Gamal Ghoniem,*, Jacques Corcos, Craig Comiter, Peter Bernhard, O. Lenaine Westney and Sender Herschorn

Transcription

1 Cross-Linked Polydimethylsiloxane Injection for Female Stress Urinary Incontinence: Results of a Multicenter, Randomized, Controlled, Single-Blind Study Gamal Ghoniem,*, Jacques Corcos, Craig Comiter, Peter Bernhard, O. Lenaine Westney and Sender Herschorn From the Cleveland Clinic Florida (GG), Weston, Florida, Urology Associates (PB), Minneapolis, Minnesota, McGill Urology Associates (JC), Montreal, Quebec and University of Toronto (SH), Toronto, Ontario, Canada, Stanford University Medical School (CC), Stanford, California, and University of Texas (OLW), Houston, Texas Abbreviations and Acronyms I-QOL Urinary Incontinence Quality of Life Scale ISD intrinsic sphincter injury SUI stress urinary incontinence UBA urethral bulking agent Submitted for publication May 19, Study received institutional review board approval at each participating site. * Correspondence: Section of Voiding Dysfunction, Female Urology and Reconstruction, Cleveland Clinic Florida, (telephone: ; FAX: ; ghonieg@ ccf.org). Financial interest and/or other relationship with Astellas, Coloplast, Uroplasty and Bulkamid. Financial interest and/or other relationship with Johnson & Johnson, Astellas, Purdue, Triton and Allergan. Financial interest and/or other relationship with Coloplast and Astellas. Financial interest and/or other relationship with American Medical Systems. Financial interest and/or other relationship with Pfizer, Astellas, Johnson & Johnson, Allergan and Lilly. Purpose: In a pivotal trial we evaluated the effectiveness and safety of Macroplastique as minimally invasive endoscopic treatment for female stress urinary incontinence primarily due to intrinsic sphincter deficiency. Materials and Methods: A total of 247 females with intrinsic sphincter deficiency were randomized 1:1 and treated with a transurethral injection of Macroplastique or Contigen. The latter group served as the control. Repeat treatment was allowed after the 3-month followup. Effectiveness was determined 12 months after the last treatment using Stamey grade, pad weight and Urinary Incontinence Quality of Life Scale scores. Safety assessment was recorded throughout the study. Results: After 12 patients were excluded from study 122 patients received Macroplastique injection and 125 received Contigen injection. Mean patient age was 61 years and the average history of incontinence was 11.2 years. Of the patients 24% had undergone prior incontinence surgery. At 12 months after treatment 61.5% of patients who received Macroplastique and 48% of controls had improved 1 Stamey grade. In the Macroplastique group the dry/cure rate was 36.9% compared to 24.8% in the control group (p 0.05). In the Macroplastique and control groups the 1-hour pad weight decrease was 25.4 and 22.8 ml from baseline (p 0.64), and the mean improvement in Urinary Incontinence Quality of Life Scale score was 28.7 and 26.4 (p 0.49), respectively. Conclusions: Macroplastique injection was statistically more effective than Contigen for stress urinary incontinence primarily due to intrinsic sphincter deficiency with a 12.1% cure rate difference. Macroplastique can be administered on an outpatient basis. It should be considered a primary or secondary treatment option for stress urinary incontinence. Key Words: urethra; urinary incontinence, stress; injections; prostheses and implants; female STRESS urinary incontinence is a debilitating and dynamic condition affecting millions of individuals worldwide. In the United States alone SUI is the most prevalent form of incontinence in women and it has a negative impact on almost 30% of women older than 18 years (approximately 31 million). 1 This is especially relevant to the baby boomer generation in the United States since prevalence as well as severity increases with age /09/ /0 Vol. 181, , January 2009 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2009 by AMERICAN UROLOGICAL ASSOCIATION DOI: /j.juro

2 CROSS-LINKED POLYDIMETHYLSILOXANE INJECTION FOR URINARY INCONTINENCE 205 Of women with stress incontinence 10% who have severe incontinence are 25 to 44 years old compared with 15% of women who are 45 to 59 and 33% who are older than 60 years. Furthermore, in women with urge incontinence the corresponding rates are 8%, 18% and 45%, and in those with mixed incontinence the rates are 19%, 33% and 53%, respectively. 3 Common treatment options for SUI include behavioral modification, pelvic muscle strengthening such as Kegel exercises or biofeedback, sling placement surgery and UBAs. The latter have been used successfully for many years, including autologous fat, collagen and polytetrafluoroethylene. 4 However, these early treatment options posed problems of reabsorption, allergic reaction or hypersensitivity and migration. 4 In recent years additional materials have been introduced as UBAs for SUI, including polydimethylsiloxane elastomer, dextranomer/hyaluronic acid copolymer, zirconium carbon coated beads and calcium hydroxylapatite. One such product is the Macroplastique implant, an injectable soft tissue UBA. Since 1991, Macroplastique has been used outside the United States for female and male urinary incontinence, and vesicoureteral reflux. 5,6 Macroplastique consists of a soft, flexible, highly textured implant of fully cross-linked polydimethylsiloxane (solid silicone elastomer) with a mean diameter of 140 m that is suspended in an inert bio-excretable polyvinylpyrrolidone carrier. This product is nonallergenic, causes a minimal inflammatory reaction, is ready to use and effective, and has not been shown to migrate. 7 Upon implantation the elastomer implant is encapsulated in fibrin and remains as a bulking agent, while the carrier gel is absorbed by the reticuloendothelial system and excreted unmetabolized through the kidneys. The fibrous capsule remains stable after formation, which is thought to prevent any subsequent movement or migration. 8 A systematic review of Macroplastique treatment for SUI showed a success rate of between 46% and 88%. 4 However, a lack of large, prospective, randomized trials of sufficiently high methodological quality limits the usefulness of the previously published data. Furthermore, we noted that in the majority of trials sample size was too small to determine any significant differences among the subgroups. Therefore, there is an obvious need for randomized, controlled comparative trials of SUI treatment with UBAs. To our knowledge this study represents the first large, multicenter, randomized trial investigating the long-term safety and effectiveness of Macroplastique compared to the commercially available, collagen-based urethral bulking agent Contigen, which served as the control. MATERIALS AND METHODS Study Design Between November 1999 and February 2003, a total of 260 patients from 12 investigational sites in the United States and Canada were randomized 1:1 to the Macroplastique or Contigen (control) group. Institutional review board approval was obtained locally at each participating site. Patients were blinded to treatment. However, due to the obviously different appearance and handling characteristics of the 2 study materials, it was impossible to blind the treating physicians. This clinical trial was done after obtaining written informed consent from each patient. Patients were recruited through investigational sites, physician referrals, newspaper advertisements and direct patient mailing. Inclusion and Exclusion Criteria Eligibility for inclusion required a diagnosis of SUI primarily due to ISD without improvement with conservative treatments, such as behavior modification (biofeedback) or exercise (Kegel). Additional criteria were a viable mucosal lining and normal bladder capacity. Patients with urinary tract infection, uncontrolled detrusor overactivity, high post-void residual urine volume, high grade pelvic organ prolapse, confounding bladder pathology, pregnancy or morbid obesity were excluded from study. The study involved baseline assessment, treatment and followup at 1, 3, 6 and 12 months. In the 2 arms repeat treatment was allowed after the 3-month followup in all consenting patients who were not cured by the first treatment, at which time the followup visit schedule was reinitiated. Baseline assessment included patient demographics and medical history, 3-day voiding diary, physical examination, cystoscopy, urodynamics with medium fill cystometry and abdominal leak point pressure measurement, I-QOL score and pad weight test. Procedure Macroplastique or Contigen implantation was performed using a transurethral endoscopic procedure with a rigid 12-degree lens cystoscope. Approximately 5 ml were delivered through a 5Fr or 7Fr needle with the patient under local or general anesthesia, occasionally in conjunction with mild sedation. Macroplastique was administered with an injector device. Outcome Measures Incontinence status was measured at baseline and at all followup visits by the investigators using the Stamey incontinence grading and pad weight testing. Stamey grading is a 4 level scale of incontinence severity ranging from 0 continent-dry to 3 total incontinence regardless of activity. Pad weight testing was done using a standardized format measuring urine loss during a 1-hour period following a series of activities outlined by the International Continence Society. 9 Quality of life was measured at baseline and at each followup visit using I-QOL. 10 At each visit patients and investigators subjectively evaluated treatment success as dry, markedly improved, slightly improved or unchanged. Safety was assessed by recording any adverse events.

3 206 CROSS-LINKED POLYDIMETHYLSILOXANE INJECTION FOR URINARY INCONTINENCE Statistical Analysis A required sample size of 208 participants was calculated based on a noninferiority test using the Blackwelder formula ( 0.05, 0.20 and 0.15) and run on PASS 6.0 software (NCSS, Kaysville, Utah). To account for dropouts 260 participants were recruited and 247 underwent implantation as randomized. All analyses were done elsewhere with SAS, version 9.1 using SAS data files. A decrease in baseline I-QOL grade of at least 1 Stamey grade at 12 months indicated improvement and served as the primary efficacy end point. The null hypothesis stated that the difference (Contigen minus Macroplastique) in the proportion of patients showing improvement in incontinence would be greater than 15%. Stamey grade as the primary end point and the 15% differential in the null hypothesis were selected according to the recommendation of the United States Food and Drug Administration, which provided regulatory oversight for this investigational device exemption clinical study. Additional end points were change in pad weight and change in I-QOL from baseline, the proportion of patients who were dry (Stamey grade 0) and the proportion of patients who were markedly improved or dry by subjective report. Analysis of the primary efficacy end point was performed using intent to treat analysis, which included all 247 patients treated per protocol but excluded those who did not receive the randomized treatment. Patients who were lost to followup or otherwise withdrawn were considered treatment failures regardless of any success seen at previous visits and, thus, they were considered evaluable at 12 months. The last treatment carried forward was not used to avoid the potential bias of increased success. The Macroplastique group and Contigen control group were compared with a 2-step approach using the Blackwelder test of noninferiority with a noninferiority margin of 15%. 11 Additionally, the 95% CI for the difference in proportions was compared to 0 for a 1-sided test of significance. The within-subject incontinence grade improvement from baseline was also calculated 12 months after the last treatment in each group and compared to 0 in a 1-sample median test. Subgroup comparisons of the primary efficacy end point were done with a logistic regression model. Additional end points were analyzed by calculating differences and the corresponding 95% CI. Safety assessment, which included all patients treated according to protocol, were recorded throughout the study. The incidence of adverse events is reported as the difference of proportions and the corresponding 95% CI. RESULTS Not treated with Macroplastique n = 8 Randomized n = 260 Not treated with Collagen n = 5 Patient Demographics Of the 260 patients randomized into the study 247, including 122 in the Macroplastique group and 125 in the control group, were treated according to the study protocol (fig. 1). Eight patients in the Macroplastique group and 4 in the control group withdrew prior consent to treatment and 1 who was randomized to the control group received Macroplastique and, thus, was excluded from further analysis. At the 12-month followup, 20 patients with Macroplastique and 31 controls were considered discontinued due to loss to followup, withdrawal for noncompliance or patient request for other treatment. Fol- Intent-totreat Group Macroplastique n = 122 Controls n = 125 Discontinued n = 20 Lost to follow-up (6) Withdrew other treatment (9) Other (5) n = 31 Lost to follow-up (8) Withdrew other treatment (14) Other (9) Completed Study n = 102 n = 94 Figure 1. Study flow diagram

4 CROSS-LINKED POLYDIMETHYLSILOXANE INJECTION FOR URINARY INCONTINENCE 207 Table 1. Patient baseline characteristics Macroplastique Control p Value No. pts Mean SD pt age (t test) Mean SD incontinence history (yrs) (t test) No. previous incontinence procedure (%) 29 (23.8) 30 (24.0) 0.97 (t test) No. hysterectomy (%) 63 (51.6) 65 (52.0) 0.95 (t test) No. Stamey grade (%): I 36 (29.5) 48 (38.4) 0.55 (chi-square test) II 84 (68.9) 69 (55.2) III 2 (1.6) 8 (6.4) 1-Hr pad wt test: No. pts (t test) Mean SD loss (ml) lowup visits at 12 months were completed by 102 patients with Macroplastique and 94 controls. The 2 treatment groups were well balanced relative to demographic variables (table 1). Average age was 61 years, 95% of the women were white and the mean history of urinary incontinence was 11.2 years. Of the women 51.8% had undergone hysterectomy, 72.8% were postmenopausal and 23.9% reported a previous surgical incontinence procedure. The total number of treatments was similar in the 2 groups with 47.5% of patients with Macroplastique and 41.6% of controls receiving a single treatment. In addition, there was no difference in treatment volume between the Macroplastique and control groups (table 2). Efficacy Of all patients treated 61.5% (75 of 122) with Macroplastique and 48% (60 of 125) of controls had an improvement of at least 1 Stamey grade at 12 months, demonstrating that Macroplastique is not inferior to Contigen (p 0.001, table 3). The 95% upper bound for the difference in proportions was less than 0, demonstrating that the Macroplastique group had a significantly improved Stamey grade compared to the control group using a 1-sided test of significance. The 2 groups had a median withinsubject improvement in Stamey grade of 1 and demonstrated significant improvement in Stamey grade at 12 months from baseline (p 0.001, fig. 2). At 12 months the proportion of patients with a Stamey grade of 0 or dry outcome was significantly Table 2. Treatment characteristics Macroplastique Control p Value % Pts with max allowed treatments Mean SD total implant vol (ml): Treatment Treatment Overall higher for Macroplastique than for Contigen ((36.9% vs 24.8%, p 0.05, table 3 and fig. 2). Subject and physician assessments of dry/improvement showed good agreement with similar results. Patient and physician scores of dry/markedly improved for Macroplastique were 77.4% and 80.4% vs 68.1% and 74.4% for controls, respectively (table 3). At 12 months the average SD urine loss was and 5.9 ml 14.4 ml in the Macroplastique and control groups, respectively. This represented an average decrease in urine loss from baseline at ml for Macroplastique compared to ml for Contigen (p 0.64, table 3). Relative to I-QOL, the 2 groups were significantly improved from baseline (p 0.001). Each showed a similar improvement in I-QOL subscales, including avoidance and limiting behavior, psychosocial impacts and social embarrassment, with no difference in improvement between the groups. Overall there was no statistical evidence that the percent of participants with an improvement in Stamey grade or dryness was affected by previous incontinence surgery, as reported at baseline in the Macroplastique and control groups (p 0.58 and 0.65, respectively). Furthermore, there was no statistical evidence of a difference in treatment effect related to age or hormonal status (p 0.69 and 0.75, respectively, table 4). Safety There was no significant difference between the Macroplastique and control groups relative to the number of adverse events experience by patients (59% and 54.4%, respectively, table 5). For purposes of analysis all genitourinary adverse events regardless of timing or investigator designation were considered treatment related during the study course. No serious treatment related adverse events were reported for Macroplastique, while only 1 serious treatment related event (kidney infection) was reported in controls.

5 208 CROSS-LINKED POLYDIMETHYLSILOXANE INJECTION FOR URINARY INCONTINENCE Table 3. Macroplastique and Contigen effectiveness at 12 months Macroplastique Controls p Value No. Stamey grade (%):* (dry) 45 (36.9) 31 (24.8) 0.05 (chi-square test) Improvement 75 (61.5) 60 (48.0) (noninferiority) No. pt assessment (%): (chi-square test) Dry 34 (33.3) 25 (26.6) Improved 45 (44.1) 39 (41.5) Slightly improved 15 (14.7) 19 (20.2) Unchanged 8 (7.8) 11 (11.7) No. physician assessment (%): (chi-square test) Dry 43 (42.2) 32 (34.0) Marked improvement 39 (38.2) 38 (40.4) Slight improvement 14 (13.7) 14 (14.9) Unchanged 6 (5.9) 10 (10.6) Mean SD 1-hr pad wt test (t test) decrease from baseline (ml) Mean SD I-QOL improvement (t test) * On intent to treat analysis with all patients lost to followup at 12 months considered failures. As followed analysis with only patients attending the 12-month followup analyzed. DISCUSSION The results of this study are notable in light of other reports in the published literature of synthetic bulking agents The reported success rate at 1 year in this study was statistically higher for Macroplastique vs the biological control (61% vs 48%, p 0.05). This result is noteworthy, considering that this trial was done in a large, randomized population of patients with statistically similar baseline characteristics. Additionally, the dry rate for Macroplastique at 1 year was statistically higher than the dry rate in the control group (37% vs 25%, p 0.05). Thus, in these respects Macroplastique is the first synthetic bulking agent to clinically demonstrate a greater potential for long-term success compared to biological bulking agents. Finally, Macroplastique was an acceptable treatment in patients with previous surgical therapy for incontinence. Since 23.8% and 24.0% of all randomized patients with Macroplastique and controls had undergone previous surgical Macroplastique Contigen Percentage of Subjects Stamey Improvement Stamey Dry Figure 2. Mean percent of patients improved and cured at 12 months (each p 0.05). Bars indicate 95% CI

6 CROSS-LINKED POLYDIMETHYLSILOXANE INJECTION FOR URINARY INCONTINENCE 209 Table 4. Treatment effect by baseline characteristics No. Pts/Total No. (%) Macroplastique Control Logistic Regression* Age: Younger than /63 (57.1) 27/59 (45.8) or Older 39/59 (66.1) 33/66 (50.0) Premenopausal 15/32 (46.9) 13/35 (37.1) Postmenopausal 59/89 (66.3) 47/90 (52.2) 0.75 Treatment effect defined as percent improved by 1 Stamey grade. * Test for interaction across baseline strata. treatment, there was no significant effect of previous surgery on a successful outcome at 12 months. To our knowledge this study represents the first North American clinical investigation of Macroplastique for SUI. Since 1991, thousands of patients with SUI outside the United States have undergone treatment with Macroplastique. As a textured solid silicone elastomer implant, Macroplastique fulfills the criteria of being nonallergenic, causing minimal inflammatory reaction and having no known implant site migration. Additionally, since silicone is nonresorbable and nondegradable, Macroplastique is a permanent implant capable of providing longterm improvement of SUI. Although silicone materials were subject to adverse public scrutiny in the 1990s due to the use of silicone gels in the breast implant controversy, cured silicone elastomers such as Macroplastique continue to be one of the most widely studied and safe materials used in medical device implants. Silicone elastomers are used in implants such as hydrocephalic shunts, pacemaker and lead wire coatings, and finger joint implants. Silicone elastomer has the advantage that it can be formed into highly textured implants while still maintaining a rubber-like suppleness that may decrease the potential for erosion, which is sometimes seen with more rigid implant materials, making it ideal for UBAs. 15 The primary benefit of UBAs is to provide an effective and minimally invasive primary or secondary treatment option for SUI. Radley et al assessed the effect of previous surgical treatment on the effectiveness of Macroplastique for SUI and found no statistically significant difference. 16 Patients with a fixed urethra have a lower success rate with tape procedures compared to women with urethral hypermobility only. 17 Thus, patients in whom previous surgical or nonsurgical treatment for SUI has failed can be considered candidates for a UBA such as Macroplastique. If sling surgery fails to adequately treat SUI, patients with a residual ISD component to SUI may need addition treatment with a bulking agent. The role of UBAs for SUI has changed since their introduction into the United States market in Once considered a primary treatment option, UBAs are currently used more as a secondary option due to the popularity and reportedly higher effectiveness of sling procedures (80% to 85%). 18 However, sling surgery carries inherent risk, ranging from voiding dysfunction to vaginal extrusion and even urethral erosion. 19,20 UBAs are an attractive primary treatment option in patients with impaired health in whom the increased risks associated with sling procedures outweigh the potential benefits of treatment. Additionally, UBAs are an effective secondary treatment option when incontinence due to urethral hypermobility may have been corrected by a urethral sling Table 5. Adverse events No. Macroplastique (%) No. Control (%) Difference (95% CI) Urinary tract infection (0 365 days after implantation) 29 (23.8) 31 (24.8) 1.0 ( 9.7, 11.7) Dysuria 11 (9.0) 10 (8.0) 1.0 ( 8.0, 5.9) Urgency 11 (9.0) 9 (7.2) 1.8 ( 8.6, 5.0) Frequency 10 (8.2) 12 (9.6) 1.4 ( 5.7, 8.5) Urinary retention 8 (6.6) 4 (3.2) 3.4 ( 8.7, 2.0) Hesitancy 6 (4.9) 8 (6.4) 1.5 ( 4.3, 7.2) Urge incontinence 6 (4.9) 5 (4.0) 0.9 ( 6.1, 4.2) Slowed urine stream 5 (4.1) 10 (8.0) 3.9 ( 2.0, 9.8) Incomplete bladder emptying 5 (4.1) 5 (4.0) 0.1 ( 5.0, 4.8) Transient hematuria 5 (4.1) 5 (4.0) 0.1 ( 5.0, 4.8) Implantation site pain 4 (3.3) 5 (4.0) 0.7 ( 3.9, 5.4) Overactive bladder 3 (2.5) 0 (0.0) 2.5 ( 5.2, 0.3) Yeast infection 3 (2.5) 3 (2.4) 0.1 ( 3.9, 3.8) Bladder pain 2 (1.6) 2 (1.6) 0.0 ( 3.2, 3.1) Urine stream change 2 (1.6) 2 (1.6) 0.0 ( 3.2, 3.1) Increased/worsening nocturia 2 (1.6) 1 (0.8) 0.8 ( 3.6, 1.9) Urethral erosion 2 (1.6) 1 (0.8) 0.8 ( 3.6, 1.9) Other, including headache nausea 22 (18.0) 16 (12.8) 5.2 ( 14.2, 3.8) Totals 72/122 (59.0) 68/125 (54.4) 4.6 ( 17.0, 7.7)

7 210 CROSS-LINKED POLYDIMETHYLSILOXANE INJECTION FOR URINARY INCONTINENCE but the patient still experiences some degree of incontinence due to continued ISD. Finally, in our study greater 12-month efficacy would likely have been achieved without protocol limitations to the number of re-treatments (1) or the period for allowing re-treatment (within 4 weeks after the 3-month followup). These restrictions were necessary because of time constraints for study completion. However, in real life circumstances in a community based practice such limitations would likely not have a role. CONCLUSIONS The results of this study demonstrate that Macroplastique is more effective than Contigen for SUI primarily due to ISD based on the observed cure rates and overall improvement in Stamey scores. Other study end points, such as pad weight and quality of life results, favored Macroplastique but were not statistically significant. Macroplastique is a safe, efficacious, minimally invasive injectable silicone material that can be administered on an outpatient basis. It should be considered a primary or secondary treatment option for SUI. ACKNOWLEDGMENTS Statistical analysis was done at The Integra Group, Brooklyn Park, Minnesota. APPENDIX Study Investigators Gamal Ghoniem, Cleveland Clinic Florida, Weston, Florida; Peter Bernhard, Urology Associates, Minneapolis, Minnesota; Jacques Corcos, McGill Urology Associates, Montreal, Quebec and Sender Herschorn, University of Toronto, Toronto, Ontario, Canada; Craig Comiter, University of Arizona, Tucson, Arizona; Kevin Tomera, Alaska Clinical Research Center, Anchorage, Alaska; O. Lenaine Westney, University of Texas, Houston, Texas; Vincent Lucente, Lehigh Valley Hospital, Allentown, Pennsylvania; John Smith, Lahey Center, Burlington, Massachusetts; and Gregory Wahle, Urology of Indiana and John Mulcahy, Indiana University, Indianapolis, Indiana. REFERENCES 1. 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