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| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P970003 S050/ PAS002 |
| Date Original Protocol Accepted |
07/15/2005
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| Date Current Protocol Accepted |
07/15/2005
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| Study Name |
Dosing Study D-21
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| Device Name |
VNS THERAPY 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 |
Transit. Adolescent B (as adults) : 18-21 yrs,
Adult: >21
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| Detailed Study Protocol Parameters |
| Study Objectives |
This study is a multicenter, randomized, double-blind comparison of VNS Therapy using output currents of 0.25 mA, 0.5-1.0 mA, or 1.25-1.5 mA.
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| Study Population |
The device is indicated for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments. The study Inclusion Criteria: 1. Patient has a diagnosis of chronic (¿ 2 years) or recurrent (two or more prior episodes) depression and is currently experiencing a major depressive episode as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria (DSM-N-TR); the diagnosis will by determined based on the Mini-International Neuropsychiatric Interview (MINI). 2. Patient has not had an adequate response to four or more adequate antidepressant treatments from at least two different antidepressant treatment categories. 3. Patient must have minimum prestudy and baseline scores of 24 on the MontgomeryAsberg
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| Sample Size |
Approximately 460 patients will be implanted with the VNS Therapy System at up to 30 study sites. Enrollment may not be equal at all sites. Each site will be permitted to enroll (implant) a maximum of 40 patients. Patients will be randomized to each of the three treatment groups in a 1: 1: 1 ratio.
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| Key Study Endpoints |
The following effectiveness evaluations will be obtained at the intervals specified on the study procedures flow chart. - Inventory of Depressive Symptomatology Clinician Administered Version (IDS-C)-- a clinician-rated 30-item multidimensional depression rating - Montgomery-Asberg Depression Rating Scale (MADRS)--a clinician-rated 10item multidimensional depression rating
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| Follow-up Visits and Length of Follow-up |
During the treatment period, the investigator obtains the evaluations specified on the study procedures flow chart at the specified intervals (2, 3, 4, 5, 6, 10, 18, 18, 22, 26, 32, 38, 44, and 50 weeks post-implant; some latitude is permitted in scheduling these visits as indicated on the study procedures flow chart). The investigator may schedule additional non-study visits to manage the patient's depression as necessary and according to the investigator's usual practice.
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| Interim or Final Data Summary |
| Interim Results |
The study has been completed but the sponsor has not submitted the final data to FDA yet. Report Due July 14, 2010
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| Actual Number of Patients Enrolled |
331
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| Actual Number of Sites Enrolled |
29
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| Patient Follow-up Rate |
95.8% at the end of the acute 22-week phase (primary endpoint)
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| Final Safety Findings |
AEs were relatively well tolerated, as suggested by the low rate of subjects discontinuing due to
AEs (1 subject in the Medium Dose group during the Acute Phase, and 1 subject in the Low Dose group during the Long-term Phase). Dose-effect relationships were generally absent: 97% of subjects experienced at least 1 AE, and the distribution across treatment groups was similar (95.5%, 97.2%, and 98.2% for the Low Dose, Medium Dose, and High Dose groups, respectively).
However, some AEs showed a dose-response trend: asthenia (7.1% high vs. 2.8% medium vs. 4.5% low), pain (41.6% high vs. 28% medium vs. 25.2% low), dysphagia (15.9% high vs. 15.9% medium vs. 9.0% low), metabolic system adverse events (12.4% high vs. 8.4% medium vs. 6.3% low), nervous system AEs overall (75.2% high vs. 64.5% medium vs. 69.4% low) and paresthesia in particular (34.5% high vs. 32.7% medium vs. 27.9% low), and voice alteration (76.1% high vs. 76.6% medium vs. 64.0% low).
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| Final Effect Findings |
The study did not meet the primary effectiveness outcome. The mean IDS-C 30-item change from baseline over weeks 10, 14, 18, and 22 (the Acute Phase) was not statistically different between the high dose and the low dose groups (Low vs. High stimulation group: P=0.8027) as well as between the medium dose and the low dose groups (Low vs. Medium stimulation group: P=0.8131).. Although on average the score for all 3 groups showed an improved score over time, this was not set as the primary study outcome and could be due to response to other treatments as well as natural course of the disorders or statistical regression to the mean, and perhaps to a placebo effect since the study was blinded to dosage but not to VNS Therapy implant. No statistically significant differences were noted between treatment groups for any of the effectiveness outcomes, in either of the study periods (Acure Phase or Long-term Phase).
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| Study Strengths & Weaknesses |
The main study strength is the randomized nature of the design. A weakness is that masking was not perfect since most patients in the low dose group could correctly guess that they were assigned to the low dose.
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| Recommendations for Labeling Changes |
Labeling changes are recommended to incorporate in the labeling the results of the randomized dosing study which showed no dose-response for VNS in TRD patients.
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