The Vesair Balloon is a free-floating intravesical device constructed of a thin polyurethane film inflated with 30 mL of air (Fig. 1 ). Although most treatments for female stress urinary incontinence (SUI) focus on the bladder outlet to either increase urethral resistance or reduce hypermobility with slings, sphincters, or bulking agents,1,2
FIGURE 1: Vesair Balloon.
In the “closed” hydraulic system of a normal urinary bladder, external pressures transmit directly to urine within the bladder lumen. Urine in the bladder is relatively incompressible; therefore, the pressure within the bladder increases when the surrounding abdominal pressure increases. In a susceptible patient, this intravesical pressure increase subsequently results in urinary incontinence by overcoming urethral closure pressures.2 3,4
The Vesair Balloon has been evaluated previously in several studies. The mechanism of action was evaluated in an in vitro acrylic bladder model.5 6 7 8 9
METHODS
The SUCCESS trial is a multicenter, prospective, single blinded, randomized, sham-controlled study of the investigational Vesair Balloon for the treatment of female SUI. This study received institutional review board approval and was conducted under a US Food and Drug Administration (FDA)–approved Investigation Device Exemption (G110162). Participant enrollment occurred at 20 investigational sites across the United States. All participants signed a written informed consent before study enrollment.
To establish baseline characteristics and determine study eligibility, all potential participants completed comprehensive incontinence testing before enrollment, including the following: history and physical examination, urinalysis, 1-hour provocative pad weight test, urodynamic evaluation, 7-day voiding diary, questionnaires (Incontinence Quality of Life Scale [I-QOL], International Consultation on Incontinence Modular Questionnaire: Female Sexual Matters associated with Lower Urinary Tract Symptoms (ICIQ-FLUTSsex); International Consultation on Incontinence Modular Questionnaire: Urinary Incontinence Short Form (ICIQ-SF); Medical, Epidemiologic, and Social Aspects of Aging [MESA]), and cystoscopy. The study population included female adults 18 years or older with SUI symptoms for at least 12 months in duration as evidenced by visual confirmation during stress maneuvers and self-report of incontinence on a voiding diary. Participants must have failed noninvasive incontinence treatments and lacked complicating factors, such as urge predominant symptoms, recurrent urinary tract infections (UTIs), or urethral anatomic anomalies. In addition, all participants had incontinence severity sufficient to produce at least 5 g of leakage on an in-office provocative 1-hour pad weight test. Complete inclusion and exclusion criteria are provided in Table 1 . Hypermobility and hypermobility with intrinsic sphincter deficiency (ISD) were determined using the investigator's opinion after review of urodynamic results and patient-reported symptoms. Stress predominate mixed incontinence was determined using the investigator's opinion after evaluating the urodynamic results, MESA, and patient-reported symptoms.
TABLE 1: Inclusion and Exclusion Criteria
Vesair Balloon placement and removal in this study was performed in an identical manner to what has previously been described.8
Eligible and consenting participants were randomly assigned to either the treatment arm or the control arm, and randomization was stratified by clinical site. All participants were blinded to their randomization until the 3-month study visit. The investigator performing the procedure was necessarily unblinded to participant randomization; however, a blinded third-party evaluator performed all efficacy assessments through 3 months.
Participants randomized to the treatment arm received the Vesair Balloon on day 0 and were followed up for 12 months, with assessments at 1, 3, 6, and 12 months. All participants in the treatment arm had their balloons exchanged at 12 months or sooner if clinically indicated. Data collection at each scheduled follow-up visit included documentation of any adverse events (AEs) or change in medical history, a 7-day voiding diary, participant questionnaires (Patient Global Impression of Improvement [PGI-I], I-QOL, ICIQ-FLUTSsex, ICIQ-SF, MESA), and urinalysis if symptomatic. At the 3-month visit, participants also underwent cystoscopy to document appropriate balloon integrity and positioning, and lack of bladder pathology.
Participants in the control arm underwent a sham procedure on day 0 without a Vesair Balloon placed. After completion of efficacy evaluations through the initial 3 months without the Vesair Balloon, control group participants were unblinded and were offered a Vesair Balloon placement at the 3-month visit. Follow-up assessments for the control group were completed at 1, 3, 4, 6, and 12 months. Data collected at each study visit for control group patients were identical to that in the treatment group. Participants were paid $50 per hour for time spent during follow-on visits (Table 2 ).
TABLE 2: Schedule of Visits
Based on the FDA's guidance for clinical studies of SUI,9
Power analysis was performed to determine sample size requirements based on the primary efficacy end point. On the basis of previously published data,9
Statistical analysis was performed on SAS software, version 9.4. For the 3-month end points, missing data were imputed on the basis of the last observation carried forward when the data were missing secondary to participant withdrawal due to a device-related AE. All other missing data were imputed using a multiple-imputation model with 20 imputations performed for each missing piece of data as is current standard practice. To evaluate the 12-month end points, only participants who chose to continue with the study beyond the 3-month primary end point and had evaluable data beyond 6 months were included in the intent-to-treat analysis with no imputation being performed.
RESULTS
Participant enrollment and randomization is depicted visually in Figure 2 . Baseline characteristics of the 157 participants in the treatment arm are seen in Table 3 . Mean age of the entire cohort was 50.0 years, with an average body mass index of 29.2 kg/m2 . Most participants (74.5%) had pure stress incontinence, with the remainder experiencing stress-predominant mixed urinary incontinence with mean symptom duration before randomization of 107.2 months.
FIGURE 2: CONSORT flow diagram of the SUCCESS study. CONSORT, CONsolidated Standards of Reporting Trials.
TABLE 3: Baseline Characteristics
Evaluable results were obtained from 67 participants in the treatment arm who remained in the study beyond 6 months (42.7% of participants enrolled), herein referred to as the “12-month cohort.” The composite end point was defined as the number of participants who had both a greater than 50% reduction on the provocative pad weight test and an at least 10-point increase in their I-QOL scores. At 3 months, 55.2% of the participants in the 12-month cohort met the composite end point and 56.3% met the end point at 12 months (Table 4 ). Improvements were also observed in other end points, analyzed on an intent-to-treat basis. For example, the percentage of participants with a greater than 50% reduction in their provocative pad weight increased from 67.7% at 3 months to 78.7% at 12 months. Furthermore, 44.6% of participants were “dry” on their provocative pad weight test (dry is defined as ≤2-g posttest pad weight) at 3 months compared with 59% at 12 months. An improvement in symptoms was reported on the participant's PGI-I questionnaire, with 65.7% of participants in the 12-month cohort reporting improvement (including “a little better,” “much better,” and “very much better”) at 3 months and 71.6% at 12 months. Mean reduction in absorbent pad usage was 1.3 pads/d at 3 months and 1.1 pads/d at 12 months. Additional improvements were demonstrated in participants with a 10-point or greater improvement in I-QOL scores (score, 0–100), mean change in I-QOL scores, participants with at least a 50% reduction in incontinence episode frequency, and mean reduction in incontinence leaks per day (see Table 4 ).
TABLE 4: End Points at 3 and 12 Months (ITT Analysis*)
In an analysis of the patients in the treatment arm who remained in the study at 12 months, 71.9% of the patients with a baseline pad weight of greater than 20 g achieved a 50% reduction in pad weight, and 86.2% of the patients with a baseline pad weight between 5 and 20 g met the end point. In those patients from the control arm who had the Vesair Balloon placed at 3 months and remained in the study at 12 months, 50% of the patients with a baseline pad weight of greater than 20 g achieved a 50% reduction in pad weight, and 71.4% of the patients with a baseline pad weight between 5 and 20 g met the end point.
No device- or procedure-related serious AEs or unanticipated AEs were reported, and no cases of urinary retention were observed. Adverse events in this study are reported as a cumulative incidence with all AEs recorded even if the symptom was transitory. A complete list of “treatment-related” (device- or procedure-related) AEs with an incidence of greater than 1% for those participants in the treatment arm is seen in Table 5 . One hundred thirty-three participants in the treatment arm (85.9%) had at least 1 treatment-related AE. In the 12-month cohort, 42 participants (66.7%) had at least 1 treatment-related AE. The most common AEs reported in the 12-month cohort were gross hematuria (36.9%), UTI (25.4%), and dysuria (17.5%). Urinary tract infections were defined as participants with positive urine cultures (>10,000 colony-forming units) or when participants were treated empirically at the clinical site and had resolution of symptoms. A dipstick urinalysis was performed with a clean catch specimen at enrollment, and any time cystoscopy was performed or the participants presented with symptoms. If the urinalysis result was positive, a catheter specimen was obtained when possible and cultured to confirm the UTI. All treatment-related AEs completely resolved with the balloon indwelling or after removal of the balloon.
TABLE 5: AEs at Months 0 to 12
In a separate efficacy analysis of the participants in the control arm, evaluable results were obtained from 30 participants who remained in the study at 12 months (46.9% of the control arm participants enrolled). At the 12-month study visit, the control arm participants had the balloon indwelling for a total of 9 months. At the 12-month visit, 46.4% of the participants met the composite end point, 60.7% of the participants had a greater than 50% reduction in their provocative pad weight from baseline, 50% of the patients reported an improvement in symptoms on the PGI-I questionnaire, 66.7% of participants had a 10-point or greater improvement in I-QOL scores (score, 0–100), and 64.3% of the participants reported at least a 50% reduction in incontinence episode frequency. A complete list of “treatment-related” (device- or procedure-related) AEs with an incidence of greater than 1% for those participants in the control arm is seen in Table 5 .
Two hundred sixty-six balloons were deployed across the total population during the entire 12-month study period. One hundred seventy-five participants received 1 balloon, 44 received 2 balloons, 1 received 3 balloons, and 1 did not receive a balloon. In the treatment arm (n = 157), 123 patients had a single balloon insertion, 33 had an exchange, and 1 had 2 balloon exchanges. Twenty of the exchanges occurred between months 0 and 3, and 15 occurred between months 3 and 12. For those participants in the treatment arm who remained at 12 months (n = 67), 45 had a single balloon, 21 had 1 exchange, and 1 had 2 exchanges. Ten of the exchanges occurred between months 0 and 3, and 13 occurred between months 3 and 12. In the control arm (n = 64), 44 participants received a single balloon, 11 had an exchange, and 1 did not receive a balloon. Six of the exchanges occurred between months 0 and 3, and 5 occurred between months 3 and 12. For those participants in the control arm who remained at 12 months (n = 30), 21 had a single balloon and 9 had 1 exchange. Four of the exchanges occurred between months 0 and 3, and 5 occurred between months 3 and 12. Exchanges occurred at the discretion of the investigator because of premature deflation of the balloon or in an effort to resolve an AE. Adverse events that were concurrent with balloon removal are listed in Table 6 , including all patients in the treatment arm and those patients in the treatment arm who remained in the study at 12 months.
TABLE 6: AEs Concurrent With Balloon Removal at Months 0–12 By Treatment Group
Forty-one participants (26%) in the treatment arm discontinued within the first 3 months of the study: 40 participants because of lack of tolerability of the balloon and 1 participant who was lost to follow-up. Forty-nine participants (31%) in the treatment arm discontinued between months 3 and 12: 36 because of AEs including dysuria, bladder irritation, suprapubic discomfort, UTI, and urgency; 9 because of unsatisfactory treatment effect, 2 because of the time commitment of follow-up visits, 1 because of physician decision, and 1 who was unwilling to undergo follow-up cystoscopy. One participant in the control group discontinued within the first 3 months of the study. Thirty-three participants (61%) in the control arm discontinued between months 3 and 12: 27 because of AEs including dysuria, bladder irritation, suprapubic discomfort, UTI and urgency and 6 because of unsatisfactory treatment effect. In an intent-to-treat analysis treating all participants who did not continue with the balloon as failures, 24% of the participants achieved the composite end point and 33.6% had a greater than 50% reduction in pad weight from baseline.
DISCUSSION
Female SUI is a growing clinical problem, with a predicted 167 million women affected worldwide by 2018.10
Three-month efficacy end points demonstrated clinically and statistically significant improvements in incontinence in treated participants when compared with sham control, not only in the primary composite end point but also in the clinically significant secondary end points. Treated participants experienced significantly more reduction in urinary incontinence episode frequency and more often reported improvement on PGI-I.
In the 12-month cohort, comparison of the primary end point and the secondary end points demonstrates the durability of the treatment for those participants who tolerate the balloon.
In an intent-to-treat analysis treating all participants who did not continue with the balloon as failures, 24% of the participants achieved the composite end point and 33.6% had a greater than 50% reduction in pad weight from baseline. These efficacy results were negatively impacted by less than 50% of the participants remaining in each arm in the study at 12 months. In addition to the typical reasons participants withdrew from the study, participants had the balloon removed for reasons related to tolerability. Although some participants did not feel the balloon in place, others felt the balloon in the bladder, particularly when the bladder was empty at the end of voiding. Select participants accommodated the sensation, with the benefit from the therapy outweighing the sensation, whereas others could not and requested balloon removal. All symptoms were mitigated upon removal of the balloon. Balloon modifications may be needed to reduce or eliminate this sensation, and additional screening methods could be developed in future studies. Given the relative ease of balloon placement and removal, balloon insertion for 30 days as a screening method to determine which patients can tolerate the balloon should be considered.
No treatment-related serious AEs were reported in this study, and most of the reported AEs were transient rather than persistent symptoms (Table 5 ). Growing clinical experience with this device led us to consider that there may be a proportion of patients who simply cannot tolerate an indwelling Vesair Balloon. Comparing the AE rates between the full-treatment arm and the 12-month cohort, the AE rates in this “balloon-tolerant” group of participants were noticeably less than those in the overall cohort. One of the unique features of the Vesair Balloon as a treatment modality, especially when interpreting AEs, is ease of reversibility. All AEs resolved upon balloon removal.
Compared with midurethral slings, the Vesair Balloon is a less invasive treatment option for female SUI. Similarly, urethral bulking agents have been suggested as an alternative to midurethral sling placement for those women who either cannot or choose not to undergo sling placement. However, the long-term results after bulking agent injection have been modest. A Cochrane Database review of bulking in 2012 failed to demonstrate any consistent improvement in urinary incontinence over placebo.11 12
The Vesair Balloon for female SUI is comparable to urethral bulking agents in both outcomes and AEs. It also has the advantage of a longer-lasting result, being easily reversible in those participants who do not derive a benefit or do not tolerate balloon placement. Although slings remain the surgical criterion standard in many centers, not all women desire one or are appropriate candidates for sling placement; the Vesair Balloon offers a safe alternative to these participants. Furthermore, it is possible that patients with residual stress incontinence after sling placement who desire further improvement may benefit from balloon placement rather than repeat surgery or injection of a bulking agent. In addition, the reversibility of the procedure allows the Vesair Balloon to be considered as a potential treatment option for women who wish to have children in the future.
The primary weakness of the study is the inability to blind the providers performing the study procedures. Efficacy evaluations are performed by a blinded third party to mitigate any potential bias. Additional weaknesses of the study include the lack of reproducibility of the pad weight test, the high placebo and Hawthorne effect inherent in the I-QOL questionnaire, and the inability to keep all treatment patients blinded because some patients “feel” the balloon in their bladder. The quantity of visits and evaluations were a burden for patients.
The trial has several strengths. It is the largest prospective RCT to date using the Vesair Balloon for female SUI. This trial documents significant improvements in subjective and objective measures of incontinence outcomes and follows current FDA guidance for SUI study methodology. The study included rigorous follow-up with several subjective and objective outcome end points, allowing for analysis to evaluate the appropriate clinically relevant end points in future studies.
The data reported herein were only from those participants in the treatment arm who remained in the study beyond 6 months—it did not include all participants enrolled in the study. Additional studies of those participants who did not tolerate the balloon will help further screen out patients who are not appropriate candidates for this therapy. Additional studies are also warranted to evaluate the use of an intravesical balloon in combination with existing therapies directed at urethral function to better improve outcomes.
CONCLUSIONS
This randomized, sham-controlled trial evaluated efficacy and safety outcomes for a novel intravesical pressure-attenuation system designed to reduce or eliminate symptoms of SUI for participants who were not candidates for surgery, had failed surgery, or chose not to have surgery. In this trial, for those participants who tolerated the balloon and met 3-month primary and secondary end points both objectively and subjectively, symptom relief continued for the duration of treatment (12 months). For those participants who did not tolerate the therapy or had an unsatisfactory treatment effect, the balloon was simply removed, permitting the patient to pursue alternative treatment options. The pressure-attenuation system was safe and caused no urinary retention. Additional larger studies are warranted to better understand which patient populations better tolerate the balloon and to assess the efficacy and safety of its use beyond 12 months. Additional balloon development is needed to improve balloon tolerability, and additional screening methods are needed in future studies.
ACKNOWLEDGMENTS
In addition to the named authors, the following clinicians participated in the study: Jennifer Miles-Thomas, MD, and Jessica DeLong MD, of the Urology of Virginia, Virginia Beach, VA; Douglas Van Drie, MD, and Jason Bennett, MD, of Grand Rapids Women's Health, Grand Rapids, MI; Deborah Myers, MD; Sandra Carberry, MD; B. Star Hampton, MD; and Kyle Wohlrab, MD, of the Women & Infants Hospital of Rhode Island, Providence, RI; Daniel Katz, MD, of the Premier Medical Group, Poughkeepsie, NY; Kevin Benson, MD, of Sanford Female Pelvic Medicine and Reconstructive Surgery Clinic, Sioux Falls, SD; Scott Serels, MD, of the Urology Associates of Norwalk, Norwalk, CT; Jaspreet Singh, MD, and Praneeth Vemulapalli, MD, of Premier Medical Group, Newburgh, NY; Andrew Shapiro, MD, of Chesapeake Urology Associates, Owings Mills, MD; Tovia Smith, MD, of Virginia Women's Center, Richmond, VA; Shazia Malik, MD; Paul Marshburn, MD; and Felipe Videla, MD, of Valley Urogynecology Associates, Phoenix, AZ; Brad Jacobs, MD, of Lyndhurst Clinical Research, Winston-Salem, NC; Ashley Baker, MD, of Regional Urology Associates, Shreveport, LA; Dara Shalom, MD, of Northwell Health, Great Neck, NY; and Denise Elser of the Women's Health Institute of Illinois, Oak Lawn, IL.
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