Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Wei JT, Nygaard I, Richter HE, et al. A midurethral sling to reduce incontinence after vaginal prolapse repair. N Engl J Med 2012;366:

2 PFDN Protocol 15P01 03/15/2007 OPUS OUTCOMES FOLLOWING VAGINAL PROLAPSE REPAIR AND MID URETHRAL SLING (OPUS) TRIAL PFDN Protocol 15P01 Protocol Version 01 March 15, 2007 Approvals: Steering Committee Approval: 09/28/2006 DSMB Approval: 12/20/2006 Advisory Board Approval: 12/01/2006 Protocol Working Group: Loyola University: Kim Kenton University of North Carolina: Anthony Visco University of Alabama at Birmingham: Holly Richter Cleveland Clinic: Matthew Barber University of California-San Diego: Charlie Nager University of Teas Southwestern: Joseph Schaffer University of Utah: Ingrid Nygaard (Protocol committee co-chair) University of Michigan Data Coordinating Center: Morton Brown, Nancy Janz, Xiao Xu, John Wei (Protocol committee chair) NICHD: Anne Weber Page 1 of 32

3 PFDN Protocol 15P01 03/15/2007 OPUS TABLE OF CONTENTS A. STUDY AIMS... 3 B. BACKGROUND AND SIGNIFICANCE... 4 C. STUDY SCHEMA... 6 D. OUTCOME MEASURES... 7 D1. PRIMARY OUTCOME MEASURE... 7 D2. SECONDARY OUTCOME MEASURES... 8 E. STUDY POPULATION... 9 F. PATIENT RECRUITMENT G. DATA COLLECTION G1. BASELINE VISIT: STUDY SCREENING, INITIATION AND ENROLLMENT H. RANDOMIZATION AND MASKING I. SURGICAL INTERVENTIONS J. ADVERSE EVENT REPORTING K. FOLLOW-UP EVALUATIONS K1. POST-OP VOIDING TRIAL K2. 2 WEEKS POST-OP K WEEKS POST-OP K4. 3 MONTHS POST-OP K5. 6 MONTHS POST-OP TELEPHONE INTERVIEW K6. 9 MONTHS POST-OP TELEPHONE INTERVIEW K7. 12 MONTHS POST-OP K8. ADDITIONAL TREATMENT FOR URINARY INCONTINENCE K9. STUDY FLOWCHART K10. TIMELINE OF VISITS AND MEASURES L. STATISTICAL AND DATA MANAGEMENT L1. SAMPLE SIZE L2. STATISTICAL ANALYSIS L3. ECONOMIC EVALUATION L4. DATA FROM THE PATIENT PREFERENCE TRIAL (PPT) L5. DATA MANAGEMENT M. ETHICAL CONCERNS INFORMED CONSENT M1. ETHICAL CONCERNS M2. INFORMED CONSENT M3. DATA AND SAFETY MONITORING BOARD M4. QUALITY ISSUES M5. REPORTING OF SERIOUS ADVERSE EVENTS N. STUDY COSTS O. DISCONTINUATION OF PARTICIPATION P. REFERENCES APPENDIX 1: TVT SURGICAL PROCEDURE Page 2 of 32

4 PFDN Protocol 15P01 03/15/2007 OPUS A. STUDY AIMS The PFDN CARE trial established that performing a Burch colposuspension (an antiincontinence procedure) in stress continent women undergoing an abdominal sacral colpopey (ASC) significantly reduced postoperative stress urinary incontinence (SUI) with no increase in irritative or obstructive voiding symptoms. 1 While important, these results do not provide guidance on how to decrease postoperative stress incontinence after vaginal (rather than abdominal) prolapse repair in stress continent women. Some have suggested that a urethral sling procedure should be performed routinely during transvaginal prolapse surgery; however, the risk-benefit of this approach is unknown. There may be less benefit from adding a sling procedure during vaginal, rather than during abdominal, surgery because the position of the vaginal ape (and therefore, the position of the anterior vagina) is oriented differently following vaginal, rather than following abdominal, surgery. The patient population may also differ between those choosing vaginal versus abdominal surgeries for prolapse. For eample, women undergoing vaginal prolapse repair may be older than women undergoing abdominal prolapse repair; increasing age is also associated with changes in bladder function, including detrusor dysfunction and urinary urgency symptoms that occurs more frequently than in younger women. Postoperative risks may also differ; the literature suggests that pubovaginal slings are associated with a higher risk of urinary retention and urinary urgency symptoms, compared to Burch colposuspension. These risks may be mitigated by the recent introduction of minimally invasive slings, such as the Tension-free Vaginal Tape (Gynecare TVT, Ethicon, Johnson & Johnson), a midurethral sling that seems to have high efficacy with fewer side effects than traditional slings. 2 This is supported by a single trial comparing TVT with Kelly plication in stress continent women with pelvic organ prolapse. 3 The overall objective of this randomized clinical trial is to determine whether symptom-specific treatment of incontinence after prolapse surgery is equally effective to prophylactic treatment by adding TVT at the time of the prolapse surgery among women with anterior vaginal prolapse but without pre-operative symptoms of stress urinary incontinence. Primary Aims: In stress continent women planning vaginal surgery for pelvic organ prolapse: I. Specific Aim 1: To determine if the failure rate defined by subsequent treatment for urinary incontinence, signs or symptoms of bothersome urinary incontinence (defined as having at least moderate bother for any of 4 PFDI incontinence items) differs between vaginal prolapse repair and vaginal prolapse repair plus TVT during the first 3 months after the inde surgery. H o : Among women undergoing vaginal prolapse surgery who do not have overt stress urinary incontinence, those that undergo a concomitant TVT procedure will have similar rates of urinary incontinence and further treatment for urinary incontinence during the first 3 months after surgery as women that do not undergo the TVT. It is anticipated that we would reject this hypothesis. II. Specific Aim 2: To determine if the prevalence of bothersome urinary incontinence at 12 months after the inde surgery differs between vaginal prolapse repair and vaginal prolapse repair plus TVT, whether or not there was subsequent treatment for symptoms of urinary incontinence; i.e., to determine whether symptom-specific treatment of incontinence after prolapse surgery is equally effective to prophylactic treatment by adding a TVT at the time of the prolapse surgery. Page 3 of 32

5 PFDN Protocol 15P01 03/15/2007 OPUS H o : Among women undergoing vaginal prolapse surgery who do not have overt stress urinary incontinence, those who do not undergo a concomitant TVT procedure will have similar prevalence of bothersome urinary incontinence at 12 months after surgery as women who undergo a concomitant TVT. In this hypothesis, additional treatment(s) for symptoms of urinary incontinence will be considered part of the overall clinical treatment regimen rather than an indication of treatment failure. It is anticipated that we will fail to reject this hypothesis. III. Specific Aim 3: To measure the total cost of care and relate the difference in cost of care between the two groups to differences in health utilities and health-related quality of life, which will allow us to eamine the cost-effectiveness of prophylactic use of a TVT at the time of prolapse surgery versus symptom-specific treatment of stress incontinence after prolapse surgery. IV. Specific Aim 4: To carry out a Patient Preference Trial (PPT) to determine if the demographic/disease characteristics, type of treatment received for incontinence and treatment failure rates differ between those women participating in the RCT and those who decline participation in the RCT. H o : Among stress continent women planning vaginal surgery for prolapse, participants in the RCT and the PPT will have similar prevalence of urinary incontinence at 3 and 12 months after inde surgery; and will have similar adverse effects profiles after adjusting for the treatment strategy chosen by the subject and demographic differences between the samples. It is desirable to accept this hypothesis; rejection of the hypothesis may mean that the generalizability (eternal validity) of the RCT findings is limited. Secondary Aims: I. Secondary Aim 1: To determine whether there is a difference between the two randomized treatment arms in overall lower urinary tract symptoms (LUTS), health related quality of life, and urinary retention and other complications. II. Secondary Aim 2: To identify risk factors for postoperative SUI, urinary retention, and additional treatment for SUI. III. Secondary Aim 3: To eamine changes in the use of adaptive behaviors for pelvic floor disorders following vaginal prolapse surgery. IV. Secondary Aim 4: To eamine differences in anterior vaginal prolapse between treatment groups B. BACKGROUND AND SIGNIFICANCE Pelvic floor disorders, particularly pelvic organ prolapse and urinary incontinence, are common in women. A population-based, cross-sectional study by Samuelsson et al found that as many as 30% of women have some degree of prolapse and that the risk of prolapse increases with age, parity, infant birth-weight and loss of pelvic floor muscle strength. 4 Half of parous women have some degree of pelvic organ prolapse. 5 The risk that women will undergo at least one surgery for pelvic organ prolapse or urinary incontinence by the time they reach the age of 80 is 11.1%. 6 According to data from the National Hospital Discharge Survey, 200,000 women undergo inpatient surgery for prolapse annually 7 and approimately 21-29% of women having surgery for prolapse had undergone a previous surgical procedure for prolapse or urinary incontinence. 6 The most common prolapse surgery performed is for prolapse of the anterior vagina which is present in more than 80% of all surgeries for prolapse. 7 Page 4 of 32

6 PFDN Protocol 15P01 03/15/2007 OPUS Stress urinary incontinence may occur in previously stress-continent women after prolapse surgery. It is conventionally held that the prolapse surgery may unmask underlying stress incontinence. 8,9 The prevalence of this de novo stress urinary incontinence ranges from 15 to 80%. 10 This contributed to the rationale for the CARE trial. The CARE trial conducted by the PFDN was the first RCT to demonstrate a clinically and statistically significant improvement in urinary symptoms 3 months after surgery when Burch colposuspension was performed at the time of abdominal sacrocolpopey (ASC). 1 However, there have been few randomized trials evaluating the prophylactic effect of anti-incontinence procedures in combination with vaginal prolapse repair. Thus, controversy persists over whether or not a prophylactic anti-incontinence procedure such as the Tension-free Vaginal Tape procedure (Gynecare TVT, Ethicon, Johnson & Johnson) should always be included when performing prolapse surgery via the vaginal approach, particularly when elevating the ape or anterior vagina. 11 To date, there has only been a single small randomized clinical trial that addresses the issue of surgical stress incontinence prophylais with TVT at the time of vaginal prolapse surgery. 3 Fifty women with occult stress urinary incontinence (SUI), defined as a positive stress test with prolapse reduction, were randomly assigned to undergo TVT or Kelly plication at the time of prolapse surgery. At a median follow up of months, 4% of women in the TVT group reported stress incontinence, compared to 36% in the plication group (p=0.01). Objectively, 8% of the TVT group had a positive cough stress test (CST) compared to 44% in the plication group (p<0.01). Additional treatment for SUI did not differ significantly between the 2 groups (3 women in the plication group versus none in the TVT group; p=0.31). De novo urge urinary incontinence (UUI) occurred in 12% of the TVT group and 4% of the plication group (p=0.66). Urinary retention occurred equally in both groups (8%) and resolved by 10 days postoperatively. There was a single bladder perforation and hematoma in the TVT group only (each 4%). Operation time was increased by an average of 19 minutes in the TVT group (131 vs 112 minute). Although this was a positive trial, only women who were incontinent with prolapse reduction were included and any de novo incontinence, regardless of bother, was used as an endpoint. Thus, the use of prophylactic TVT among women who are continent with prolapse reduction remains an unanswered but important clinical question. Other randomized trials have reported lack of effect when a prophylactic bladder neck procedure is performed among continent women. In one trial, 29 women with stage 3-4 prolapse but without stress incontinence were randomized regardless of prolapse reduction testing results to either a needle suspension (not TVT ) or endopelvic fascial plication. The investigators demonstrated significantly greater detrusor instability but no difference in urinary continence. 12 Colombo et. al. randomized 102 women with stage 2-4 prolapse but without stress incontinence when prolapse was reduced to cystopey with or without pubourethral ligament plication. 13 This trial also failed to demonstrate a benefit for prevention of stress incontinence. Given these conflicting trial findings for prophylactic bladder neck procedures, and the increasing number of women undergoing prolapse surgery who may be subjected to a TVT, it is important to demonstrate benefit for a prophylactic TVT at the time of prolapse surgery among a broader population of women. Increasingly, the economic consequences of medical therapies are being considered in the reimbursement decisions made by third party payers, and clinicians are being held accountable for controlling costs. Justification for medical interventions from a societal perspective is warranted given the limited health care resources and rapid growth of health care ependitures in the United States. However, costs are only part of the picture and must be balanced by the potential benefits of intervention. Does the incorporation of a TVT at the time of anterior or apical vaginal prolapse repair preserve quality of life? Moreover, will a TVT be cost-effective Page 5 of 32

7 PFDN Protocol 15P01 03/15/2007 OPUS and will it outweigh potential side effects, such as urinary retention? Though intuitive, the assumption that preventing urinary incontinence will save health care dollars is not yet substantiated by empiric evidence, particularly when the prevention strategy is relatively epensive, the benefits accrue to only a minority of patients, and a downstream effective treatment for the condition is available for those who need it. Thus, it is incumbent upon health providers to demonstrate benefit for the use of prophylactic TVT at the time of transvaginal prolapse repair. As it stands, the health care costs for pelvic floor disorders, such as urinary incontinence, are already quite substantial. Updated estimates by Wagner and Hu 14,15 placed the annual cost in the United States at $19.5 billion with an average cost of $3,500 per individual suffering from urinary incontinence; nearly 2/3 of this cost was due to therapy and the majority of therapy costs were accounted for by surgical procedures. Similarly, Subak and colleagues estimated the direct costs for prolapse surgery to be over $1 billion per year (1997 costs) based on the National Hospital Discharge Survey. 16 Of note, 21% of these prolapse surgeries included a concomitant procedure for stress urinary incontinence, which accounted for $218 million in direct costs in Increasing prophylactic use of stress incontinence procedures during prolapse surgery holds the potential to significantly increase these direct costs of care. Given the invasive nature of surgical intervention trials, some patients may be reluctant to agree to random assignment. Consequently, the representativeness of surgical randomized controlled trials may be substantially compromised, limiting the generalizability (eternal validity) of results to the general population. In a patient preference trial (PPT) design, the RCT is presented to all eligible subjects. Those who wish to participate in the RCT are enrolled and randomized. However, those who decline to participate in the randomized trial are asked to consent to be followed; those subjects receive therapy of their choice and are followed using the same followup protocol as in the RCT. 17,18 We will refer to the randomized component as the RCT and to the non-randomized component as the PPT. Combining an RCT and a PPT in one overarching trial has 3 important advantages over a standard RCT. 18 First, if the PPT results are similar to those of the RCT, this will enhance the eternal validity of the RCT; since patients who decline randomization may represent the majority of patients seen in clinical practice, a consistent finding in both the randomized and non-randomized cohorts can provide some reassurance regarding generalizability. Second, if the findings are inconsistent between the RCT and PPT studies, one can describe the direction and magnitude of the bias introduced through self-determination of treatment (or physician selection of treatment), which currently is a major threat to the application of RCT findings. Third, the additional subject information improves the statistical power to identify risk factors that may be associated with surgical outcomes. 19 The completion of all four specific aims will provide pivotal evidence that will allow surgeons to better counsel women with pelvic organ prolapse in regards to the benefits of prophylactic antiincontinence surgery when a transvaginal approach is applied. The cost effectiveness analyses will greatly enhance the knowledge gained from this randomized trial by informing policy makers of the incremental costs and benefits of a prophylactic TVT. C. STUDY SCHEMA The primary study is a randomized, single-blind, sham-controlled clinical trial of prophylactic TVT among women undergoing vaginal surgery for prolapse who have anterior vaginal prolapse but who do not have overt symptoms of stress urinary incontinence. Participants will be randomized to TVT or control in a 1:1 randomization by the Data Coordinating Center. Page 6 of 32

8 PFDN Protocol 15P01 03/15/2007 OPUS Although formally single-blind, the evaluators at the clinical sites and at the Quality of Life Interviewing Center will also be blinded to treatment. The objectives of this randomized clinical trial (RCT) are 1) to determine, at 3 months postoperatively, whether treatment with tension-free vaginal tape (TVT ) is superior to no intervention in prevention of urinary incontinence among women undergoing vaginal surgery for prolapse that were stress continent pre-operatively, 2) to determine whether symptomatic treatment of lower urinary tract symptoms after the inde prolapse surgery will result in similar relief of urinary symptoms at 12 months in both treatment arms (in this aim, additional treatment will not be considered to be a treatment failure), and 3) to eamine the cost-effectiveness of prophylactic TVT compared to symptomatic treatment post-surgery. By including the PPT component, the fourth objective is 4) to eamine whether biases were introduced into the trial as a result of refusals to participate in the RCT. The rationale for this RCT is that: (a) it is epected that there will be fewer women with postoperative incontinence with prophylactic TVT ; however, (b) the surgery takes longer, is more epensive, and may result in greater urinary retention, irritative voiding symptoms including urgency, frequency, and urge incontinence and serious adverse events (SAEs). It is possible that similar long-term (one-year) results are obtainable by treating urinary symptoms after the inde surgery in the subjects who have bothersome symptoms. Consequently, the prophylactic strategy may not necessarily be preferred. The secondary objectives are 1) to determine whether prophylactic TVT will result in different overall lower urinary tract symptoms (LUTS), difference in incidence of urinary incontinence, health related quality of life, and urinary retention and other complications, 2) to eamine risk factors for postoperative urinary incontinence, 3) to eamine changes in the use of adaptive behaviors following vaginal prolapse surgery, and 4) to eamine differences in anterior vaginal prolapse based on the Pelvic Organ Prolapse Quantitation (POP-Q) eamination between those with and without prophylactic TVT. All subjects will be followed for 12 months after the inde procedure, or until they withdraw from the study whichever occurs first. D. OUTCOME MEASURES D1. Primary Outcome Measure The primary endpoint of this study will be the occurrence of signs (positive cough stress test at the lower volume of either 300cc or maimal bladder capacity with or without prolapse reduction using swab technique), symptoms of ANY urinary incontinence that are also characterized as being at least moderately bothersome to the subject (as measured by a moderately or quite a bit response to any of 4 items from the Urinary Distress Inventory (UDI) regarding leakage, see D1a-D1c below) or need for treatment (including sling, suspension surgery, collagen injections, supervised pelvic muscle therapy, medication, pessary, etc) for any urinary incontinence. The 3 SUI items are identical to those used in the primary endpoint in PFDN CARE trial and a single urge incontinence item has been added in order to also capture urge incontinence. (See all 4 items listed below, D1a-D1c.) For the first aim, treatment failure is defined as initial occurrence of the endpoint by 3 months. For the second aim, failure is defined by signs (positive cough stress test at the lower volume of either 300cc or maimal bladder capacity), and symptoms of urinary incontinence (as measured by a moderately or quite a bit response to any of 4 items from the UDI regarding leakage) at 12 months independent of additional treatment; if the subject withdraws from the study, this will be considered a failure as well. Page 7 of 32

9 PFDN Protocol 15P01 03/15/2007 OPUS D1a. PFDI Stress Urinary Incontinence items: 1. Do you usually eperience urine leakage related to coughing, sneezing, or laughing? 2. Do you usually eperience urine leakage related to physical eercise such as walking, running, aerobics, or tennis? 3. Do you usually eperience urine leakage related to lifting or bending over? D1b. PFDI Urge Urinary Incontinence items: 1. Do you usually eperience urine leakage associated with a feeling of urgency, that is, a strong sensation of needing to go to the bathroom? D1c. Responses to items in D1a-b: i. Yes / No, ii. If yes, how much does this bother you? Not at all / Somewhat / Moderately / Quite a bit D2. Secondary Outcome Measures Other endpoints include: D2a. Other bladder symptoms with or without incontinence, urinary tract infections (UTIs), urinary retention and serious adverse events (SAE) (e.g., mesh erosion) as these are anticipated to be in the opposite direction from the primary endpoints and may be indicative of a significant added risk due to the TVT. D2b. Pelvic Organ Prolapse-Q as described by Bump: the etent of the prolapse will be estimated using the POP-Q measurement scale. 20 D2c. Medical resource use based on a record of medications since the last visit (or for 6 months prior to the first) and dosages, new symptoms or complaints, life events, and intercurrent therapies for incontinence and other urinary symptoms, intercurrent complications from treatment, intercurrent therapies for complications. Medical resource use will include both direct and indirect costs. D2d. Quality of life measures: Health-related quality of life (HRQOL) data will be collected by centralized telephone interviews by the QOL Telephone Interviewing Center (part of the Data Coordinating Center, University of Michigan) in order to increase response rates, allow for more timely data collection and to allow data collection by a third party blinded to the study intervention. Even if unmasking occurred to research staff at the clinical site, the HRQOL centralized telephone interviewers would not be unblinded and the data would still be unbiased. Our prior work on the CARE study has had a 94% response rate with complete data at 2 years. 1 The quality of life instruments are: 1. Medical Outcome Study Short Form (SF-36) Version 2, a generic health-related quality of life measure Health Utility Measure: EuroQOL 5D (EQ-5D) 3. Pelvic Floor Distress Inventory (PFDI), a symptom inventory for pelvic floor disorders Pelvic Floor Impact Questionnaire (PFIQ), an assessment of how symptoms of pelvic floor disorders affect activities of daily living Sandvik-Hunskaar measure, a two item urinary incontinence severity instrument Pelvic Organ Prolapse/Urinary Incontinence Seual Functioning Questionnaire short form (PIS-Q) 26,27 7. PFDN Adaptations Inde Page 8 of 32

10 PFDN Protocol 15P01 03/15/2007 OPUS Analog Pain Scale (specifically for suprapubic pain) 9. Patient Global Impression of Improvement (PGI-I) Physical activity items from the International Physical Activity Scale. E. STUDY POPULATION Women presenting for evaluation and treatment of prolapse at one of the participating PFDN clinical centers with anterior vaginal prolapse and without overt stress incontinence as defined by an answer of No to all of the three PFDI Stress Urinary Incontinence questions (see D1a) may be screened for participation. Specific criteria include: Inclusion criteria: Vaginal bulge symptoms as indicated by an affirmative response to either questions 4 or 5 of the PFDI: o Do you usually have a sensation of bulging or protrusion from the vaginal area? o Do you usually have a bulge or something falling out that you can see or feel in the vaginal area? Anterior vaginal prolapse defined by POP-Q Point Aa -1 cm (i.e., -1,0,1,2, or 3 cm) Surgical plan that includes a vaginal approach for apical or anterior prolapse repair Able and willing to complete data collection per protocol, including written informed consent Eclusion criteria: Pregnancy or planning pregnancy in the first postoperative year Any prior mid urethral sling Currently participating in another interventional study for urinary incontinence Untreated urinary tract infection (may be included after resolution) Overt symptoms of stress urinary incontinence as defined by a positive response to any of the following 3 PFDI items: o Do you usually eperience urine leakage related to coughing, sneezing, or laughing? o Do you usually eperience urine leakage related to physical eercise such as walking, running, aerobics, or tennis? o Do you usually eperience urine leakage related to lifting or bending over? Currently being treated for stress urinary incontinence with pessary/incontinence ring, pelvic floor muscle eercise or medication (duloetine and imipramine, and alpha agonists). Current use of vaginal or systemic (oral, skin patch) estrogen is not an eclusion criterion. In some clinical practices, partial urinary retention, demonstrated by an elevated post-void residual (PVR), is a contraindication to an anti-incontinence procedure in women without prolapse. However, many women with pelvic organ prolapse have an elevated PVR that resolves after prolapse surgery. Because 1) there is no cut-point of PVR in women with prolapse that is associated with difficulty voiding post-operatively, 2) elevated PVRs in women with prolapse resolve in most cases after prolapse surgery and 3) the anti-incontinence procedure planned in this study (TVT ) is associated with a very low risk of urinary retention postoperatively in women without prolapse, we intentionally did not make elevated PVR an eclusion criterion for this study. The rationale for not ecluding urge urinary incontinence at baseline is that many women with prolapse have symptoms of urgency, frequency and urge incontinence and eclusion of them would limit the study s generalizability; furthermore, treatment with TVT has been shown to decrease pre-eisting urge incontinence in addition to preventing de novo SUI. Page 9 of 32

11 PFDN Protocol 15P01 03/15/2007 OPUS F. PATIENT RECRUITMENT All women presenting to network clinical centers with the complaint of pelvic organ prolapse will be screened (see study flow chart below) using standardized procedures and the 3 SUI items of PFDI for screening (see Eclusion Criteria above). Eligibility will be determined and eligible subjects will then be offered the opportunity to participate in the randomized clinical trial (RCT). Only those eligible subjects who decline to participate in the RCT may be offered participation in the Patient Preference Trial (PPT); i.e., the PPT will not be offered initially. The inclusion and eclusion criteria for the PPT are identical to the RCT; in addition, the subject will also have to have chosen one of the two treatment regimens that are in the RCT; i.e., in the preoperative period they cannot choose to have prophylactic treatment for SUI other than a TVT. There are separate consent forms for the RCT and the PPT. G. DATA COLLECTION There are 4 components to the data collection: a. Demographic data b. Medical history and physical eamination including POP-Q, post void residual and Cough Stress Test; the surgeon is blinded to result of the cough stress test c. Quality of life assessment d. Medical resource use related to any urinary or gynecologic condition Throughout the study, subject data may be collected by any of three methods: during an office visit by the research staff, during a telephone call by the research staff, and/or during a telephone interview by the Quality of Life Interviewing Center staff. Forms will be completed and tests will be performed at the times shown in the Timeline table in Section K9. This table represents the schedule of evaluations for a subject enrolled at the onset of the study through the end of the follow up period. G1. Baseline Visit: Study Screening, Initiation and Enrollment Study coordinators will screen eligible individuals. The POP-Q results and PFDI items (see D1a- D1b) will be collected as standard clinical practice prior to the referral. Study eligible patients will be approached to consent for the RCT, or for the PPT only after the RCT is declined. Following the consent process, demographics, medical history and medications will be collected by interview with the subject. Research staff will perform a physical eam that will include measurement of a catheterized PVR, a pregnancy test as clinically indicated, a urine dip to rule out infection, a POP-Q (if not done within past 2 months) and a cough stress test in the lithotomy position (prolapse unreduced and reduced) while the bladder is full or at 300 cc (whichever is smaller) and standing position. Findings from the baseline Cough Stress Test will remain blinded to the surgeon. All physical eaminations will be performed by appropriately trained research staff at the clinical site. Prior to surgery, a female interviewer at the QOL Interviewing Center who is masked to study treatment will contact the subject by phone and administer the quality of life measures listed in Section D2. In addition, the interview will include additional questions about demographics. The QOL Interviewing Center at the University of Michigan is under the supervision of Dr. Nancy Janz who has over 15 years eperience managing a central quality of life telephone interview facility and over 5 years eperience with the PFDN. After eligibility is ascertained and informed consent received, the data on the subject will be entered into a contact database through a password-protected website (using SSL) maintained by the DCC. Staff of the QOL Interviewing Page 10 of 32

12 PFDN Protocol 15P01 03/15/2007 OPUS Center will be able to access this database; however, it will be separate from the database containing research data from the trial and will not be accessible to staff of the DCC who analyze research data. The contact information will also include the projected date of surgery and later, the actual date. The central interviewing facility will use the contact information to phone the subject and schedule a time for the interview prior to the surgery. H. RANDOMIZATION AND MASKING Randomization will be stratified by surgeon (within clinical site) and by whether a colpocleisis procedure is planned (yes/no) and if not, whether an apical procedure is planned (yes/no) and whether an anterior repair is planned (yes/no). In order to ensure lack of bias both on the part of the surgeon and the subject, subjects will be randomized in the operating room. A member of the surgical team will open a sealed randomization envelope and inform the surgeon of the randomization. This approach avoids the possibility that knowledge of the randomization before surgery may affect the subject s decision to participate. This method of randomized treatment assignment also ensures easy access to randomization. The randomization number in the envelope is entered into the DCC website to inform the DCC which procedure was supposed to be performed. In addition, a short form and stamped return envelope are enclosed in the sealed envelope that contains the subject s research identifier. The short form is completed immediately after surgery by the study surgeon to indicate what procedures were performed and to eplain any deviations from protocol. The form is then mailed back to the DCC in the return envelope. Randomization will use a random block design. To reduce possible subject bias and ascertainment bias, subjects and research staff involved in collecting outcome data will be masked to group assignment until the 1-year follow-up. The rationale for masking the subject to group assignment is that the primary endpoint includes subjective reporting of symptoms or the desire for additional incontinence intervention that may be sensitive to the subject s knowledge of group assignment. Alternatively, there may be a significant placebo effect that would not be observed if we do not include masking. This masking will be accomplished with the following procedures: Although the dictated operative note will describe the operation(s) as performed, in the handwritten operative note in the subject s hospital chart, the procedure will be indicated as "[name of transvaginal procedure] as per the OPUS trial protocol (see the dictated operative note)." A sham incision will be used in the control arm is to mask the subject with regards to the TVT procedure (performed or not). Masking will consist of 2 small sub centimeter sham partial thickness skin incisions in the suprapubic region in the control arm to mimic TVT incisions. As much as possible, these will be covered by Steri-strips for the first week. Subcuticular sutures to close the skin will not be used for skin closure in the TVT arm to mimic the control group incision. The procedure on the surgical consent form (not the research consent form) will be listed as [name of transvaginal procedure], cystoscopy, and possible TVT. Other procedures will be listed as appropriate. Page 11 of 32

13 PFDN Protocol 15P01 03/15/2007 OPUS The study surgeon (not the research coordinator or other research staff who will be completing postoperative data collection) will complete the intraoperative portion of the Hospitalization Form and seal it in an envelope that is mailed to the Data Coordinating Center. (This procedure worked successfully in the CARE trial.) I. SURGICAL INTERVENTIONS Based upon medical history and physical eamination, the subject will be classified by type of prolapse and severity based on the POP-Q method. 20 The types of pelvic prolapse include: a. Anterior vaginal prolapse (required for study inclusion): Anterior repair plus randomization to TVT or no TVT ; or an apical procedure that corrects the anterior vaginal prolapse plus randomization to TVT or no TVT. b. Any or no concurrent posterior vaginal prolapse c. Any or no concurrent apical prolapse (vaginal vault prolapse) d. Any or no concurrent uterine prolapse. Surgical techniques The surgical technique for the TVT will be standardized. The allowable anterior vaginal prolapse repairs are noted below. Additional prolapse procedures (apical or posterior or colpocleisis) will be carefully recorded but not controlled by the protocol. Tension-free Vaginal Tape (TVT ) See appendi 1. The protocol committee etensively debated the merits of the various mid urethral slings that are currently available. We had narrowed the choices to the TVT and Trans Obturator Tape (TOT). The first decision was to select the TVT over TOT. This choice was grounded on the strength of clinical evidence. TVT has the longest duration of followup published in the literature, with the best description of potential adverse events. There has also been a small randomized trial that eamined the issue of surgical incontinence prophylais at the time of vaginal prolapse surgery 3 that is used as preliminary evidence and justification for the current trial. No comparable study has been published for TOT. In addition, there is much less information available on TOT as detailed below. The protocol committee also debated whether or not to allow both the TOT and TVT as the study interventions. We ultimately decided against this for the following reasons. First, TVT is the mid urethral sling procedure with the most evidence. The rapid dissemination of TOT has been industry-sponsored and marketing-driven rather than evidence-based. The data on TOT consist primarily of case reports and case series, while longer term outcomes and reports on adverse effects were not published in the peer reviewed literature at the time the study protocol was finalized. The only adequately powered, level I evidence using either TVT or TOT in incontinent women is comparing TVT to traditional continence procedures. 29,30 Given the lack of evidence available for TOT as a treatment, we decided against using it in a large trial for prophylais. Historically, many surgical interventions have not stood the test of time (e.g., vaginal wall slings, Protegen slings) once longer term data on efficacy or complications were reported. Moreover, the proposed mechanism for TOT in preventing urinary incontinence is comparable to TVT, at least as suggested by various makers of the TOT products. Net, the incremental sample size that would be required to allow us to make clinically relevant comparisons between TVT and TOT in a 3-arm trial would be ecessive and does not improve our ability to address the primary hypotheses. Lastly, the TOMUS trial, which is currently underway by the NIH-funded Urinary Incontinence Treatment Network (UITN), is designed and Page 12 of 32

14 PFDN Protocol 15P01 03/15/2007 OPUS powered to compare TVT and TOT procedures with regards to effectiveness and adverse events. Though TOMUS is a therapeutic rather than prophylactic trial, the mechanisms for improving continence and adverse effects may not differ by study population, making it possible to etrapolate the better procedure from the TOMUS trial once it has been completed. Each participating surgeon must have personally performed at least 20 TVT cases prior to enrolling subjects in this trial. Anterior vaginal surgery All anterior vaginal surgery will be performed from an incision separate from the TVT incision and above (that is, moving toward the vaginal ape) the urethrovesical junction, which is defined as the most caudal portion of the anterior vagina where a urethral Foley balloon can be palpated. For the purpose of this study, any anterior vaginal repair may be performed as clinically indicated and recorded on the appropriate form; however, the anterior incision must be above (that is, moving toward the vaginal ape) the level of the urethrovesical junction. Neither a Kelly plication nor fibromuscular plication of peri-urethral tissue of any type may be performed in either arm of the study. Periurethral sutures outside of TVT procedure is not permitted as this may confound the incontinence endpoint (theoretically, such sutures could decrease SUI by supporting the urethra or increase SUI by disrupting nerves to the urethral sphincter). Any eceptions to this must be reported as a protocol deviation (e.g., suture needed for acute operative bleeding). Allowable techniques of anterior vaginal surgery include: Plication of vesicovaginal fibromuscular tissue (pubocervical fascia) Vaginal paravaginal repairs with suture technique requiring careful description of details including suture location and type. The prolapse repair may include colpocleisis; or use of allograft, enograft, or synthetic graft material in the anterior vagina; or use of allograft, enograft, or synthetic graft material at the vaginal ape. Sham incisions (control arm only) The sham incisions should consist of partial thickness skin abrasions rendered using the back point of the scalpel. They are to be located and sized to be identical to the 2 subcentimeter TVT suprapubic incisions. All incisions (sham and real) will be covered by a Steri-strip for one week unless there is a clinical reason for removal (e.g., suspicion of a postoperative incision-related bleeding or infection). Bladder drainage Postoperatively, the bladder will be drained with an indwelling Foley catheter and a voiding trial should take place on postop day 1, unless clinically contraindicated. Page 13 of 32

15 PFDN Protocol 15P01 03/15/2007 OPUS J. ADVERSE EVENT REPORTING Subjects will be asked to report any adverse events post-surgery immediately to the study coordinator or physician, including but not limited to: voiding dysfunction, need for catheter use, urinary tract pain, bleeding, fever, or cystitis. All adverse events will be reported on a standardized form that will elicit the number and specify the type of tests used, therapy (or therapies) used, and clinical visits (office, ER and hospitalization) required until the event is resolved. Serious adverse events will be promptly reported to the clinical center IRB, the data coordinating center, the NICHD Project Scientist and the PFDN Data and Safety Monitoring Board. Serious adverse events are defined as any untoward medical occurrence that (1) results in death, (2) is life-threatening, (3) requires inpatient hospitalization (with the eception of hospitalization for stress incontinence surgery) or (4) prolongation of eisting hospitalization, (5) results in persistent or significant disability or incapacity, (6) is a congenital anomaly/birth defect, or (7) is another medically important condition. Hospitalization for stress incontinence surgery is not considered a serious adverse event in order to avoid double-counting because it is already captured as part of the primary outcome (i.e., treatment or re-treatment for stress incontinence). K. FOLLOW-UP EVALUATIONS At each visit or call described below, the study coordinator will interview the subject to obtain a directed medical history that includes all contacts with the health care system to identify adverse events related to urological and gynecologic complaints and to identify complications from treatment, including the inde surgery. In addition, the subject will be queried about her use of catheterization, use of medications and any treatment for urinary incontinence. When serious adverse events are identified whether related to treatment or not, they are entered into the secure database in an epedited manner. K1. Post-Op Voiding Trial On postoperative day 1, the subject should receive a voiding trial. A successful voiding trial is defined as having a PVR 150cc (combined with a minimum void of at least 150cc) documented by either an ultrasound PVR measurement, a catheterized residual or the calculated difference between volume instilled and voided. If the subject does not void satisfactorily, catheterization will continue per standard of care at the clinical site with PVRs checked at least twice a week and recorded until a successful voiding trial has been demonstrated; voiding status and time to spontaneous voiding will be documented. K2. 2 Weeks Post-Op At 2 weeks post op (+/-3 days), the study coordinator will interview the subject either by phone or in person during the subject s postoperative visit. If the subject reports urinary retention, PVRs will be checked at least twice a week and recorded until a successful voiding trial is demonstrated. K Weeks Post-Op At 4-6 weeks post op, the study coordinator will interview the subject during the subject s postoperative visit. This will capture all events up to the visit such as early urinary retention, need for intermittent self catheterization or continued catheterization. A PVR will be checked and the urine will also be screened by dipstick for evidence of infection. If the PVR is > 150 cc, PVRs will be checked at least twice a week and recorded until a successful voiding trial is demonstrated. Page 14 of 32

16 PFDN Protocol 15P01 03/15/2007 OPUS K4. 3 Months Post-Op Post-op follow-ups (both telephone and office) occur at 3 months (±14 days) after the inde surgery. Telephone QOL interview: At the 3-month (±14 days) post-surgery, the Quality of Life Interview Center will contact the subject by phone and administer the quality of life measures listed in Section D2. Office visit: At the office visit, an updated, directed medical history will be obtained. In addition, a physical eamination, including cough stress test, POPQ eam, urine dipstick and PVR (by ultrasound or catheter), will be conducted. K5. 6 Months Post-Op Telephone Interview Telephone interview: At 6 months post-surgery (±14 days), the Quality of Life Interview Center will contact the subject by phone and administer the quality of life measures listed in Section D2. Coordinator interview: At 6-month (±14 days) post-surgery, the Study Coordinator will interview the subject either by phone or in person during a clinic visit to obtain an updated, directed medical history. K6. 9 Months Post-Op Telephone Interview Coordinator interview: At 9 months (±14 days) post-surgery, the Study Coordinator will interview the subject either by phone or in person during a clinic visit to obtain an updated, directed medical history. K7. 12 Months Post-Op The post-op follow-ups (both telephone and office) occur at 12 months (±14 days) after the inde surgery. Telephone QOL interview: At 12 months (±14 days) post-surgery, the Quality of Life Interview Center will contact the subject by phone and administer the quality of life measures listed in Section D2. Office visit: At the office visit, an updated, directed medical history will be obtained. In addition, a physical eamination including cough stress test, POPQ eam, urine dipstick and PVR (by ultrasound or catheter) will be conducted. K8. Additional Treatment for Urinary Incontinence If a subject has failed symptomatically by reporting bothersome urinary incontinence (defined in section E1), additional treatment for either stress or urge incontinence will be offered. This will consist of appropriate procedures as clinically indicated for all subjects (e.g., urethral bulking injections) and may include a TVT for women who did not receive a concomitant TVT at the inde surgery. Additional treatment is defined as: - any subsequent surgical procedure for treatment of urinary incontinence; and/or - injection of urethral bulking agents; and/or - pelvic floor muscle therapy (PFMT); and/or - formal bladder training; and/or - medication(s); and/or - pessary, if used for treating urinary incontinence. Page 15 of 32