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| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P120024 / PAS001 |
| Date Original Protocol Accepted |
06/11/2015
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| Date Current Protocol Accepted |
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| Study Name |
Post-Approval Clinical Study
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| Device Name |
ACTIVL ARTIFICIAL DISC
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| General Study Protocol Parameters |
| Study Design |
Randomized Clinical Trial
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| Data Source |
Sponsor Registry
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| Comparison Group |
Concurrent Control
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| Analysis Type |
Descriptive
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| Study Population |
Adult: >21
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| Detailed Study Protocol Parameters |
| Study Objectives |
The PAS is a continuation of the completed pivotal IDE study which was a prospective, randomized (2:1), single-masked, controlled, multi-center, non-inferiority clinical trial to evaluate the safety and effectiveness of the activL® Disc (investigational device) as compared to two different lumbar total disc replacement devices as a combined control group (Charité or ProDisc-L according to investigator preference) in treating single-level DDD of the lumbar spine (L4/L5, or L5/S1) that has been unresponsive to at least six months of conservative treatment.
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| Study Population |
The IDE study population consisted of subjects with Degenerative Disc Disease (DDD) of the lumbar spine (L4-L5, or L5-S1) from the investigator?s practice who had failed to improve with conservative treatment for at least six months prior to enrollment. Subjects who presented for evaluation or treatment of lower back pain or leg pain were potential candidates for the study and were to be evaluated for inclusion based on the following inclusion/exclusion criteria. A screening form was completed for subjects evaluated. A subject was considered to be enrolled after signing the consent form and meeting all eligibility criteria.
The PAS study population consists of the subjects treated during the IDE study. No new patients will be treated as part of this PAS.
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| Sample Size |
The PAS sample size was calculated based on the formula of Farrington and Manning (Statistics in Medicine, 1990, 1447-1454). Calculations were performed in ADDPLAN, version 6. The following assumptions were used for the sample size calculations:
?s= 62%
??= 70%
? = 0.05 (one-sided type 1 error of 0.05)
? = 0.20 (80% power)
? = 15%
2:1 randomization ratio
Note: Success rates were estimated for both treatment groups, based upon the observed 4 year data to date for the post-approval composite endpoint of individual subject success.
Design Characteristic Solution
Sample Size at 7 Years Total: 111
(activL®: 74; Control: 37)
p-value required to pass NI at end of trial 0.05
Utilizing a delta of 10% as required by FDA, the sample size is as follows:
?s= 62%
??= 70%
? = 0.05 (one-sided type 1 error of 0.05)
? = 0.20 (80% power)
? = 10%
2:1 randomization ratio
Note: Success rates are estimated for both treatment groups, based upon the observed 4 year data to date for the post-approval composite endpoint.
Design Characteristic Solution
Sample Size at 7 Years Total: 184
(activL®: 123; Control: 61)
p-value required to pass NI at end of trial 0.05
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| Key Study Endpoints |
PAS Primary Endpoint
The primary study endpoint for the PAS is the same composite of effectiveness and safety measures for an individual subject (individual subject success) as was used in the IDE. Primary endpoint data will be evaluated annually; however the primary evaluation time point will be 7 years post-surgery:
?Improvement of at least 15 points in the ODI score at 7 years compared to baseline;
?Maintenance or improvement in neurological status at 7 years compared to baseline as measured by motor and sensory evaluations. A decrease of one grade in either evaluation will be considered a failure.
?Maintenance or improvement in motion at the index level, defined as:
7 year ROM ? preoperative ROM > 0 (with +2º measurement error applied) in a patient who does not meet the definition of fusion.
?No device failures requiring Subsequent Surgical Intervention (SSI) (e.g., revision, re-operation, removal, or supplemental fixation at the level of the original implant).
?Absence of serious device-related adverse events as adjudicated by the CEC.
In addition, because the ROM success component of the primary endpoint was such a notable driver of the difference in overall success rates in favor of activL when comparing the two randomized treatment groups during the IDE, FDA will request an additional analysis of overall success without the ROM success component for the PAS as was done during the IDE.
PAS Powered Secondary Endpoints
?Back Pain, measured at rest using a visual analog scale (VAS). A patient will be considered a responder if, at the 7 year visit, they achieve at least a 20 mm VAS improvement compared to baseline on a 100 mm VAS scale.
?Leg Pain, measured at rest using a visual analog scale (VAS). A patient will be considered a responder if, at the 7 year visit, they achieve at least a 20 mm VAS improvement compared to baseline in the leg with the maximum pain at baseline on a 100 mm VAS scale, with no worsening in the other leg.
PAS Unpowered Secondary Endpoints
?The mean Oswestry Disability Index score, as well as the mean improvement, will be compared between groups across all study visits. The incidence of both 15% and 15 point improvements will be compared.
?Quality of Life, measured using the Short Form-36 Questionnaire (SF-36) will be compared between groups across all study visits; improvement of 15% in the overall score at each visit compared to baseline will be considered clinically significant.
?Disc height (incidence of 3mm change), as measured by standard lateral radiographs, will be compared between groups across all study visits.
?Incidence of subsidence of the device (>3 mm) at all study visits.
?Neurological status at all study visits compared to baseline.
?Safety: The individual incidence rates of all adverse events at all study visits through 7-years follow-up.
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| Follow-up Visits and Length of Follow-up |
7 years
Annually
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
29 non-randomized investigational subjects, 129 randomized investigational subjects, 6 non-randomized control subjects, 67 randomized control subjects. Overall 231 patients continued participation from the IDE study.
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| Actual Number of Sites Enrolled |
15 sites were enrolled for the Post-Approval Study
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| Patient Follow-up Rate |
200/231 (90%) presented for Year 7 follow up.
208/231 (87%) presented for Year 7 follow up.
67/151 (44%) of randomized investigational patients from the original IDE study returned for Year 7 follow up with complete data for the primary endpoint
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| Final Safety Findings |
During the post-approval study time period (Years 2-7), a total of 630 adverse events (activL = 387; control = 243) were reported in 199 patients (activL = 129; control = 70), for a rate of 3.2 events per patient. The most common event reported was Musculoskeletal-Non-Lumbar (activL = 19.38%; control = 16.46%), followed by Pain-Lumbar and Lower Extremity (activL = 13.95%; control = 13.99%), Trauma (activL = 14.21%; control = 7.00%) and Gastrointestinal (activL = 11.37%; control = 9.88%).
While the overall rate of adverse events in the PAS phase (199 per year) appears to be less than during the IDE phase (498 per year), there are several adverse events that occur at a higher rate in the activL group compared to the control group, which persists through the PAS period (e.g, lumbar pain).
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| Final Effect Findings |
At Year 7 non-inferiority was demonstrated for Overall Success in the ITT population both with the ROM component (p=0.0447) and without the ROM component (p=0.0131).
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| Study Strengths & Weaknesses |
The main strength of the study is the randomized design. The main weakness of the study is the low follow up rate, especially for patients with all data within window. This low follow up rate makes multiple sensitivity analyses, especially in the Per Protocol population, inconclusive and introduces significant uncertainty at later follow up timepoints.
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| Recommendations for Labeling Changes |
Yes
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