Apical Suspension Repair for Vault Prolapse In a Three-Arm Randomized Trial Design

Study Overview
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Brief Summary
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The study is a multi-center, randomized, surgical trial of women with symptomatic post-hysterectomy apical (cuff) prolapse desiring surgical treatment. This study will compare the three available surgical treatments performed in usual practice. The purpose of this study is to compare two commonly performed mesh apical repair (sacral colpopexy vs. Apical Transvaginal Mesh) and vaginal native tissue apical repairs with mesh reinforced repairs. The primary outcome is measured over time (up to 60 months) using a survival analysis approach. The investigators hypothesize that treatment failure will not differ between vaginally and abdominally placed mesh for vault vaginal prolapse, and mesh repairs (regardless of route of implantation) will be superior to native tissue apical suspension.

Detailed Description
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The primary purpose of this three arm randomized clinical trial is to determine if apical transvaginal mesh placement is non-inferior to sacral colpopexy for anatomic correction of post-hysterectomy vaginal vault prolapse and to determine if mesh reinforced repairs performed by abdominal or vaginal approach are superior to native tissue vaginal repair. This trial has the following primary aims: 1. To determine if Apical Transvaginal Mesh is non-inferior to Sacral Colpopexy for anatomic correction of post-hysterectomy vaginal vault prolapse at time points through 3 years. 1A. In the case where Apical Transvaginal Mesh is shown to be statistically significantly non-inferior to Sacral Colpopexy for anatomic correction of post-hysterectomy vaginal vault prolapse at time points through 3 years, to determine if Apical Transvaginal Mesh is superior to Sacral Colpopexy for anatomic correction of post-hysterectomy vaginal vault prolapse at time points through 3 years. 2. To determine if Sacral Colpopexy is superior to Native Tissue Repair for anatomic correction of post-hysterectomy vaginal vault prolapse at time points through 3 years. 3. To determine if Apical Transvaginal Mesh is superior to Native Tissue Repair for anatomic correction of post-hysterectomy vaginal vault prolapse at time points through 3 years. Additional secondary aims include: Evaluate the development of a valid and reliable Global Composite Outcome that balances adverse events and patient-centered outcomes to anatomic definitions of failure and success. Determine the impact of preoperative frailty and mobility on surgical treatment outcomes and postoperative complications of older women following surgical correction of apical pelvic organ prolapse. Evaluate the patient's perspective about adverse events and their role in patient decision-making outcomes. The aims include comparing patient versus surgeon rankings of complication grade, outcome, expectedness and seriousness, to estimate the association between patient rankings of adverse events (AEs) with decision-making and quality of life outcomes and to determine if their perspective about AEs changes over time.

Official Title
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Three Arm Apical Suspension Trial for Post-Hysterectomy Vault Prolapse: Prospective Randomized Trial Involving Sacral Colpopexy, Transvaginal Mesh and Native Tissue Apical Repair

Conditions
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Visceral Prolapse

Intervention / Treatment
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* Procedure: Open, Robotic, or Laparoscopic
* Procedure: Transvaginal Native Tissue Repair
* Procedure: Uphold™ LITE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women age 21 or older Prior total hysterectomy (no cervix present) Prolapse beyond the hymen (defined as Ba, C, or Bp > 0 cm) Vaginal cuff descent into at least the lower two thirds of the vagina (defined as point C> -2/3 TVL) Bothersome bulge symptoms as indicated on question 3 of the PFDI-20 form relating to 'sensation of bulging' or 'something falling out' Desires surgical treatment for post-hysterectomy vaginal prolapse Available for up to 60 month follow-up Exclusion Criteria: Previous synthetic material or biologic grafts (placed vaginally or abdominally) to augment POP repair including anterior, posterior and/or apical compartments Known previous formal SSLS performed for either uterovaginal or post-hysterectomy vaginal vault prolapse * Known adverse reaction to synthetic mesh or biological grafts; these complications include but are not limited to erosion, fistula, or abscess Unresolved chronic pelvic pain-active Prior abdominal or pelvic radiation Contraindication to any of the index surgical procedures Known Horseshoe Kidney or Pelvic Mass overlying the sacrum Active diverticular abscess or active diverticulitis Shortened vaginal length (<6 cm TVL) NOTE: Only documented SSLS will be an exclusion. Mesh used for only mid-urethral sling will NOT be an exclusion If prior POP repair is unknown and unable to be documented, subjects will be eligible based on clinician judgment. The investigator will examine and assess for evidence of mesh or graft if no evidence of mesh or graft is present on examination subject remains eligible.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sacral Colpopexy<br>Sacral Colpopexy performed via open, robotic, or laparoscopic procedure. | Procedure: Open, Robotic, or Laparoscopic<br>* Sacral Colpopexy is a surgery performed either through an incision in the abdomen or through several small incisions with the help of a laparoscope (a slender tube) or robot. The surgery is done with a permanent synthetic (man-made) mesh. The mesh is sutured (stitched) to the vagina and sacrum (tail bone) and is used as reinforcement. It provides additional support to weakened tissues and/or muscles.<br>|
| Active Comparator: Transvaginal Native Tissue Repair<br>Transvaginal Native Tissue Repair: Sacrospinous Ligament Suspension (SSLS) and Uterosacral Ligament Suspension (USLS) | Procedure: Transvaginal Native Tissue Repair<br>* Transvaginal Native Tissue Repair is a surgery performed with an incision through the vagina (transvaginal). The surgery is done using both permanent and absorbable sutures (stitches), to support weakened tissue and/or muscles, and attach the top of the vagina to ligaments in the pelvis (either to the sacrospinous ligament or uterosacral ligament).<br>|
| Active Comparator: Apical Transvaginal Mesh Repair<br>Uphold™ LITE | Procedure: Uphold™ LITE<br>* Transvaginal Mesh Repair is a surgery performed with an incision through the vagina (transvaginal). The surgery is done with a permanent synthetic (man-made) mesh. The mesh is attached to ligaments in the pelvis and is used to reinforce natural tissue and/or muscles, which are no longer able to provide support to the vagina.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical Treatment Success | Treatment success is the primary outcome and treatment success is defined as: Absence of bothersome bulge symptoms Absence of retreatment No prolapse past the hymen (points Ba, C, and Bp <=0 cm) | Up to 60 months using a survival treatment analysis approach | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictors of treatment failure, with treatment failure being a binary outcome as defined for the Primary Outcome | Identify risk factors for treatment failure including method of vault suspension, baseline degree of prolapse, age, obesity, smoking, menopausal status, estrogen use, and previous prolapse surgery. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Effect of treatment on how a woman feels (her perceptions and attitudes) about her body (Body Image) as measured by the mean score for each treatment group on the body image scale. | Describe changes in body image as measured by a validated scale (BIS) in a group of women undergoing apical repair with and without mesh and to evaluate whether or not changes in sexual function are associated with changes in body image. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Cost of surgical procedures as measured by mean direct and indirect costs for participants in each treatment group. | Data on each participant's use of medical and non-medical resources related to urologic or gynecologic conditions will be collected during the follow up period. Direct and indirect costs of the treatment of apical pelvic organ prolapse (POP) with sacral colpopexy, Native Tissue surgical repair or Transvaginal Mesh Repair and women's preference for health states for improvement in POP will be estimated. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Treatment arm mean levels of anatomic: Pelvic Organ Prolapse Quantification (POPQ) System values (Aa, Ap, Ba, Bp, C) determined from anatomic measures. | Mean levels in of anatomic measures of key pelvic floor metrics (Aa, Ap, Ba, Bp, C) obtained from the POPQ exam. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Proportion of participants in each treatment group with POPQ levels of C > -2/3 TVL | Obtained by comparing the cervical or cuff location (Point C) to the total vaginal length (TVL) from the POPQ exam obtained at 6-month post-operative intervals. A participant will be defined as positive at any time point if C > -2/3 total vaginal length (TVL). | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Mean levels in each treatment group of maximum extent of prolapse (Defined as leading edge of prolapse-Ba, C, Bp). | Measures maximum extent of prolapse (defined as leading edge of prolapse - Ba, C, or Bp as measured by the POPQ). | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Proportion of patients within each treatment group with adequate prolapse improvement as measured by Patients Global Impression of Improvement (PGI-I) | The PGI-I is a single question form collected every 6 months that asks for a response to the question: Check the number that best describes how your post-operative condition is now, compared with how it was before you had the surgery. The response is a 7-level Likert scale from 1 Very much better to 7 Very much worse. Adequate prolapse improve is defined as a participant response of either 1 (very much better), 2 (much better), and 3 (better). | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Mean overall prolapse symptoms using Pelvic Organ Prolapse Distress Inventory (POPDI-6) scores (sub-scale of PFDI-20) | The Pelvic Floor Distress Inventory is a 20-question, validated, self-reported instrument used to evaluate pelvic floor symptoms. It consists of an overall scale (range: 0-300) comprised of 3 sub-scales: 1. Pelvic Organ Prolapse Distress Inventory (range: 0-100), 2. Colorectal Anal Distress Inventory (range: 0-100), and 3. Urinary Distress Inventory (range: 0-100). The range of responses on the CRADI is 1-4 with (1) Not at all, (2) Somewhat, (3) Moderately, and (4), Quite a bit. Scores are calculated by multiplying the mean value of all questions answered by 25 for the scale. The range of responses is: 0-100 with 0 (least distress) to 100 (most distress). Lower scores indicate better function / fewer symptoms. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Length of urinary complications after surgery as measured by duration of postoperative catheterization | Measures time to removal of the catheter post-operatively. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Postoperative urinary success as measured by mean Urogenital Distress Inventory (UDI-6) scores (sub-scale of PFDI-20) | The Pelvic Floor Distress Inventory is a 20-question, validated, self-reported instrument used to evaluate pelvic floor symptoms. It consists of an overall scale (range: 0-300) comprised of 3 sub-scales: 1. Pelvic Organ Prolapse Distress Inventory (range: 0-100), 2. Colorectal Anal Distress Inventory (range: 0-100), and 3. Urinary Distress Inventory (range: 0-100). The range of responses on the CRADI is 1-4 with (1) Not at all, (2) Somewhat, (3) Moderately, and (4), Quite a bit. Scores are calculated by multiplying the mean value of all questions answered by 25 for the scale. The range of responses is: 0-100 with 0 (least distress) to 100 (most distress). Lower scores indicate better function / fewer symptoms. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Urinary dysfunction as measured by proportion of participants in each group with de novo voiding dysfunction. | Measures risk of de novo voiding dysfunction at 6-month post-operative intervals. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Urinary incontinence as measured by proportion of participants in each group with stress, urge, or mixed incontinence | Measures risk of de novo incontinence at 6-month post-operative intervals for stress, urge, and mixed incontinence. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Quality of sexual/body image after surgery as measured by mean Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) and Body Image in the Pelvic Organ Prolapse Questionnaire (BIPOP) scales in each treatment group | Mean BIPOP and PISQ-IR scores in each treatment group. The BIPOP is scored from 1 to 5, with higher scores indicating worse body image. The PISQ-IR is a 31-item questionnaire where higher scores reflect better sexual functioning. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Quality of sexual/body image after surgery as measured by of proportion of participants in each treatment group with de novo dyspareunia | Defined as an event of dyspareunia as listed on adverse event form. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Bowel function measured as the Colorectal-anal Distress Inventory (CRADI-8) scores (sub-scale of PFDI-20) in each treatment group | The Pelvic Floor Distress Inventory is a 20-question, validated, self-reported instrument used to evaluate pelvic floor symptoms. It consists of an overall scale (range: 0-300) comprised of 3 sub-scales: 1. Pelvic Organ Prolapse Distress Inventory (range: 0-100), 2. Colorectal Anal Distress Inventory (range: 0-100), and 3. Urinary Distress Inventory (range: 0-100). The range of responses on the CRADI is 1-4 with (1) Not at all, (2) Somewhat, (3) Moderately, and (4), Quite a bit. Scores are calculated by multiplying the mean value of all questions answered by 25 for the scale. The range of responses is: 0-100 with 0 (least distress) to 100 (most distress). Lower scores indicate better function / fewer symptoms. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| General quality of life as measured by mean quality of life scales in each treatment group on 4 Short-Form Health Survey Support Loss (SF-12) total scores and physical function and mental function sub-scales | Physical component summary scale (PCS-12) will be computed at 6 month post-operative intervals using standard algorithms from the SF-12 developer. Mental component summary scale (MCS-12) will be computed at 6 month post-operative intervals using standard algorithms from the SF-12 developer. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Pelvic QOL as measured by mean Pelvic Floor Impact Questionnaires (PFIQ) score in each treatment arm | The Pelvic Floor Impact Questionnaire short form (PFIQ-7) measuring the impact of bladder, bowel, and vaginal symptoms on a woman''s daily activities, relationships and emotions is composed of 3 scales of 7 questions each: the Urinary Impact Questionnaire (UIQ; range 0-100), the Pelvic Organ Prolapse Impact Questionnaire (POPIQ; range 0-100), and the Colorectal-Anal Impact Questionnaire (CRAIQ; range 0-100). The range of responses on the CRAIQ is 0-3 with (0) Not at all, (1) Somewhat, (2) Moderately, and (3), Quite a bit. Scores are calculated by multiplying the mean value of all answered questions for a scale by 100 divided by 3. The range of responses is: 0-100 with 0 (least negative impact) to 100 (most negative impact). Change = (Month [12, 24, 36] Score - Baseline Score). Lower scores indicate better function / fewer symptoms. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Level of function as measure by mean Functional Activity Scale score for each treatment group | The Activities Assessment Scale (AAS) score will be computed at 6 month post-operative intervals using standard scoring algorithms described by McCarthy (2005) to create a measure scaled 0 to 100 at each time point. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Patient Regret/Satisfaction after surgery as measured by mean scores in each treatment group of Regret with Decision Regret Scale (DRS-PFD), and Satisfaction with Decision Scale (SDS-PFD) | The Decision Regret Scale (DRS) measures regret after health care decision. It is a 5-item measure and the answers range from strongly agree to strongly disagree on a five point Likert scale. Scores on DRS range from 0 to 100, were higher score indicate more regret after health care decision. Satisfaction with Decision scale (SDS) is a 6-item scale measuring satisfaction with health care decisions, The scale uses a 1-5 rating (1=strongly disagree; 5 = strongly agree). Scores from these 6 items were linearly transformed to a 0-100 scale. A higher score reflects a higher level of satisfaction with the decision. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Interoperative blood loss in each treatment group. | Measured by mean estimated blood loss in each treatment group and proportion of participants in each treatment group with a blood transfusion. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Extent of interoperative complications in each treatment group. | Extent of interoperative complications is measured by Dindo complication scale. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Interoperative safety in each treatment group. | Measured as the proportion of participants in each arm with listed operative complications | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Risk of mesh-related complications in each treatment group. | Measured as the proportion of participants in each treatment group with mesh exposure in the vagina or mesh erosion into another organ and the classification of the intervention. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Risk of surgical pain in each treatment group. | Measured as proportion of participants with pain captured from the modified Surgical Pain Scale, pain medication use, and location of pain with Body Part Pain Score. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Risk of post-surgical complications in each treatment group | Measured as the proportion of participants in each treatment group with de novo vaginal bleeding, atypical vaginal discharge, fistula formation, or neuromuscular problems (including groin, buttock and leg pain). | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Risk of need for additional treatment/subsequent procedures for pelvic floor disorders. | Measured as the proportion of participants on each treatment arm with the need for subsequent procedures- any surgical or non-surgical treatment for pelvic floor disorders. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Risk of vaginal scarring requiring medical or surgical intervention in each treatment group. | Measured as the proportion of participants in each treatment group with de novo scar requiring medical or surgical intervention. | Baseline, 6, 12, 24, 36, 48, and 60 months | 
| Rates of vaginal shortening (TVL<6cm), de novo dyspareunia, or worsening dyspareunia. | Defined as an event of vaginal shortening, de novo dyspareunia, or worsening dyspareunia as listed on adverse event forms. | Baseline, 6, 12, 24, 36, 48, and 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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POP, pelvic organ prolapse, vault prolapse, cystocele, vaginal prolapse, post-hysterectomy vaginal prolapse