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| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P960009 S007/ PAS001 |
| Date Original Protocol Accepted |
01/14/2002
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| Date Current Protocol Accepted |
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| Study Name |
VA Study
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| Device Name |
MEDTRONIC ACTIVA PARKINSON'S CONTROL SYSTEM
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| General Study Protocol Parameters |
| Study Design |
Randomized Clinical Trial
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| Data Source |
New Data Collection
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| Comparison Group |
Concurrent Control
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| Analysis Type |
Analytical
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| Study Population |
Adult: >21
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| Interim or Final Data Summary |
| Interim Results |
BMT and DBS: An AE was reported in 82% of the patients (209/255). There were 2056 AE in 209 unique patients. On average, there were 9.8 AEs per patient. The majority occurred in nervous system disorders (65.1%), psychiatric disorders (45.5%), general disorders and administration site conditions (43.9%), injury, poisoning and procedural complications (42.4%), and muscloskeletal and connective tissue disorders (39.6%).
DBS Only: An AE was reported in 96.7% of the patients (290/300). There were 6501 AE in 290 unique patients. On average, there were 22.4 AE per patient. The majority of AE were nervous system disorders (92%), injury, poisoning and procedural complications and psychiatric disorders (78.3% each), general disorders and administration site conditions (71.7%), and gastrointestinal disorders (64%).
Serious Adverse Events: The SAE dataset contained 107 SAE in 64 unique patients. BMT and DBS : Events from randomization to 6 month visit date. A SAE was reported in 25.1% of the patients randomized (64/255). There were 107 SAE in 64 unique patients with an average of 1.7 SAE per patient who reported a SAE. Within the 107 SAE, 16 were the following infections 12 implant infections and 4 post-operative infections in 13 unique patients. Study population incidence rate is 5.1% (13/255). The 107 SAE were in seventeen SOCs with the most frequent being infections and infestations (7.1 %), nervous system disorders (6.3%), injury, poisoning and procedural complications (5.5%) and general disorders and administration site conditions and psychiatric disorders (3.1%).
Gender - There are 208 males and 47 females randomized in this group. The most frequent AEs were implant site infection and fall (3.4% each), postoperative infection and confusional state (1.4% each) and pneumonia, cerebrovascular accident and hallucinations at 1% each in males and implant site infection and air embolism (4.3% each) in females.
DBS Only
Events in surgical arm from randomization date
A SAE was reported in 51% of the patients randomized (153/300). There were 327 SAE in 153 patients with an average of 2.1 SAE per patient. Within the 327 SAE, 27 were the following infections - 23 implant infections and 7 post-operative infections in 23 unique patients. Study population incidence rate is 7.7% (23/300). The most frequent SOCs were injury, poisoning and procedural complications (17.0%), infections and infestations (13.3%), nervous system disorders (13.0%), and psychiatric disorders (9.3%).
Gender: There are 250 males and 50 females randomized in this group. The most frequent AEs terms were fall (6.4%), implant site infection (5.2%), medical device complication (4.0%) and pneumonia (3.6%) in males and medical device complication (10.0%), fall and implant site infection (8.0% each), and syncope (6.0%) in females.
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| Actual Number of Patients Enrolled |
299
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| Actual Number of Sites Enrolled |
13
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| Patient Follow-up Rate |
At the 24-month, primary analysis there were 261 completers, for a follow-up rate of 261/299 = 87% follow-up rate. For the 36-month effectiveness analysis there were 159/299 subjects = 53% follow-up rate. For the 36-month safety analysis there were 187/299 subjects = 62.5% follow-up rate.
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| Final Safety Findings |
In terms of safety, no unexpected adverse events occurred. There was not a trend for any of the two stimulation sites to present a significantly higher number of adverse events, including deaths (5/152 subjects GPi, 8/147 STN), suicidality (2 GPi, 3 STN), intracranial hemorrhages (5 GPi, 3 STN), device-related infections (2 GPi, 2 STN) and general paralysis/paresis (12 GPi, 11 STN). AEs were reported in 100% of the patients, while serious AEs (SAEs) were reported in 52% of the subjects randomized to GPi (54/104) as well as 55% of the subjects randomized to STN.
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| Final Effect Findings |
The device showed continued effectiveness at 24-months: the results for the blinded UPDRS III On stim/Off med test are statistically significantly improved from baseline to 24 months for the GPi (11.8 points) and the STN (10.7 points) target sites. At 24 months a minimal clinically important change of 5 points in the UPDRS III measure On stim/Off med was achieved in 66% of GPi subjects and 71% of STN subjects. At 24 months the motor diary demonstrated an increase of 4-5 hours of On time without troublesome dyskinesias, a decrease of approximately 3 hours of On time with troublesome dyskinesias, a decrease of approximately 2 ½ hours of Off time, and an increase of approximately 1 hour of asleep time.
The Post-Approval Study also showed an ameliorated quality of life according to one of the measurements adopted but not the others: quality of life was characterized using the PDQ-39, SF-36, and Quality of Well-Being measurements for both 24- and 36-month data sets. The PDQ-39 single index and subscales of mobility, activities of daily living, stigma, and bodily discomfort were statistically significantly improved as compared with baseline for both target sites (-11.2% for GPi and -8.9% for STN in the 24-month ITT data set). The change from baseline for the SF-36 and Quality of Well-Being scores for both target sites were not consistently statistically significantly improved on these general quality of life measures. None of the differences in quality of life outcomes between target sites were considered clinically significant for PDQ-39, SF-36, or Quality of Well-Being.
Neuropsychological changes over time through 24 months in 6 domains showed no clinically significant changes from baseline. The only exception to this was the measure of overall cognitive function, which declined in both groups to 24 months, especially in terms of verbal fluency declines.
Medication reduction was higher in STN patients at 24 months, compared to Gpi patients: the percent reduction in the average LED (levodopa equivalent dose) from baseline at 24 months was 31.4% for STN and 16.4% for GPi, while at 36 months it was 35.5% for STN and 18.3% for GPi.
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| Study Strengths & Weaknesses |
The major strength of the study: the design was randomized and blinded (independent neurologist or nurse, and subject) to the assigned stimulation site.
A major limitation: given the relatively extended follow-up of the study (24 months for the primary effectiveness analysis, 36 months for the secondary, longer term effectiveness analysis and for the safety analysis) the follow-up rates at 36 months were not high (53% for the effectiveness analysis and 62.5% for the safety analysis). This element may have introduced bias in the comparison between the 2 groups randomized to receive STN vs. GPi stimulation sites. The primary effectiveness analysis, both the intention-to-treat and the completer analysis, is not affected by this potential problem: indeed the loss to follow up rate for the primary effectiveness analysis was 13%, showing a good follow up rate.
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| Recommendations for Labeling Changes |
DBS in the PAS Phase II showed continued effectiveness, a safety profile that is not different from expected and that does not differ between the two stimulation sites, with a partially ameliorated quality of life in these patients and a declined overall cognitive function for both stimulation sites. Medication reduction was twice as large in STN patients compared to GPi patients.
No major clinical differences emerged between the STN and the GPi in terms of effectiveness, besides a significantly reduced use of medications in STN patients compared to GPi patients.
Serious adverse events were reported in 52% of GPi patients and 55% of STN patients.
No unexpected adverse events occurred. There was not a trend for either of the two stimulation sites to present a significantly higher number of adverse events, including deaths, suicidality, intracranial hemorrhages, device-related infections and general paralysis/paresis.
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