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U.S. Department of Health and Human Services

Post-Approval Studies (PAS)

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The FDA has the authority to require sponsors to perform a post-approval study (or studies) at the time of approval of a premarket approval (PMA), humanitarian device exemption (HDE), or product development protocol (PDP) application. Post-approval studies can provide patients, health care professionals, the device industry, the FDA and other stakeholders information on the continued safety and effectiveness (or continued probable benefit, in the case of an HDE) approved medical devices. This database allows you to search Post-Approval Study information by applicant or device information.

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OSB Lead-Dosing Study D-21

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Application Number P970003 S050/ PAS002
Current Plan Approved 07/15/2005
Study Name OSB Lead-Dosing Study D-21
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 Design Description 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.
Study Population Description 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
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.
Data Collection 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
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.
Final Study Results
Interim Safety Information The study has been completed but the sponsor has not submitted the final data to FDA yet. Report Due July 14, 2010
Number of Patients 331
Number of Sites 29
Follow-up Rate 95.8% at the end of the acute 22-week phase (primary endpoint)
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).

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).
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.
Label 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.

OSB Lead-Dosing Study D-21 Schedule

Report Schedule
Date Due
FDA Receipt
Applicant's Reporting Status
6 month dosing study report 01/13/2006 01/12/2006 On Time
1 year dosing study report 07/15/2006 07/12/2006 On Time
18 month dosing report 01/13/2007 01/10/2007 On Time
2 year dosing report 07/15/2007 07/12/2007 On Time
30 month dosing report 02/01/2008 01/11/2008 On Time
3 year dosing report 08/01/2008 07/31/2008 On Time
42 month dosing report 02/06/2009 02/04/2009 On Time
4 year report 08/07/2009 08/05/2009 On Time
Final Report 01/11/2011 08/27/2010 On Time

Contact Us

Julie Unger
Project Manager, Post-Approval Studies Program
Food and Drug Administration
10903 New Hampshire Ave
WO66-4206v Silver Spring, MD

Phone: (301) 796-6134
Fax: (301) 847-8140

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