|
|
| General |
| Study Status |
Other |
| 522 Number / Requirement Number |
PS120089 / PSS001 |
| Date Original Plan Accepted |
01/31/2013
|
| Date Current Plan Accepted |
08/29/2014
|
| Study Name |
SUI AE and Effectiveness rates
|
| Device Name |
Miniarc precise single-incision sling system
|
| Root Document Number |
K073703
K100807
K071902
K121641
|
| General Study Protocol Parameters |
| Study Design |
Randomized Clinical Trial
|
| Data Source |
New Data Collection
|
| Comparison Group |
Concurrent Control
|
| Analysis Type |
Analytical
|
| Study Population |
Transit. Adolescent B (as adults) : 18-21 yrs,
Adult: >21
|
| Detailed Study Protocol Parameters |
| Study Objectives |
This is a multi-center randomized controlled trial comparing efficacy and morbidity of MiniArc and transobturator Monarc.
|
| Study Population |
The study population is women with symptomatic stress urinary incontinence treated with Monarc or MiniArc
|
| Sample Size |
172 subjects (86 patients treated with MiniArc Sling System and 86 patients treated with Monarc Subfascial Hammock as controls) were enrolled at 5 sites in the Netherlands, Belgium and France
|
| Key Study Endpoints |
Primary Effectiveness Endpoints: 1. Subjective cure; 2. Pain. Secondary Endpoints: 1. Objective cure; 2. Device-related serious adverse events; 3. Morbidity; 4. Duration of catheter use; 5. Disease and domain specific quality of life; 6. Quality of life; 7. Performed interventions in the first year after SUI surgery.
|
| Follow-up Visits and Length of Follow-up |
The length of study follow-up is 3 years. Follow-up will be conducted at 1 month, 6 months, 12 months, 18 months, 24 months and 36 months.
|
| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
193
|
| Actual Number of Sites Enrolled |
5
|
| Patient Followup Rate |
78.1%
|
| Final Safety Findings |
Primary Safety Objective - Device Related Severe Adverse Events (SAEs): At 36 months the overall SAEs rate for MiniArc 3.4% (2/88) is [statistically] non-inferior to Monarc 5.3% (5/94) (Non-inferiority significance = 0.0001). The device-related SAEs rates difference between arms is small, and may not be clinically relevant. The hypothesis was rejected in favor of non-inferiority. Therefore Min-Arc is not inferior to Monarc regarding SAEs.
All device-related AEs were resolved in the MiniArc arm and all but one device-related AE in the Monarc arm were resolved.
Pain: In the first three days post-implant, MiniArc subjects experienced less pain reporting a pain score of 11.1+/-14.0 (94) compared to Monarc subjects 23.3 +/-19.7 (93). This difference was statistically significant (p < 0.0001). However, as per protocol, a difference in pain score of 20 was determined as clinically relevant and the difference between the two pain scores was 12.2. Therefore, the difference was not clinically relevant. This difference is probably due to the fact the MiniArc is a less invasive device than Monarc.
The data related to Adverse Events (AEs) and SAEs were difficult to interpret because the study included four different urinary incontinence (UI) outcomes. By combining all UI categories into one of recurrent incontinence resulting from failure of the device, the MiniArc would have an 18% failure rate, while the Monarc would have an 8% failure rate. Therefore, MiniArc has 2.3 times higher failure rate, and this indicates a MiniArc potential poor performance.
Mesh Extrusion and Erosion: Mesh Extrusion events occurred at comparable rates in both study arms: MiniArc (2%) and Monarc (2%). However, patients implanted with Monarc did not reported erosions while those with MiniArc reported 2% erosion events. Erosions and extrusions were Mild-Moderate in severity in both arms and all resolved either spontaneously or with interventions including local estrogen application, excision or surgery.
Resurgery for recurrent Stress Urinary Incontinence (SUI): Subjects in the MiniArc arm had a 4-fold higher rate (8.3%) of resurgery for recurrent SUI through 36 months compared to subjects in the Monarc arm (2.1%), RR = 4.0, 95% CI (0.9, 18.4) as calculated by FDA DEPI reviewer. This is a safety concern because this is not only a SAE but it should be considered a device failure.
|
| Final Effectiveness Findings |
At 36 months, following the Intention to Treat study subjects (ITT), the study did not meet its primary effectiveness endpoint. The subjective cure rate at 36 month was 84.4% for MiniArc versus 94.7% for Monarc. Although the difference was not clinically or statistically significant (p= 0.18), the sample size was smaller than anticipated because data from the additional 40 MiniArc patients of a Single-Arm Cohort (SAC) are not included. Therefore, there was not enough power to assess the statistical significance of the difference.
A meta-analysis provided by the sponsor shows Monarc having better effectiveness [86.1 % (Cl 81.9% - 89.4%)] than MiniArc [79.2% (95% CI 63.7%- 89.2%)]. This data was used by the sponsor in an attempt to explain why the effectiveness endpoints were not met. However, these results could not be verified by FDA because the source of the data was “on file at ASTORA” and not published or available otherwise.
Though the 522 order FDA recommended an objective means of measuring efficacy (consistent with the Agency’s “Guidance for Industry and FDA Staff - Clinical Investigations of Devices Indicated for the Treatment of Urinary Incontinence”), the sponsor used a subjective tool (the PGII) that is not specific to UI. Even using this relatively low standard for success, the study did not meet its primary effectiveness endpoint.
Similarly, the secondary objective effectiveness endpoint of Cough Stress Test (CTS) was not met either (p=0.12). At 36M post-implant, 88% (66/75) Monarc subjects attending this visit and 80.5% (62/75) MiniArc subjects passed the CST, P=0.12. Again Monarc subjects seem to have higher improvement rate than MiniArc subjects contradicting sponsor’s expectations. However, the difference seems to be not clinically significant and the study was underpowered to assess the statistical significance of the difference.
PGIS: At 36 months, no statistically significant (p = 0.09) difference in PGIS (subjective improvement of SUI test) between MiniArc and Monarc arms was observed 74% (63/74) vs. 85% (54/73) respectively. These results show again that although an -11.2% (-24.1%, 1.8%) difference was found, the study was underpowered to assess the statistical significance of the difference.
Effectiveness results are not acceptable because the sponsor did not follow the protocol by using subjective instruments to assess effectiveness, and the study was underpowered because the sponsor excluded data from the 40 patients of the SAC.
|
| Study Strengths and Weaknesses |
Strengths:
Study design: randomized clinical trial
A 100% enrollment was reached for sites and patients
A comparison group was used with a similar device
Weaknesses:
The follow-up rate was 78.1%. This leads to incomplete study results, which in turn can put a bias on the result of the study.
Though the 522 order recommended an objective means of measuring efficacy a subjective tool (the PGII) was used that is not specific to UI.
One subject in the Monarc arm discontinued at the discretion of her physician. This is a protocol violation.
Meta-analysis results could not be verified by FDA because the source of the data was “on file at ASTORA” and not published.
UI was divided in four different outcomes. By combining these categories into one resulting from failure of the device, MiniArc would have an 18% failure rate, while Monarc would have 8% indicating that MiniArc has poorer performance than the one reported.
The adjudication of failure as both device and procedure related is misleading. The failure of the device to correct UI is a failure of the device itself, not the procedure.
The study did not fulfill the 522 order.
|
| Recommendations for Labeling Changes |
No labeling update can be implemented because the sponsor has ceased business operation, including manufacture and distribution of all the MiniArc family of devices subject to the 522 order in the US.
|
