI, and overall UI episodes are measured separately using both patient-reported outcome (PRO) questionnaires and bladder diaries, thus providing valuable data on mechanisms that contribute to the pathophysiology of MUI and potential treatment algorithms.

The objective of the Mid-urethral Sling vs. Botulinum toxin A (MUSA) trial in women with MUI is to determine if an office-based procedural treatment directed at the urgency component, onabotulinumtoxinA, is more efficacious than a surgical treatment directed at the stress component, MUS. It is hypothesized that onabotulinumtoxinA, directed at the more bothersome urgency component, is superior to MUS in improving MUI symptoms.

MATERIALS AND METHODS

A. Study Design

The MUSA trial is being conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development sponsored Pelvic Floor Disorders Network (PFDN). MUSA is a randomized controlled trial designed to assess whether onabotulinumtoxinA is superior to MUS for improving MUI symptoms in women.

Study aims and outcomes are summarized in Table 1. The primary aim is to compare the efficacy of intradetrusor injection of 100 units of onabotulinumtoxinA to MUS for improving MUI symptoms 6 months following treatment. Participants continue to be followed from 6 to 12 months. The primary outcome is change from baseline in severity of MUI symptoms 6 months post treatment as measured using the Urogenital Distress Inventory²² (UDI) total score. Secondary and exploratory aims are listed in Table 2. Figure 1 summarizes the MUSA trial design.

TABLE 1:

MUSA Aims and Outcomes

Aims		Outcomes
Primary Aim		Primary
Treatment of MUI symptoms		Total MUI symptom score (UDI) at 6 months
Secondary Aims		Secondary
Other urinary treatment benefits		OAB symptoms (UDI-irritative) at 6 months SUI symptoms (UDI-stress) at 6 months MUI symptom score (UDI) at 3 months
Exploratory Aims		Exploratory
Other potential treatment benefits		Observational 6–12 month period (MUI, OAB, SUI symptoms) Urinary incontinence episodes at 6 and 12 months Predictors of poor treatment response at 6 and 12 months Quality of life, global impression at 6 and 12 months Safety, additional treatments Cost-effectiveness at 6 and 12 months

For all outcomes, the primary assessment time is 6 months and exploratory assessment times are 3, 9, and 12 months (with additional treatments allowed 6–12 months)

MUI = mixed urinary incontinence, UDI = Urogenital Distress Inventory, OAB = overactive bladder, SUI = stress urinary incontinence

TABLE 2:

MUSA Secondary and Exploratory AIMS

Secondary Aims:

1. To compare the efficacy of intradetrusor injection of 100 units of onabotulinumtoxinA to mid-urethral sling for change in SUI symptoms 6 months following treatment, using the stress subscale of the UDI.

2. To compare the efficacy of intradetrusor injection of 100 units of onabotulinumtoxinA to mid-urethral sling for change in UUI symptoms 6 months following treatment, using the irritative subscales of the UDI.

3. To compare the efficacy of intradetrusor injection of 100 units of onabotulinumtoxinA to mid-urethral sling for change in MUI symptoms 3 months following treatment, using the UDI total score.

Exploratory Aims:

4. Observational 6–12 month period: To compare the efficacy of intradetrusor injection of 100 units of onabotulinumtoxinA to mid-urethral sling for change in MUI symptoms 12 months following treatment, using the total score and stress and irritative subscales of the UDI.

5. Secondary urinary outcomes: To compare treatment with onabotulinumtoxinA to treatment with mid-urethral sling for improving the number of urinary incontinence episodes on bladder diary 6 and 12 months following treatment.

6. Predictors of poor treatment response: To develop models to identify baseline predictors of change of MUI, OAB, and SUI outcomes measured using the UDI from baseline to 6 and 12 months following treatment.

7. Quality of life and global impression: To compare quality of life outcomes and Patient Global Impression-Improvement (PGI-I), Patient Global Impression-Severity (PGI-S) between groups randomized to onabotulinumtoxinA versus mid-urethral sling 6 and 12 months following treatment.

8. Safety and additional treatments: To describe rates of reoperation (sling revision) after mid-urethral sling and intermittent catheterization due to voiding dysfunction/partial urinary retention after onabotulinumtoxinA detrusor injection, to compare the proportion of women in each group with urinary tract infection and recurrent urinary tract infection, rates of other serious and non-serious adverse events, and to compare the proportion of women in each group initiating additional (off protocol) treatment other than onabotulinumtoxinA and mid-urethral sling for SUI and/or OAB.

9. Cost-effectiveness analysis: To determine the cost effectiveness of onabotulinumtoxinA injection versus mid-urethral sling for the treatment of MUI symptoms on an intent-to-treat basis 6 and 12 months following treatment.

10. UDI minimally important difference (MID): To explore MIDs for UDI total score and stress and irritative subscores for this MUI population.

FIGURE 1:

MUSA Participant Flow

B. Study Population

The study population consists of women with bothersome MUI who may benefit from either onabotulinumtoxinA or MUS. Women must report both SUI and UUI that is at least moderately bothersome, and they must objectively demonstrate both SUI and UUI. Inclusion and exclusion criteria are listed in Table 3.

TABLE 3:

MUSA Inclusion / Exclusion Criteria

Inclusion Criteria

1. Reporting at least “moderate bother” from urge urinary incontinence (UUI) item on Urogenital Distress Inventory (UDI):

“Do you experience urine leakage associated with a feeling of urgency?”

2. Reporting at least “moderate bother” from stress urinary incontinence (SUI) item on UDI:

“Do you experience urine leakage related to physical activity, coughing, or sneezing?”

3. Diagnosis of SUI defined by a positive cough stress test (CST) or Urodynamic evaluation (UDE) within the past 18 months. If participant does not demonstrate SUI during cystometrogram (CMG) they must demonstrate SUI through a cough stress test or other comparable Valsalva maneuver to be eligible.

4. Presence of UUI on bladder diary with > 4 urgency incontinence episodes (UIE) per 3-day diary

5. Urinary symptoms >3 months

6. Persistent symptoms despite at least one or more conservative treatments (e.g. supervised behavioral therapy, physical therapy) as determined adequate by the physician.

7. Inadequate response to oral overactive bladder medications (including anti-cholinergic and/or beta-mimetic medication) unless:

a. patient is intolerant of oral overactive bladder medications, or

b. oral overactive bladder medications are contraindicated as determined by the treating provider.

8. Urodynamics within past 18 months prior to enrollment or done after enrollment, prior to randomization.

9. Demonstrates understanding (or have caregiver demonstrate understanding) to perform clean intermittent self-catheterization (CISC). Provider and patient review CISC process and patient (and/or caregiver) demonstrates understanding to the satisfaction of the provider.

Exclusion Criteria

1. Anterior or apical compartment prolapse at or beyond the hymen (>=0 on Pelvic Organ Prolapse Quantification [POPQ]), regardless of whether patient is symptomatic

a. Women with anterior or apical prolapse above the hymen (<0) who do not report vaginal bulge symptoms will be eligible

2. Planned concomitant surgery for anterior vaginal wall or apical prolapse > 0

a. Women undergoing only rectocele repair or other repair unrelated to anterior or apical compartment are eligible

3. Women undergoing hysterectomy for any indication will be excluded

4. Active pelvic organ malignancy

5. Age <21 years

6. Pregnant or plans for future pregnancy in next 6 months, or within 12 months post-partum

7. Post-void residual >150 cc on 2 occasions within the past 6 months, or current catheter use

8. Participation in other trial that may influence results of this study

9. Unevaluated hematuria

10. Prior sling, synthetic mesh for prolapse, implanted nerve stimulator for urinary incontinence. Women with known Burch or Marshall-Marchetti-Krantz (MMK) are excluded.

11. Spinal cord injury or advanced/severe neurologic conditions including Multiple Sclerosis, Parkinson’s, Myasthenia Gravis, Charcot-Marie-Tooth

12. Women on overactive bladder medication/therapy will be eligible after 3-week wash-out period

13. Non-ambulatory

14. History of serious adverse reaction to synthetic mesh

15. Not able to complete study assessments per clinician judgment, or not available for 6-month follow-up

16. Diagnosis of and/or history of bladder pain or chronic pelvic pain

17. Women who had intravesical onabotulinumtoxinA injection within the past 12 months

18. Women who have undergone anterior or apical pelvic organ prolapse repair within the past 6 months

There is no single instrument that provides objective documentation of both SUI and UUI.¹⁵ A bladder diary allows documentation of both conditions; however, women are frequently unable to clearly characterize a leakage episode as either SUI or UUI. Similarly, more invasive urodynamic evaluation (UDE) also allows objective documentation of SUI and detrusor overactivity (DO). Yet DO correlates poorly with OAB symptoms and UDE does not predict treatment outcomes of either SUI or UUI.^23–26 Therefore, the study uses a variety of instruments to identify women with MUI who have both subjective and objective evidence of MUI. This includes: 1) subjective symptoms measured by two items on the UDI: at least moderately bothersome SUI (“Do you experience urine leakage related to physical activity, coughing, or sneezing”) and UUI (“Do you experience urine leakage associated with a feeling of urgency?”); 2) objective documentation of UUI on a 3-day bladder diary; and 3) objective documentation of SUI on clinical examination (either office cough stress test or during UDE).

Non-pregnant adult females at least 21 years of age reporting symptoms of MUI are identified and screened for enrollment. Consent is obtained if there are no apparent exclusionary criteria. Once consent is obtained, the participant is enrolled into the study, and further eligibility evaluation is conducted by the physician and study coordinator. Patients on OAB medication/therapy are eligible after 3-week wash-out period. After full eligibility is assessed, the patient is randomized to receive either MUS or onabotulinumtoxinA.

C. Study Procedures

Mid-urethral Sling Procedure:

Full length retropubic or transobturator MUS are allowed, based on the findings of trials that demonstrated equivalence between these approaches in objective and subjective success of SUI, as well as similar effects on UUI.^27,28 Full length MUS from all manufacturers are allowed.²⁹ Partial length, or single-incision variations of MUS are not included.³⁰ A voiding trial is performed before the patient is discharged, and indwelling foley catheter or clean intermittent self-catheterization (CISC) is initiated per surgeon discretion. Certified surgeons participating in MUSA must have performed a minimum of 20 full length MUS. Women who undergo a sling revision / replacement are considered as having “additional treatment” regardless of indication which is documented as: 1) urinary retention / incomplete bladder emptying (abnormal post void residual (PVR) defined as > 150 cc), 2) worsening OAB/lower urinary tract symptoms with a normal PVR, or 3) persistent SUI symptoms.

OnabotulinumtoxinA Procedure:

The dosage of intradetrusor injection of onabotulinumtoxinA is 100 units, the current FDA approved dose for the treatment of idiopathic OAB and for which safety and efficacy was established in several large RCTs.^21,31–33 An Investigation New Drug exemption was obtained from the FDA for this study. Participating physicians must have performed a minimum of 10 intradetrusor injection procedures.

Detailed standardization of the treatment process followed the ROSETTA^34, study of onabotulinumtoxinA compared to sacral neuromodulation for treatment of refractory UUI. Briefly, the bladder is catheterized, and 50 mL of 2% lidocaine is placed in the bladder and 10 mL of 2% lidocaine jelly is placed in the urethra. Cystoscopic surveillance of the bladder is used to confirm normality. Botulinum toxin A dissolved into 10 mL of injectable saline and Indigo carmine or methylene blue 0.1 mL is injected into approximately 15 to 20 different detrusor muscle sites under direct visualization. Injections are spread out to equally cover the posterior bladder wall and dome but spare the bladder trigone and ureteral orifices. An additional 1mL of saline flush is injected into the bladder at the end to ensure that all study drug has been delivered. Participants receive antibiotics orally per standard of care immediately after injection and for 3 days post injection. The participant is assessed for voiding dysfunction at 2 weeks (+/− 1 week) following injection. Criteria to initiate CISC is PVR > 200 mL, per surgeon discretion.

Participants with persistent bothersome UUI are eligible to receive one additional injection of 100 units between 3 and 6 months after initial injection, allowing at least 14 days before the 6-month assessment, if all of the following criteria are met: 1) persistent bothersome UUI as determined by reporting at least “moderate bother” from UUI item on UDI: “Do you experience urine leakage associated with a feeling of urgency?”; 2) continued UI bother based on the Patient Global Symptom Control (PGSC): “My current treatment is giving me adequate control of my urinary leakage”, score of 1 (disagree strongly) to 3 (neither agree nor disagree); 3) participant desires additional treatment with onabotulinumtoxinA; 4) no urinary tract infection as determined by the health care provider; 5) PVR < 200 ml; 6) no medical contraindication for the procedure as determined by the physician; 7) continuing to meet study inclusion/exclusion criteria, except inclusion items 2, 3, 4, 7 and 8 and exclusion 7 (Table 3).

D. Randomization and Stratification

Participants are randomized after eligibility is confirmed and all baseline assessments are completed. Allocation to the treatment groups is 1:1. Randomization is implemented centrally through an electronic data capture system and is stratified by clinical site and age group (≥ 65 or < 65 years³⁴) using permuted blocks. Age is a well-known predictor for reduced treatment response for both onabotulinumtoxinA and MUS.^35–37 Although evidence suggests that the severity of UUI can affect outcomes of both treatments^35,38,39, definitions of UI severity in a MUI population are complex, and there are limited data to provide guidance, so participants were not stratified by UI severity.

E. Study Masking

It is not feasible to mask the patients or surgeons to the intervention. While the use of saline as a placebo for onabotulinumtoxinA has been established³², sham MUS surgery would require suprapubic and vaginal incisions that would expose patients to the risks of sedation/anesthesia. To minimize ascertainment bias, study personnel were designated as masked or unmasked. Masked roles include research staff administering questionnaires to participants and evaluating post treatment bladder diaries, and the study’s senior statistician; all other personnel were designated unmasked. All study personnel are masked to summary displays of data by treatment group except the study statistician producing reports for the data and safety monitoring board. All patient reported outcome (PRO) measures are administered prior to clinical assessments to minimize any bias that may occur due to clinical findings.

F. Measures and Follow-up

Participants undergo clinical and PRO assessments at baseline and at 2-weeks, 3 months, 6 months, 9 months, and 12 months postoperatively. The primary assessment is change in UDI score, measured at 6 months. Alternative treatment for UI outside of the study protocol is not permitted within the first 6 months. Participants continue to be followed for observation from 6 to 12 months, and those with ongoing urinary complaints are permitted other clinical treatments (including the other study treatment to which they were not randomized) after the 6-month assessment.

Similar to the ESTEEM study, the total UDI score was chosen as the primary outcome.¹⁶ The UDI comprehensively captures the presence and bother from both SUI and UUI, and the UDI separately characterizes improvement, worsening, or no change from the patient perspective. The long form of the UDI was selected as the primary outcome based on its domain coverage and validity properties.²² It is a self-administered, 19 item questionnaire that measures 3 urinary symptom domains: 1) irritative symptoms (OAB/UUI), 2) SUI, and 3) obstructive symptoms.²² The three subscale scores of the UDI are summed to provide a total score ranging from 0–300, with higher scores representing more severe symptoms and bother. The UDI correlates significantly with the number of UI episodes on bladder diaries and pad weight tests, correlates with clinical UI diagnoses, discriminates between known UI subgroups, and responds to change with published MID estimates for the total, SUI subscale, and UUI subscale scores.^16,40,41 Other outcome measures include: bladder diary; UUI instruments (Overactive Bladder treatment satisfaction (OAB-SAT-q)⁴² and Overactive Bladder Questionnaire- subscales (OAB-q)⁴³); Quality of Life instruments (Incontinence Impact Questionnaire Long Form (IIQ-LF)⁴⁴, Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-IR)⁴⁵, European Quality of Life-5 Dimensions (EQ-5D)⁴⁶, Short Form 36 (SF-36)⁴⁷ and Short Form 6D (SG-6D)⁴⁸); Global Impression instruments (Patient Global Impression of Improvement (PGI-I)⁴⁹ and Patient Global Impression of Severity (PGI-S)⁴⁹); safety (return to the operating room, urinary retention, urinary tract infections, adverse events): and additional treatments for SUI or UUI.

G. Adjustments for COVID

The COVID-19 pandemic created several disruptions for the trial. The trial launch, planned for early 2020, was delayed until July, and enrollment was negatively impacted through subsequent surges with limitations on in-person care, remote work of study personnel, and reluctance of patients to seek healthcare. Methods were modified to accommodate performing clinical research during the COVID pandemic and maintain robust participant follow-up, including remote consent, expanding remote study assessments, and extending visit windows prior to treatment. (Table 4)

TABLE 4:

Methods that Addressed Study Implementation During the COVID-19 Pandemic

• Recruitment video was developed to enhance awareness of the study more broadly through digital platforms.

• Added an E-consent process, to allow consent remotely rather than in-person.

• Allowed masked staff to handle pre-randomization study assessments, to address intermittent staffing shortages.

• Defined a subset of mandatory in-clinic study activities (urodynamics, pre-procedure urine test and study procedure), and allowed all other activities to be completed via remote study contact (check-ins by phone or email, completing questionnaires digitally or by mail).

• Visits at 9 and 12 months are phone calls rather than in-person.

• Inclusion criterion #3, Diagnosis of SUI defined by a positive cough stress test (CST) or UDE within the past 18 months, was clarified to include: If participant does not demonstrate SUI during CMG, they must demonstrate SUI through a cough stress test or other comparable Valsalva maneuver to be eligible. Allowing other maneuvers to demonstrate SUI avoided the necessity of in-person observation of patients coughing during COVID.

• Inclusion criterion #9, Demonstrates understanding (or have caregiver demonstrate understanding) to perform clean intermittent self-catheterization was updated from “ability” to “understanding” to allow the provider and patient to review CISC process, and the patient (and/or caregiver) to demonstrate understanding of the CISC process to the satisfaction of the provider rather than requiring an in-person CISC training, which would have been planned pre-COVID.

• Time from consent to determining eligibility (completion of the baseline visit) was not limited and the participant was allowed to continue the eligibility process per their clinician’s judgment. However, once a participant was found to be eligible, the participant was required to repeat baseline assessments (bladder diary, urine dip, UDI, and all PRO measures) if they were not randomized within 91 days of completing the primary baseline measure, the UDI.

• After randomization, treatment should occur within 8 weeks, but was not limited and the participant was retained in the study at the investigator’s discretion until the intervention was scheduled. This flexibility addressed both unavailability of in-patient procedure facilities and local COVID infection levels. Follow-up timing began after treatment and so was not impacted. Time from baseline to post-baseline UDI was longer than would have been planned pre-COVID. Yet we anticipate this to have minimal impact on study results as MUI symptoms rarely wax and wane over this timepoint and this would equally affect both groups.

• Enrollment timeline was extended, and an additional subsite location was added in response to the slower enrollment than was planned pre-COVID.

H. Analysis Considerations

Analysis population:

The primary analysis population will include all randomized and treated participants in a modified intent-to-treat approach. Participants who discontinue from the study prior to receiving study intervention provide no post-baseline data and are therefore excluded.

Primary outcome:

The mean change from baseline in UDI total score will be compared between the 2 groups at 6 months at the p<0.05 statistical significance level using a mixed effects model for repeated measures (MMRM) with adjustment for baseline UDI score and the randomization stratification factors clinical site and age group. The model will include fixed effect categorical factors for treatment group, visit (3, 6, 9, and 12 months), and treatment × visit interaction. This model assumes missing data due to a missed visit or early study discontinuation is missing at random. If more than 10% of treated participants are missing the 6-month UDI score, then sensitivity analyses will be performed to assess the robustness of the primary results to missing data.

I. Economic Evaluation and Analysis

A prospective, cost effectiveness analysis of onabotulinumtoxinA versus MUS for the treatment of MUI will be conducted from the Health Care Sector and Societal perspectives to assess the incremental cost per quality adjusted life year (QALY) gained. Our approach follows the current guidelines for cost-effectiveness analysis.^50,51 Effectiveness will be measured by QALYs calculated from the EuroQol - 5 Dimension instrument (EQ-5D) with responses summarized in a single, preference-weighted, health-related quality of life score.^52–54 The incremental cost per UI episode averted per person per day is a secondary outcome. Health care unit costs will be assigned primarily from the Medicare Fee Schedule. Resource utilization data will be collected during the 12-month follow up period.

J. Sample Size and Power

MUSA is designed to randomize 146 women in order to provide 90% power to detect a minimally important difference (MID) between treatment groups for change in UDI total score at 6 months. The ESTEEM trial of MUI reported the MID as 26.¹⁶ The standard deviation (SD) for change in UDI at 6 months was estimated as 46.5 from a mixed effects repeated measurers model of ESTEEM 3- and 6-month data, adjusting for baseline UDI and clinical site to mirror the planned MUSA analysis. ESTEEM participants with <4 UIEs on the 3-day baseline diary were excluded from the model to match MUSA inclusion criterion. Thus, the effect size is 26/46.5 = 0.56. The sample size needed for 90% power is 69 women per treatment arm. Because data from ROSETTA and ESTEEM suggests that follow-up at 6 months should be about 95%, the sample size was increased to 73 women per treatment arm.

K. Alternative Design Considerations

We originally considered a larger and more complex trial in which participants would be re-randomized after non-response at 3, 6, or 9 months in a sequential multiple assignment randomized trial (SMART) design.⁵⁵ Using this approach, we planned for two co-primary aims comparing the randomized arms at 3 months for the effect of initial mono-therapy treatment and an intent-to-treat model at 12 months following randomized adaptive treatment algorithms for non-response to initial and subsequent treatments. A key secondary aim was the identification of optimal adaptive treatment algorithms for MUI overall that are based on a participant’s baseline characteristics among embedded adaptive interventions. While we expected this SMART design to provide deeper information about treatment options for MUI, it required well over twice the sample size of the current trial and was operationally more complex. With the onset of the COVID pandemic in March 2020, the simpler design was implemented because the SMART design would have had further operational challenges. Nevertheless, by its nature, MUI is a condition that may be best treated by a series of interventions. It is the intent to use the information learned from the current trial, particularly the non-response rates at 3 and 6 months, and the additional treatments received during the 6–12-month observational period to evaluate the benefit of a SMART design to further address treatment of MUI with onabotulinumtoxinA and MUS.

RESULTS TO DATE

The participant flow is shown in Figure 1. All 7 clinical sites received local Institutional Review Board approval. Participants were enrolled from July 2020 to September 2022. Randomization of 150 participants is complete; treatment and follow-up will continue through the end of 2023.

DISCUSSION

Patients with MUI who elect treatment are usually seeking to improve their overall urinary incontinence symptoms; however, most treatments are designed to improve either SUI or UUI only, thereby leading to high failure rates and patient dissatisfaction. Few studies have explicitly evaluated women with MUI⁵⁶, and there is a gap in knowledge regarding comparison of active interventions in women with MUI. The MUSA study compares onabotulinumtoxinA, an office-based treatment directed at the more bothersome urgency component, and MUS, a surgical treatment directed at the stress component.

The ESTEEM trial¹⁶ provided valuable insight for the treatment of MUI with MUS; however, a key gap in knowledge remains: what is the effect when the more bothersome UUI component is treated before the SUI component? First, ESTEEM found that MUS alone is a highly effective treatment for the stress component of MUI, and MUS can improve the urgency component; however, it remains unknown as to which women with MUI would require additional treatment for SUI if UUI symptoms were treated first. Second, in ESTEEM, combined MUS with behavioral treatment contributed to better quality of life and better UUI outcomes in women with MUI compared to MUS alone. The number of SUI episodes was not significantly different between groups; however, women in the combined group reported significantly fewer UUI episodes and fewer additional treatments with OAB medications than the MUS only group. These findings suggest that improvement in UUI and OAB outcomes were important contributors to the better quality of life in the combined treatment group. As such, treatments that target UUI symptoms could potentially be highly effective for the treatment of MUI. Clinical trials of MUI that have used highly effective treatments for UUI such as onabotulinumtoxinA are lacking. Third, the ESTEEM trial showed that women with worse baseline OAB symptoms are more likely to be treatment failures at 12 months.^16,57

OnabotulinumtoxinA has proved highly effective for the treatment of UUI.^20,58–64 Studies have also been performed in women with urgency-predominant MUI, and some demonstrated a reduction in total UI episodes that exceeded the reduction in UUI episodes.^{20,58–60,63} The ROSETTA^20,58 study conducted by the PFDN in women with refractory UUI compared onabotulinumtoxinA 200 units to sacral neuromodulation, at 6 months. An unpublished ad hoc evaluation of a subset of “MUSA-like” participants in ROSETTA who received onabotulinumtoxinA had improvement of both UUI and SUI episodes on bladder diary. These findings suggest that the beneficial effects of onabotulinumtoxinA may extend beyond UUI to SUI in women with MUI; however, data on the efficacy of onabotulinumtoxinA in a MUI population that is not urgency-predominant is lacking.

The modifications to the MUSA study that accommodated limitations to in-person care and permitted remote work of study personnel did allow us to successfully conduct clinical research during the COVID pandemic. This successful adaptation of telehealth methods to research can help to inform future study methods. The integration of remote patient contact for study screening, consenting, and data collection into study methods may be utilized beyond COVID. By minimizing the number of in-person visits, this hybrid approach should enable recruitment of a geographically wider and more diverse population of participants and improve participant retention.

While the SMART design protocol was not implemented in MUSA, the current protocol will help answer the first question in comparing onabotulinumtoxinA and MUS for the treatment of MUI. Also, MUSA will allow us to gain knowledge about the extent of alternative or augmented treatments for MUI. Findings from this study may then provide more information for a SMART design trial that evaluates optimal treatment pathways for women with MUI.

In conclusion, we present the design of a randomized controlled trial comparing two very different approaches for women with MUI seeking treatment. The MUSA study compares onabotulinumtoxinA (an office-based procedure directed at the urgency component) versus MUS (a surgical procedure directed at the stress component). Our study design is intended to limit bias and provide robust data that will be directly applicable to the clinical care and decision-making of women with MUI.

Simply Stated:

Mixed urinary incontinence (MUI) is when women leak urine with BOTH sneezing/coughing/exercise (stress incontinence) AND with the feeling of urgency (urgency incontinence). MUI is a common condition that is challenging to manage, current therapies are directed at one type of incontinence and the optimal treatment for patients who fail to respond to initial treatment have not been determined. We present the design of a trial comparing two procedures for the treatment of women with MUI who fail medications and behavioral/pelvic floor exercise therapy. The Mid-urethral sling versus Botulinum toxin A (MUSA) trial compares treatment with bladder muscle injection of onabotulinimtoxinA (an office-based procedure directed at the urgency component) versus mid-urethral sling (a surgical procedure directed at the stress component). We will evaluate how bladder symptoms improve at 6 months after treatment and then follow women out to 12 months. MUSA is a multi-center, randomized trial conducted at 7 clinical centers in the NICHD Pelvic Floors Disorders network. Recruitment and randomization of 150 participants is complete and they are currently in the follow-up phase.

“Why This Matters?”:

Women with Mixed urinary incontinence (MUI) who elect treatment usually seek to improve their overall urinary incontinence symptoms; however, most treatments are designed to improve either stress urinary incontinence (SUI), or urgency urinary incontinence (UUI), leading to high failure rates and patient dissatisfaction. Few studies have explicitly evaluated women with MUI. We present the protocol design and rationale of a trial comparing the efficacy of two procedures for the treatment of women with MUI refractory to oral treatment. The Mid-urethral sling versus Botulinum toxin A (MUSA) trial compares the efficacy of intradetrusor injection of 100 units of onabotulinimtoxinA (an office-based procedure directed at the urgency component) versus mid-urethral sling (MUS) (a surgical procedure directed at the stress component). The ESTEEM trial, which compared MUS combined with behavioral treatment to MUS alone in women with MUI, found that MUS is a highly effective treatment for the stress component and can improve the urgency component; however, it remains unknown if women with MUI would require additional treatment for SUI if UUI symptoms were treated first. OnabotulinumtoxinA has proved highly effective for treatment of UUI and studies have included urgency-predominant MUI; however, data on efficacy in women with non-urgency-predominant MUI is lacking.