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

This is a randomized study designed to compare long-term treatment outcomes in pediatric patients with refractory seizures treated with VNS (Vagus Nerve Stimulation) Therapy versus anti-epileptic drugs (AEDs). Seizure reduction, quality of life measures, and side effect profiles will be evaluated. The results of this study will provide controlled comparative data to better guide physicians in determining the best overall treatment strategy for patients with seizures who have failed initial AED therapy.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Refractory seizures
2. Having tried at least two appropriate anti-epileptic drugs (AEDs) tested to tolerance or to blood levels at upper end of the target range of which at least 2 have been tolerated at normal dose;
3. Having at least 3 appropriate AEDs left to try
4. Having his/her current AED medication at an optimal dose at baseline
5. At least three seizures per month (average over 2 months prior to admission), excluding absences.
6. No more than four (4) weeks between seizures (over 2 months prior to admission)
7. Age 17 years or less
8. Having been evaluated for epilepsy surgery and resective surgery not felt indicated or patient/parents/legal guardian declined.
9. Patient is a male or patient is a nonpregnant female adequately protected from conception. Females of childbearing potential must use an acceptable method of birth control. Abstinence is an acceptable means of birth control
10. Patient or legal guardian understands study procedures and has voluntarily signed an informed consent in accordance with institutional policies.

Exclusion Criteria:

1. Having tried less then 2 AEDs tested to tolerance or to blood levels at upper end of the target range of which at least 2 have been tolerated at normal doses in the patient's lifetime
2. A progressive neurological condition (e.g. brain tumor etc.)
3. Inability of the parents or reluctance of the child to comply with the frequency of clinic visits during the treatment phase
4. Patient has a history of noncompliance for seizure diary completion.
5. Patient has taken an investigational drug within a period of five times the mean elimination half-life of the investigational drug plus two weeks.
6. Patient is currently using another investigational device or drug.
7. Patient is likely to require a whole body Magnetic resonance imaging (MRI) after VNS Therapy device implantation. (Refer to the Physician's Manual for the NCP Generator for additional information on the use of MRI.)
8. Patient is currently receiving or likely to receive short-wave diathermy, microwave diathermy, or therapeutic ultrasound diathermy after implantation (Refer to Physician's Manual for the VNS (Vagus Nerve Stimulation) Therapy device for additional information on the contraindicated use of diathermy).
9. Patient was previously enrolled in this or any other VNS Therapy device Study.
10. Patient has an active peptic ulcer
11. Patient has another unstable medical condition likely to precipitate seizures and make it difficult to evaluate to evaluate efficacy (e.g. diabetes)
12. Patient has had a unilateral or bilateral cervical vagotomy.
13. Patient is pregnant at the time of enrolment.