Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures

This was a randomized, parallel group, multi-center study. Screening Visit (visit 1) Subjects, parents, and the investigator signed and dated the informed consent after which subject eligibility was checked. Eligible subjects were entered in the baseline period.

Baseline Period (between visits 1 and 2) Eligible subjects entered an 8-week baseline period during which a seizure count was done. During this period, subjects and caregivers were contacted on a regular basis to ensure up to date information collection.

At the end of the baseline period, subjects who continued to be eligible were stratified based on previous therapy history (Early: previously treated with 2 to 5 AEDs versus Non-early: previously treated with >5 AEDs). Within each stratification, the investigator randomized each subject to receive one of the 2 treatments (VNS Therapy treatment or AED treatment) at the end of visit 2 using a randomization schedule provided by an independent third party (Synergos).

Implantation/AED Treatment Initiation (visit 3) For subjects randomized to the AED arm, a new AED treatment was initiated and gradually increased to an effective dose in accordance with the investigator's discretion and the manufacturer's suggested guidelines.

Subjects randomized to the VNS treatment arm were implanted with the VNS Therapy System and allowed adequate surgical recovery according to usual clinical practice before initiation of treatment. A delay of 2 weeks between the end of the baseline period and surgery was authorized to allow practical organization of the implantation. Extension of this period was approved in advance by the Study Director or his delegate.

Treatment Ramp-up (between visits 3 and 4) This ramp-up period for both AEDs and VNS may have taken up to 9 weeks, ending at visit 4. Additional visits were scheduled outside of the study protocol to adequately accommodate Treatment Ramp-up as needed. Initiation of treatments as well as the ramp-up schedule was documented in the Case Report Forms.

Study Treatment Period The Study Treatment Period was 12 months (52 weeks) following visit 3 and including Treatment Ramp-up. Because this study was designed to compare the natural course of treatment, changes in the study AED dose (for the AED group) or VNS stimulation parameters (for the VNS Therapy group) were allowed as clinically indicated during the Study Treatment Period. The protocol allowed approximately a 10% increase in baseline AED to allow for an increase in growth of the patient in the VNS arm.

Study End At the end of the study, subjects in the AED group who had not had significant improvement after all study assessments were completed were offered a VNS device implantation. Subjects in the VNS arm who had not had adequate improvement were evaluated for AED treatment.

Number of Subjects: Approximately 400 subjects were to be randomized at a 1:1 ratio to either AED or VNS treatment strata. Strata were to be according the AED treatment history (Early subjects were previously treated and failed treatment with 2 to 5 AEDs, Non-early subjects were treated and failed treatment with >5 AEDs). At least 15 study sites were to enroll subjects. Initially, only United Kingdom (UK) sites were to be selected. During the course of the trial, an extension was used to add non-UK centers.

A total of 151 subjects underwent screening prior to enrollment. Eight failed screening, and 143 went on to be randomized. Of those randomized, 8 subjects (4 in each of the treatment groups) were not treated. One patient in the VNS arm was explanted prior to initiation of device stimulation, so they were excluded. Therefore, 134 subjects were treated (ITT population): 65 were implanted with the VNS system and 69 were treated with AED. Nineteen investigational sites in the UK, Austria, Belgium, Germany, and Sweden participated in this study and enrolled subjects.

Study Duration: The maximum study follow-up was approximately 14 months from enrollment to study exit. The study was terminated due to insufficient enrollment prior to reaching the 400 subjects as specified in the protocol. After 4.5 years of enrollment, the Sponsor terminated enrollment and followed the remaining subjects out to the 52 week follow-up visit.