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| General |
| Study Status |
Completed |
| 522 Number / Requirement Number |
PS120106 / PSS001 |
| Date Original Plan Accepted |
05/17/2013
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| Date Current Plan Accepted |
05/25/2018
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| Study Name |
POP AE and Effectiveness rates, registry
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| Device Name |
Restorelle polypropylene mesh
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| Root Document Number |
K092207
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| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
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| Data Source |
External Registry
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| Comparison Group |
Concurrent Control
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| Analysis Type |
Analytical
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| Study Population |
Transit. Adolescent B (as adults) : 18-21 yrs,
Adult: >21
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| Detailed Study Protocol Parameters |
| Study Objectives |
This is a prospective, multi-center, cohort study comparing Restorelle mesh to native tissue repair in the treatment of pelvic organ prolapse.
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| Study Population |
The study population will consist of adult female subjects with with pelvic organ prolapse that are clinically indicated for surgical intervention for pelvic floor reconstruction.
Native tissue repair subjects will be drawn from a pool of shared controls, of which Coloplast will contribute a specified number of subjects. The exact number of subjects will be determined by the number of control subjects required for each company participating in the AUGS registry and the expected proportion of subject in each treatment combination.
In order to maintain study power and minimize subject loss in the control group, Coloplast defines eligible control subjects as follows:
• All native tissue repair subjects enrolled into the Coloplast Restorelle study
• Control subjects enrolled into another sponsor’s studies who met the Restorelle 522 inclusion and exclusion criteria
• In the event there are more than 223 subjects available in the control arm for either cohort (the Coloplast Restorelle study or other sponsor’s studies): All eligible control subjects enrolled in the Coloplast Restorelle study will be utilized
• SAS will be utilized to select a random sample of eligible subjects from the non-Coloplast Restorelle study to increase the control group size to 223.
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| Sample Size |
892 subjects (223 patients treated with Restorelle Direct Fix A Transvaginal Mesh, 223 patients treated with Restorelle Direct Fix P Transvaginal Mesh and 446 patients treated with Native Tissue Repair) will be enrolled at up to 60 study centers
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| Key Study Endpoints |
"Primary Effectiveness Endpoint: Recurrent prolapse at 12 months; Primary Safety Endpoint: The primary safety endpoint is defined as device and/or procedure-related serious adverse events (SAEs) at 12-months as determined by the Clinical Events Committee. Secondary Safety Endpoints:
Each of the following set of device or procedure related AEs at 36 months (mesh erosion into another organ, neuromuscular problems (including groin and leg pain), pelvic pain, mesh exposure in the vagina, infection (by type), stress urinary incontinence, urge incontinence, difficulty emptying bladder, de novo dyspareunia); Additional Endpoints: 1. All other AEs; 2. Primary and secondary safety endpoints stratified by compartment; 3. Primary and secondary safety endpoints listed by severity; 4. Primary and secondary effectiveness outcomes stratified by compartment; 5. Primary and secondary safety endpoints stratified by subjects requiring and not requiring re-surgery after the initial transvaginal pelvic organ prolapse surgery overall, and stratified by compartment; 6. Quality of life score differences from baseline overall, and stratified by compartment; 7. Quality of life score improvement from baseline for subjects requiring re-surgery following the index procedure overall, and stratified by compartment; 8. Quality of life score improvement from baseline for subjects with similar conditions with and without surgical intervention (e.g. pessary); 9. Prolapse at or beyond the hymenal ring just prior to mesh removal surgery among those who have and have not had all or part of their mesh removed post-operatively; 10. Bulge for each vaginal compartment in which mesh is placed; 11. Revision and/or re-surgery."
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| Follow-up Visits and Length of Follow-up |
The length of study follow-up is 3 years. Follow-up will be conducted at 2 months, 6 months, 12 months, 18 months, 24 months and 36 months.
Enrollment is expected to take approximately 4 years to complete and subjects will be followed for 36 months. It is expected the study will take approximately 7 years to complete from first subject enrollment to final clinical study report.
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
810 total subjects; 455 subjects in the mesh arms [231 anterior-apical (AA), 163 posterior-apical (PA), 61 total repair (TR)]; 355 subjects in the native tissue repair (NTR) arms (132 AA, 76 PA, 147 TR). An additional 59 NTR subjects were pulled from the AUGS PFD registry: 0 included in AA (sufficient sample size), 10 included in PA, 49 included in TR
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| Actual Number of Sites Enrolled |
49
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| Patient Followup Rate |
12 months:
89.0% (721/810) Overall, 93.4% (425/455) mesh, 91.0% (296/355) NTR
AA: 92.2% (213/231) mesh, 97.7% (129/132) NTR
PA: 93.9% (153/163) mesh, 97.4% (74/76) NTR
TR: 96.7% (59/61) mesh, 93.9% (120/147) NTR
24 months:
80.1% (649/810) Overall, 84.6% (385/455) mesh, 89.0% (316/355) NTR
AA: 85.3% (197/231) mesh, 93.2% (123/132) NTR
PA: 81.0% (132/163) mesh, 82.9% (63/76) NTR
TR: 91.8% (56/61) mesh, 88.4% (130/147) NTR
36 months:
80.1% (649/810) Overall, 77.6% (353/455) mesh, 83.4% (296/355) NTR
AA: 77.5% (179/231) mesh, 87.9% (116/132) NTR
PA: 74.8% (122/163) mesh, 78.9% (60/76) NTR
TR: 85.2% (52/61) mesh, 81.6% (120/147) NTR
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| Final Safety Findings |
Primary endpoint: The following rates of device and/or procedure-related SAEs in the target compartment at 12 months were reported in the population of all enrolled subjects where a study treatment was performed. Missing data were imputed.
AA: 1.7% (4/231) mesh, 0% (0/132) NTR
PA: 1.2% (2/163) mesh, 1.3% (1/76) NTR
TR: 1.6% (1/61) mesh, 0.7% (1/147) NTR
Non-inferiority of mesh vs. NTR for safety was established. The use of mesh for treatment of anterior-apical, posterior-apical, and total vaginal prolapse was as safe as NTR with respect to the overall rate of SAEs at 12 months. While the two groups had a comparable overall rate of SAEs, the types of SAEs differed between groups.
Secondary endpoint: Device and/or procedure-related AEs of interest of any severity at 36 months.
• Mesh erosion into another organ (perforation of mesh into a hollow organ or viscus)
o No reports
• Neuromuscular problems
o AA: 1.0% (2/197) mesh, 1.6% (2/123) NTR
o PA no reports
o TR: 1.8% (1/56) mesh, 0.8% (1/133) NTR
• Pelvic pain
o AA: 2.0% (4/198) mesh, 3.3% (4/123) NTR
o PA: 2.8% (4/141) mesh, 1.5% (1/65) NTR
o TR: 0.0% (0/56) mesh, 3.8% (5/133) NTR
• Mesh exposure in the vagina (the observation or feeling of mesh through the vaginal wall)
o AA: 5.6% (11/197)
o PA: 3.5% (5/142)
o TR: 3.6% (2/56)
• Infection
o Urinary tract infection
AA: 9.5% (19/199) mesh, 8.7% (11/126) NTR
PA: 5.7% (8/141) mesh, 7.7% (5/65) NTR
TR: 7.1% (4/56) mesh, 2.3% (3/133) NTR
Perioperative infection
AA: 2.0% (4/197) mesh, 1.6% (2/124) NTR
PA: 1.4% (2/141) mesh, 0.0% (0/64) NTR
TR: no reports
o Vaginal infection
AA: 0.5% (1/198) mesh, 0.8% (1/123) NTR
PA: 1.4% (2/141) mesh, 1.6% (1/64) NTR
TR: 1.8% (1/56) mesh, 3.0% (4/133) NTR
• Stress urinary incontinence (worsening or de novo)
o AA: 9.6% (19/198) mesh, 3.3% (4/123) NTR
o PA: 0.7% (1/141) mesh, 0.0% (0/64) NTR
o TR: 3.6% (2/56) mesh, 1.5% (2/133) NTR
• Urge incontinence (worsening or de novo)
o AA: 2.5% (5/198) mesh, 4.0% (5/124) NTR
o PA: 0.7% (1/141) mesh, 3.1% (2/64) NTR
o TR: 0.0% (0/56) mesh, 0.8% (1/133) NTR
• Difficulty emptying bladder (worsening or de novo)
o AA: 11.0% (22/200) mesh, 4.9% (6/123) NTR
o PA: 1.4% (2/142) mesh, 13.8% (9/65) NTR
o TR: 3.6% (2/56) mesh, 5.2% (7/134) NTR
• De novo dyspareunia
o AA: 2.0% (4/197) mesh, 0.8% (1/123) NTR
o PA: 2.8% (4/142) mesh, 3.1% (2/64) NTR
o TR: 0.0% (0/56) mesh, 3.0% (4/133) NTR
• Vaginal shortening
o No reports
• Vaginal scarring
o No Reports
• Vaginal bleeding, de novo
o AA: 0.5% (1/197) mesh, 0% (0/123) NTR
o PA: 1.4% (2/141) mesh, 1.6% (1/64) NTR
o TR: No reports
• Fistula formation
o No reports
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| Final Effectiveness Findings |
Primary endpoint: The following rates of recurrent prolapse defined anatomically as prolapse of the target compartment beyond the hymenal ring, or subjectively as perception of protrusion or bulge of target compartment, or as retreatment (including the introduction of a pessary after index procedure) of pelvic organ prolapse in the target compartment at 12 months were reported in the population of all enrolled subjects where a study treatment was performed. Missing data were imputed.
AA: 11.3% (26/231) mesh, 10.6% (14/132) NTR
PA: 11.7% (19/162) mesh, 13.2% (10/76) NTR
TR: 20.3% (12/59) mesh, 12.2% (18/147) NTR
Superiority of mesh was not established for any of the subgroups analyzed. As the primary effectiveness endpoint was not achieved, the overall study success criteria were not met.
Secondary endpoints:
1. recurrent prolapse using the composite endpoint as defined in the primary endpoint with an alternative definition of anatomical prolapse as at or beyond the hymenal ring at 12 months
• AA: 19.5% (45/231) mesh, 21.2% (28/132) NTR
• PA: 16.0% (26/162) mesh, 18.4% (14/76) NTR
• TR: 30.5% (18/59) mesh, 25.9% (38/147) NTR
2. recurrent prolapse, as defined in the primary endpoint, at 36 months
• AA: 26.2% (60/229) mesh, 29.8% (39/131) NTR
• PA: 18.0% (29/161) mesh, 27.0% (20/74) NTR
• TR: 28.8% (17/59) mesh, 24.5% (36/147) NTR
3. recurrent prolapse using the composite endpoint as defined in the primary endpoint with an alternative definition of anatomical prolapse as at or beyond the hymenal ring at 36 months
• AA: 37.6% (86/229) mesh, 38.9% (51/131) NTR
• PA: 24.8% (40/161) mesh, 35.1% (26/74) NTR
• TR: 40.7% (24/59) mesh, 38.1% (56/147) NTR
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| Study Strengths and Weaknesses |
• Caution should be used in drawing conclusions from these results due to multiple issues with study design and conduct. These include, but are not limited to, the following:
o It is difficult to compare the mesh and NTR groups due to an imbalance of baseline characteristics in each arm (age, estrogen deficiency, and prior pelvic surgery).
o The prespecified sample size of the posterior-apical cohort was not met for the primary safety endpoint.
o The adverse event (AE) rates reported in the study could underestimate the actual AE rates, as subjects who discontinued or were lost to follow-up prior to 36 months were imputed as no events if they had not reported any AEs prior to discontinuation.
o The number of patients lost to follow up and amount of missing data introduce significant uncertainty in the results.
o Sixteen (16) clinical trial sites received waivers permitting the clinical investigator to perform POP-Q examinations in lieu of independent examiners. Failure to use an independent examiner is a protocol violation and introduces a source of bias that cannot be quantified given the limited sample size and non-randomized design of the study.
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| Recommendations for Labeling Changes |
N/A
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