A Phase 4 interventional study of Vagus Nerve Stimulation (VNS) Therapy and Anti-Epileptic Drug (AED) in Epilepsy, sponsored by Cyberonics, Inc.. Terminated at 19 sites in 5 countries. Open to participants aged Up to 17 Years. Per ClinicalTrials.gov, last updated 2014-06-26.
Sponsored by Cyberonics, Inc. · Phase 4, Interventional, and Treatment
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.
881 studies on the registry are indexed under Seizures; 143 are open to participants now.
This study's enrollment of 134 is above the median of 64 across 610 interventional studies indexed under Seizures.
Browse Seizures studies →Cyberonics, Inc. is the lead sponsor of 22 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Vagus Nerve Stimulation (VNS) Therapy is delivered by an implantable device similar to a pacemaker that sends mild stimulation to the left vagus nerve to help improve seizure control.
Device: Vagus Nerve Stimulation (VNS) Therapy
This arm will supply a comparison between VNS and new AEDs which is necessary to determine an overall treatment regimen for the 30% to 40% of patients who fail to respond to 2 AEDs.
Drug: Anti-Epileptic Drug (AED)
Vagus Nerve Stimulation (VNS) Therapy is delivered by an implantable device similar to a pacemaker that sends mild stimulation to the left vagus nerve to help improve seizure control.
Subject has tried at least 2 appropriate AEDs tested to tolerance or to blood levels at upper end of the target range of which at least 2 had been tolerated at normal doses.
Proportion of Responders After 1 Year of Follow-up (ITT-population)
Responders are subjects who had no new AEDs added or significant dose changes in baseline AEDs within 1 year of follow-up, along with a reduction in the percentage change in seizure frequency from baseline to the 2-month period prior to the 1-year follow-up of at least 50%.
Time frame: 52 weeks post baseline
Mean Percent Change in Hague Seizure Severity Scale Score (ITT Population)
The Hague Seizure Severity Assessment (Carpay et al. 1996) is a scale completed by the patient and/or caregiver to assess the severity and post-ictal recovery of seizures. A reduction in the HSSA score reflects less seizure severity experienced.
Time frame: 52 weeks post baseline
Wellcome Quality of Life Assessment (Questionnaire A) in Epilepsy (ITT Population)
Calculate changes in the Wellcome Quality of Life Assessment (Parker et al. 1999) (Questionnaire A) for patients in both treatment arms (AED and VNS) at 52 weeks after randomization compared to baseline. The higher the quality of life score the better the quality of life experienced. An analysis of variance (ANOVA) model will be used to adjust for baseline variables (including QoL score) when comparing the two treatment groups. A two-sample t-test will be used for simple comparison QoL change from baseline. Total range for this scale is a minimum score of 81 to a maximum score of 336. There are no applicable subscales.
Time frame: 52 weeks post baseline
Hague Restriction in Childhood Epilepsy Scale (Questionnaire B) (ITT Population)
Calculate changes in the Hague Restriction in Childhood Epilepsy scale (Carpay et al. 1997) (Questionnaire B) for patients in both treatment arms (AED and VNS) at 52 weeks after randomization compared to baseline. The higher the quality of life score the better the quality of life experienced. An analysis of variance (ANOVA) model will be used to adjust for baseline variables (including QoL score) when comparing the two treatment groups. A two-sample t-test will be used for simple comparison QoL change from baseline. Total range for this scale is a minimum score of 10 to a maximum score of 40. There are no applicable subscales.
Time frame: 52 weeks post baseline
Mean Percent Change in Seizure Frequency (ITT Population)
The mean percent change in seizure frequency for the VNS and AED treatment groups at 52 weeks post baseline. Both AED and VNS treatment groups were stratified according to the patients' number of previous AED treatments ("early group" had 2 to 5 AEDs tested to tolerance or to blood levels at upper end of target range; "non-early group" had more than 5 AEDs tested to tolerance or to blood levels at upper end of target range). Seizure frequency was calculated based on number of patient/caregiver reported seizures at 52-week post baseline (percentage change in seizure frequency from baseline to the 2-month period prior to the 1-year follow-up of at least 50%). All seizures were counted. The safety population consists of 66 VNS implanted patients and the AED safety population includes 69 patients who are randomized to the AED arm. Please note one patient in the VNS safety population who was implanted but never received stimulation was excluded from the ITT population.
Time frame: 52 weeks post baseline
Number of Subjects With Any Non-Serious Adverse Events by System Organ Class and Preferred Term (Safety Population)
To compare the safety of Vagus Nerve Stimulation (VNS) treatment using the VNS Therapy device to anti-epileptic drug (AED) therapy in treating patients with seizures. The safety population consists of 66 VNS implanted patients and the AED safety population includes 69 patients who are randomized to the AED arm. Please note one patient in the VNS safety population who was implanted but never received stimulation was excluded from the ITT population.
Time frame: 0-52 weeks
Number of Subjects With Any Serious Adverse Events by System Organ Class & Preferred Term (Safety Population)
To compare the safety of Vagus Nerve Stimulation (VNS) treatment using the VNS Therapy device to anti-epileptic drug (AED) therapy in treating patients with seizures. The safety population consists of 66 VNS implanted patients and the AED safety population includes 69 patients who are randomized to the AED arm. Please note one patient in the VNS safety population who was implanted but never received stimulation was excluded from the ITT population.
Time frame: 0-52 weeks
Subjects selected for participation in this clinical investigation were chosen from the investigator's general subject population or were referred by a physician who knew the subject well. They were selected for inclusion after consideration of the indications and contraindications of the device. Subjects were outpatients or inpatients.
| Milestone | Vagus Nerve Stimulation (VNS) - ITT Population | Anti-Epileptic Drug (AED) - ITT Population |
|---|---|---|
| Started | 66 | 69 |
| Actual patients treated | 65 | 69 |
| Completed | 65 | 69 |
| Not completed | 1 | 0 |
| Withdrew: Adverse event | 1 | 0 |
| Milestone | Vagus Nerve Stimulation (VNS) - ITT Population | Anti-Epileptic Drug (AED) - ITT Population |
|---|---|---|
| Started | 65 | 69 |
| Completed | 65 | 69 |
| Not completed | 0 | 0 |
Responders are subjects who had no new AEDs added or significant dose changes in baseline AEDs within 1 year of follow-up, along with a reduction in the percentage change in seizure frequency from baseline to the 2-month period prior to the 1-year follow-up of at least 50%.
| percentage of responders | Vagus Nerve Stimulation (VNS) - Early Group | Vagus Nerve Stimulation (VNS) - Non-Early Group | Anti-Epileptic Drug (AED) - Early Group | Anti-Epileptic Drug (AED) - Non-Early Group |
|---|---|---|---|---|
| Proportion of Responders After 1 Year of Follow-up (ITT-population) | 21.7 ± 129.1 | 39.4 | 30.4 ± 90.9 | 24.0 |
The Hague Seizure Severity Assessment (Carpay et al. 1996) is a scale completed by the patient and/or caregiver to assess the severity and post-ictal recovery of seizures. A reduction in the HSSA score reflects less seizure severity experienced.
| Percent Change | Vagus Nerve Stimulation (VNS) Early | Vagus Nerve Stimulation (VNS) Non-Early | Anti-Epileptic Drug (AED) Early | Anti-Epileptic Drug (AED) Non-Early |
|---|---|---|---|---|
| Mean Percent Change in Hague Seizure Severity Scale Score (ITT Population) | -1.8 ± 19.1 | -7.7 ± 20.3 | -11.9 ± 17.1 | -1.4 ± 17.7 |
Calculate changes in the Wellcome Quality of Life Assessment (Parker et al. 1999) (Questionnaire A) for patients in both treatment arms (AED and VNS) at 52 weeks after randomization compared to baseline. The higher the quality of life score the better the quality of life experienced. An analysis of variance (ANOVA) model will be used to adjust for baseline variables (including QoL score) when comparing the two treatment groups. A two-sample t-test will be used for simple comparison QoL change from baseline. Total range for this scale is a minimum score of 81 to a maximum score of 336. There are no applicable subscales.
| Scores on a Scale | Vagus Nerve Stimulation (VNS) - Early Group | Vagus Nerve Stimulation (VNS) - Non-Early Group | Anti-Epileptic Drug (AED) - Early Group | Anti-Epileptic Drug (AED) - Non-Early Group |
|---|---|---|---|---|
| Wellcome Quality of Life Assessment (Questionnaire A) in Epilepsy (ITT Population) | 26.7 ± 27.1 | 30.6 ± 48.5 | 17.0 ± 29.9 | -2.1 ± 30.9 |
Calculate changes in the Hague Restriction in Childhood Epilepsy scale (Carpay et al. 1997) (Questionnaire B) for patients in both treatment arms (AED and VNS) at 52 weeks after randomization compared to baseline. The higher the quality of life score the better the quality of life experienced. An analysis of variance (ANOVA) model will be used to adjust for baseline variables (including QoL score) when comparing the two treatment groups. A two-sample t-test will be used for simple comparison QoL change from baseline. Total range for this scale is a minimum score of 10 to a maximum score of 40. There are no applicable subscales.
| Scores on a Scale | Vagus Nerve Stimulation (VNS) - Early Group | Vagus Nerve Stimulation (VNS) - Non-Early Group | Anti-Epileptic Drug (AED) - Early Group | Anti-Epileptic Drug (AED) - Non-Early Group |
|---|---|---|---|---|
| Hague Restriction in Childhood Epilepsy Scale (Questionnaire B) (ITT Population) | 1.6 ± 5.6 | 3.0 ± 5.3 | 2.5 ± 7.6 | 1.3 ± 6.5 |
The mean percent change in seizure frequency for the VNS and AED treatment groups at 52 weeks post baseline. Both AED and VNS treatment groups were stratified according to the patients' number of previous AED treatments ("early group" had 2 to 5 AEDs tested to tolerance or to blood levels at upper end of target range; "non-early group" had more than 5 AEDs tested to tolerance or to blood levels at upper end of target range). Seizure frequency was calculated based on number of patient/caregiver reported seizures at 52-week post baseline (percentage change in seizure frequency from baseline to the 2-month period prior to the 1-year follow-up of at least 50%). All seizures were counted. The safety population consists of 66 VNS implanted patients and the AED safety population includes 69 patients who are randomized to the AED arm. Please note one patient in the VNS safety population who was implanted but never received stimulation was excluded from the ITT population.
| Percent Change | Vagus Nerve Stimulation (VNS) Early | Vagus Nerve Stimulation (VNS) Non-Early | Anti-Epileptic Drug (AED) Early | Anti-Epileptic Drug (AED) Non-Early |
|---|---|---|---|---|
| Mean Percent Change in Seizure Frequency (ITT Population) | 28.6 ± 177.5 | -5.0 ± 80.7 | 10.5 ± 123.2 | -17.3 ± 43.3 |
To compare the safety of Vagus Nerve Stimulation (VNS) treatment using the VNS Therapy device to anti-epileptic drug (AED) therapy in treating patients with seizures. The safety population consists of 66 VNS implanted patients and the AED safety population includes 69 patients who are randomized to the AED arm. Please note one patient in the VNS safety population who was implanted but never received stimulation was excluded from the ITT population.
| Participants | Vagus Nerve Stimulation (VNS) | Anti-Epileptic Drug (AED) |
|---|---|---|
| Blood and lymphatic system disorders | 0 | 1 |
| Eye disorders | 0 | 1 |
| Gastrointestinal disorders | 1 | 4 |
| Ear and labyrinth disorders | 1 | 0 |
| Infections and infestations | 4 | 0 |
| Nervous system disorders | 6 | 6 |
| Psychiatric disorders | 1 | 6 |
| Respiratory and mediastinal disorders | 5 | 2 |
| Skin and subcutaneous tissue disorders | 1 | 2 |
| General disorders & administration site conditions | 2 | 0 |
| Injury, poisoning and procedural complications | 0 | 2 |
| Investigations - weight decreased | 0 | 1 |
| Metabolism and nutrition disorders | 2 | 2 |
| Musculoskeletal & connective tissue disorders | 1 | 1 |
To compare the safety of Vagus Nerve Stimulation (VNS) treatment using the VNS Therapy device to anti-epileptic drug (AED) therapy in treating patients with seizures. The safety population consists of 66 VNS implanted patients and the AED safety population includes 69 patients who are randomized to the AED arm. Please note one patient in the VNS safety population who was implanted but never received stimulation was excluded from the ITT population.
| participants | Vagus Nerve Stimulation (VNS) | Anti-Epileptic Drug (AED) |
|---|---|---|
| Infections and infestations | 1 | 2 |
| Injury, poisoning and procedural complications | 0 | 2 |
| Nervous system disorders | 2 | 7 |
| Skin and subcutaneous tissue disorders | 1 | 1 |
| Surgical and medical procedures | 2 | 5 |
Collected over 0-52 Weeks (1-Year). Non-serious events are listed at a 1% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Vagus Nerve Stimulation (VNS) Therapy - Safety Population | — | 5/66 (7.6%) | 20/66 (30.3%) |
| Anti-Epileptic Drug (AED) - Safety Population | — | 10/69 (14.5%) | 25/69 (36.2%) |
| Event | Vagus Nerve Stimulation (VNS) Therapy - Safety Population | Anti-Epileptic Drug (AED) - Safety Population |
|---|---|---|
| ConvulsionNervous system disorders | 2/66 | 5/69 |
| HospitalizationSurgical and medical procedures | 0/66 | 3/69 |
| Status epilepticusNervous system disorders | 0/66 | 2/69 |
| AdenoidectomySurgical and medical procedures | 1/66 | 0/69 |
| Wound infectionInfections and infestations | 1/66 | 0/69 |
| Stevens Johnson SyndromeSkin and subcutaneous tissue disorders | 1/66 | 0/69 |
| Medical device removalSurgical and medical procedures | 1/66 | 0/69 |
| TonsilitisInfections and infestations | 0/66 | 1/69 |
| FallInjury, poisoning and procedural complications | 0/66 | 1/69 |
| RashSkin and subcutaneous tissue disorders | 0/66 | 1/69 |
| Event | Vagus Nerve Stimulation (VNS) Therapy - Safety Population | Anti-Epileptic Drug (AED) - Safety Population |
|---|---|---|
| ConvulsionNervous system disorders | 2/66 | 4/69 |
| Abnormal behaviorPsychiatric disorders | 0/66 | 3/69 |
| Wound infectionInfections and infestations | 2/66 | 0/69 |
| Decreased appetiteMetabolism and nutrition disorders | 2/66 | 2/69 |
| Psychomotor hyperactivityNervous system disorders | 2/66 | 0/69 |
| CoughRespiratory, thoracic and mediastinal disorders | 2/66 | 1/69 |
| VomitingGastrointestinal disorders | 1/66 | 2/69 |
| SedationNervous system disorders | 0/66 | 2/69 |
| External ear disorderEar and labyrinth disorders | 1/66 | 0/69 |
| FatigueGeneral disorders | 1/66 | 0/69 |
| Age, Continuous(years) | Vagus Nerve Stimulation (VNS) Therapy - ITT Population | Anti-Epileptic Drug (AED) - ITT Population | Total |
|---|---|---|---|
| Mean | 10.7 ± 3.5 | 10.8 ± 3.4 | 10.7 ± 3.4 |
| Sex: Female, Male(Participants) | Vagus Nerve Stimulation (VNS) Therapy - ITT Population | Anti-Epileptic Drug (AED) - ITT Population | Total |
|---|---|---|---|
| Female | 32 | 26 | 58 |
| Male | 33 | 43 | 76 |
| Number of Failed Medications(Number of failed medications) | Vagus Nerve Stimulation (VNS) Therapy - ITT Population | Anti-Epileptic Drug (AED) - ITT Population | Total |
|---|---|---|---|
| Median | 6.0 ± 2.2 | 6.0 ± 2.4 | 6.0 ± 2.3 |
| Age at Epilepsy Onset (years)(years) | Vagus Nerve Stimulation (VNS) Therapy - ITT Population | Anti-Epileptic Drug (AED) - ITT Population | Total |
|---|---|---|---|
| Mean | 2.4 ± 2.7 | 2.7 ± 2.9 | 2.6 ± 2.8 |
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