In January 2005, the oversight responsibility of the Post-Approval Studies Program was transferred to the Division of Epidemiology (DEPI) of the Office of Surveillance and Biometrics (OSB)/Center for Devices and Radiological Health (CDRH).
The CDRH Post-Approval Studies Program encompasses design, tracking, oversight, and review responsibilities for studies mandated as a condition of approval of a premarket approval (PMA) application, protocol development product (PDP) application, or humanitarian device exemption (HDE) application. The program helps ensure that well-designed post-approval studies (PAS) are conducted effectively and efficiently and in the least burdensome manner.
CDRH has established an automated, internal tracking system that efficiently identifies the reporting status of active PAS studies ordered since January 1, 2005 based on study timelines incorporated in study protocols and agreed upon by the CDRH and applicants. This system represents CDRH's effort to ensure that all PAS commitments are fulfilled in a timely manner.
In addition, CDRH launched this publicly available webpage to keep all stakeholders informed of the progress of each PAS. The webpage displays general information regarding each PAS, as well as the overall study status (based on protocol-driven timelines and the adequacy of the data) and the applicant's reporting status for each submission due.
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
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.
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
Followup Visits and Length of Followup
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
Actual Number of Patients Enrolled
Actual Number of Sites Enrolled
Patient Followup Rate
95.8% at the end of the acute 22-week phase (primary endpoint)
Final Safety Findings
AEs were relatively well tolerated, as suggested by the low rate of subjects discontinuing due
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).
Final Effectiveness 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).
Study Strengths and 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.
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.