EpilepsyE-36NCT01325623

Seizure Detection and Automatic Magnet Mode Performance Study

A study testing Model 106 VNS Therapy System in people with Epilepsy, run by Cyberonics, Inc. at 14 sites in 5 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The purpose of this study is to confirm cardiac-based seizure detection in Cyberonics Model 106 VNS Therapy System. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Epilepsy
What is being tested?: Model 106 VNS Therapy System
Type of treatment: Medical device
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 31 participants
Where: 14 sitesin 5 countries
Study dates: Mar 2011to Jul 2015
Phase: Interventional
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Patients with a clinical diagnosis of medically refractory epilepsy dominated by partial seizures suitable for implantation with the Model 106 VNS Therapy System.
Patients with a history of increased heart rate (tachycardia) associated with seizure onset based on clinical data obtained from medical history, admission/hospital charts, or prior neurophysiologic evaluations.
Patients willing to undergo an EMU evaluation for a period of at least three days with activation of the AMM feature during that time.
Patients having an average of ≥ 3 seizures per month based upon diary or patient reporting for the 3 months prior to the screening visit.
Patients must have peak-peak R-wave amplitude greater than or equal to 0.40 mV on ECG measured from the proposed electrode location in the neck to the proposed generator location in the chest via surface ECG electrodes in 7 different body positions.
Patients must be at least 18 years old.
Patients must be in good general health and ambulatory.
Patient must be willing and able to complete informed consent.

Who cannot join

Patients have had a bilateral or left cervical vagotomy.
Patients currently use, or are expected to use, short-wave diathermy, microwave diathermy, or therapeutic ultrasound diathermy.
A VNS Therapy System implant would (in the investigator's judgment) pose an unacceptable surgical or medical risk for the patient.
Patients expected to require full body magnetic resonance imaging.
Patients have a history of VNS Therapy.
Patients have a documented history of clinically meaningful bradycardia (heart rate less than 50 bpm) associated with seizures.

Show all 14Show fewer

Patients with a significant psychiatric disorder, significant cognitive impairment, history of major depression, or suicidality as defined by DSM IV-TR that in the investigator's judgment would pose an unacceptable risk for the patient or prevent the patient's successful completion of the study.
Patients with a history of status epilepticus within 3 months of study enrollment.
Patients prescribed drugs specifically for a cardiac or autonomic disorder that in the investigator's opinion would affect heart rate response unless the patient has ictal tachycardia while taking said drugs. These include, but are not limited to, beta adrenergic antagonists ("beta blockers").
Patients with known clinically meaningful cardiovascular arrhythmias as well as patients with clinically meaningful cardiovascular arrhythmias determined by a 24-hour Holter recording obtained at the screening visit.
Patients dependent on alcohol or narcotic drugs as defined by DSM IV-TR within the past 2 years.
Patients with a history of only psychogenic or pseudo seizures.
Women who are pregnant. Women of childbearing age must take a pregnancy test.
Patients currently enrolled in another investigational study.

Trial locations and contacts

14 sites in 5 countries.

Country

City, postcode or hospital

14 sites in 5 countries

Germany6 sites

Epilepsie-Zentrum Bethel
Bielefeld
Universitätsklinikum Bonn
Bonn
Universitätsklinikum Erlangen
Erlangen
Albert-Ludwigs-Universität
Freiburg im Breisgau
Ludwig-Maximilians-Universität München
Munich
Universitätsklinikum Tübingen
Tübingen

Other trials in Germany

Belgium3 sites

Hôpital Erasme
Anderlecht
Cliniques Universitaires Saint-Luc
Brussels
Universitair Ziekenhuis Gent
Ghent

Other trials in Belgium

United Kingdom3 sites

King's College Hospital
London
The National Hospital for Neurology and Neurosurgery
London
Royal Hallamshire Hospital
Sheffield

Other trials in United Kingdom

Netherlands1 site

Kempenhaege
Heeze

Other trials in Netherlands

Norway1 site

Oslo University Hospital
Oslo

Other trials in Norway

About this study

The purpose of this study is to confirm cardiac-based seizure detection in Cyberonics Model 106 VNS Therapy System.

Read the detailed description

Prospective, observational, unblinded, multi-site study designed to collect data on patients implanted with a Model 106 VNS Therapy System from baseline through an EMU stay of up to 5 days. After the EMU stay, patients will continue follow-up for safety for approximately two years or until final regulatory approval of the product.

Conditions: Epilepsy
Being tested: Model 106 VNS Therapy System
Keywords: Automatic Magnet Mode (AMM), Vagal Nerve Stimulation
Medical subject headings: Epilepsy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Model 106 VNS Therapy SystemDevice
Also called AspireSR VNS Therapy System
The VNS Therapy System is an adjunctive therapy for the treatment of epilepsy. VNS Therapy is available as a scheduled stimulation, this is cyclic stimulation between programmable On- and Off- times (e.g., a 30-second burst every 5 minutes). VNS Therapy is also available as on-demand stimulation, that is, when a magnet is introduced briefly over the implanted device (Magnet Mode). The AspireSR VNS Therapy System includes a new feature, Automatic Magnet Mode or AutoStim. In addition to Normal Mode and Magnet Mode, AspireSR uses a Seizure Detection Algorithm to identify a potential seizure onset based on associated heart rate increases known as ictal tachycardia. The purpose is to deliver stimulation at or near the onset of a seizure.

Study groups in NCT01325623
Study group	Role	What they receive
Model 106 VNS Therapy System	Other	Model 106 VNS Therapy System includes a new Seizure Detection Algorithm (SDA) and corresponding Automatic Magnet Mode (AMM) feature. Receives: Device: Model 106 VNS Therapy System

What is being measured

The primary outcome is the main question the study is designed to answer.

Summary of Seizures Reported by Investigators and Triple Review
Subjects were admitted to the EMU and underwent standard continuous data collection of vEEG and ECG for 3 to 5 days. If a seizure occurred during the EMU stay, clinical investigators annotated the start and stop times, the type of seizure, the presumed seizure onset location, and the lobe of origin as applicable.
Following the EMU data collection phase of the trial, the de-identified, continuous electronic records (per patient) from the EMU period were provided to an independent and blinded triple review panel. This panel evaluated the EEG data and annotated seizure onset, seizure offset, and a description of seizure type. In the absence of video, seizure types could only be specified as: partial (particular type not denoted), generalized (non-absence), absence, or partial with secondary generalization.
Measured: Epilepsy Monitoring Unit Stay
Observed Sensitivity Based on Heart Rate Increase Associated With Seizures by Randomized SDA Setting
Sensitivity is the total number of seizures detected divided by the total number of seizures during EMU stay.Data used to support sensitivity analyses included digital ECG/EEG files,corresponding M106 device downloads,and CRF data.Seizure and non-seizure EEG segments were provided to independent reviewers to confirm seizure occurrence and define EEG seizure onset times.Seizure onset times were then compared with observed M106 device detections at the detection threshold setting for AutoStim that the patient was randomized to(SDA 2;60%,SDA 4;40%,SDA 6;20%).Sensitivity is only reported if the heart rate surpassed the programmed detection threshold.Number of participants is total number of subjects who had seizures during the EMU stay.
An "Ictal tachycardia Seizure" is a seizure with Ictal Heart rate >= 100 bpm \& at least 55% increase, or 35 bpm increase from baseline) Bootstrap confidence intervals using 3000 bootstrap samples. n=total number of seizures; N= number of participants
Measured: Epilepsy Monitoring Unit (EMU) Stay
Modeled Sensitivity Based on Heart Rate Increase Associated With Seizures by SDA Setting Post-Processed Through Bench-top Device Simulant
Sensitivity is defined as the total number of seizures detected divided by the total number of seizures during the EMU stay. Data used to support sensitivity analyses included digital ECG/EEG files, corresponding M106 device downloads, and CRF data. Seizure onset times were compared with modeled M106 device detections at the least sensitive setting capable of detecting the seizure based on the corresponding change in heart rate. The participants' surface ECG data collected during the trial and passed through DMSDAT, a validated bench-top simulant of the Automatic Stimulation feature, was used to produce modeled results for each threshold for AutoStim setting (1;70%, 2;60%, 3;50%, 4;40%, 5;30% and 6;20%). Number of participants is total number of subjects who experienced seizures during the EMU stay.
Bootstrap confidence intervals using 3000 bootstrap samples.
Measured: Epilepsy Monitoring Unit (EMU) Stay
Potential False Positives Based on Heart Rate Increase Associated With Seizures by Randomized SDA Setting
Potential false positive rate is defined as the sum across all patients of the total number of potential false positive detections divided by the sum across all patients of the appropriate monitoring time during the EMU stay. Data used to support the potential false positive rate analyses included digital ECG/EEG files retrieved from the EMU evaluation, corresponding M106 device downloads, and triple review results of EEG recordings.
The evaluated EMU monitoring time includes a daily 3 minutes stepping exercise during which patients stepped up and down on a step stool at a submaximal effort leve.
Measured: Epilepsy Monitoring Unit (EMU) Stay

Secondary outcomes (12)

Validation of Cardiac R-Wave Detection
Cardiac R-wave detection was evaluated against concurrent ECG data (i.e. detailed R-wave test) collected during implant, the first titration visit, at the beginning of the EMU stay, and at the 12 month visit. R-R intervals were calculated using detected R-waves from the Implantable Pulse Generator (IPG) and from a standard ECG monitor during a pre-specified time interval. A time series 10 seconds was recorded using the IPG SyncPulse feature. Simultaneously, a corresponding time series over the same interval was recorded using a standard ECG monitor. The total number of beats accurately detected in the entire study population is reported.
Measured: At Implant, First Titration Visit, Day 1 EMU and 12 Months
Characterization of Latency Period: Analysis of Observed Latency for True Positive Detections by Randomized SDA Setting
Latency is defined as the time difference between SDA detection time and the annotated seizure onset time. The earliest SDA detection was considered for each seizure. Seizure onset times were compared with M106 device detections at the randomized SDA setting. Negative latencies indicate that the SDA detection preceded the seizure onset time. The median latency is presented for seizures which met the definition of ictal tachycardia as well as all seizure types and indicate the observed latency range.
Measured: Epilepsy Monitoring Unit (EMU) Stay
Human Factors and Usability of the AspireSR® VNS Therapy® System.
Usability survey data were collected from all site personnel who used the handheld programmer to evaluate the usability of the AspireSR® VNS Therapy® System.The device usability survey contained 17 questions that measure usability on a five-point Likert scale ranging from "Extremely Difficult" (5) to "Extremely Easy" (1). Site personnel were asked to assess usability of the software features, instructions for use, training materials, and overall usability of the system at four different time points. The time points include implant/recovery and the end of EMU.
Usability was calculated as percentage of the users who found the usability of system to be "easy-2" or extremely easy-1".
Measured: At implant/recovery up to EMU Discharge (2 to 4 weeks)
Changes From Baseline in Seizure Frequency
Seizure frequency was calculated at 3, 6, 12, 18 and 24 month follow-up visits based on seizure diary information and compared to baseline estimates. Response rate was computed and summarized for partial seizures (SPS, CPS and CPS with 2nd GTCs) and overall seizure types as the percentage of patients that achieved ≥50% seizure reduction per month from baseline by visit.
Measured: Up to 24 Month visit
Changes in Seizure Severity Based on Physician Reported Questionnaire (NHS3)
Investigators completed the National Hospital Seizure Severity Scale (NHS3) questionnaire at screening, at the end of the EMU stay (provided a seizure occurred during the EMU stay), and at follow-up visits. Severity was evaluated by seizure type. The range of NHS3 scale is 1-27 with 1 being the least severe and 27 being the most severe.
Negative median value means improvement.
Measured: up to 24 Months Visit
Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Seizure Severity Questionnaire (SSQ)
Clinical outcomes such as seizure severity, intensity and post-ictal duration were also assessed during the long-term follow-up visits (3, 6, 12, 18 and 24 months) with patient reported questionnaires (SSQ; Seizure Severity Questionnaire). The range for SSQ (all sub-scores) is 1-7 with 1 being the least severe and 7 being the most severe.
Mean SSQ scores at 3, 6, 12, 18 and 24 months were compared to baseline. A change from baseline is calculated as baseline minus follow-up visit score to correspond to the Minimally Important Change (MIC) criteria as defined in the Scoring Scheme for SSQ v2. Questionnaire. Subscale scores were averaged to compute the SSQ Total Score
Measured: Up to 24 Month visit
Proportion of Seizures Ending During Stimulation by Type
Clinical outcomes including seizure duration and cessation were assessed with vEEG during EMU stay. Number of seizures treated with Automatic Stimulation during EMU were evaluated. Of these seizures, those ending during the 60 second course of Automatic Stimulation were assessed and tabulated by seizure type.
Measured: Epilepsy Monitoring Unit (EMU) Stay
Summary of Seizure Duration (Seconds) for All Seizure Types by Subgroup(ITT Population) (Only Seizures With Post Ictal Duration (Seconds) Annotated)
Seizure duration was calculated using historical EEG data from patients enrolled in the trial and compared to the duration of seizures that occurred during the study EMU stay. The seizure start and end times were determined via clinical observation and/or through an adjudication process with qualified EEG reviewers.
Measured: Historical Seizures and Seizures during Epilepsy Monitoring Unit Stay
Summary of Post Ictal Duration (Seconds) for All Seizure Types (ITT Population) (Only Seizures With Post Ictal Duration (Seconds) Annotated)
Post-ictal duration was quantified by identifying the time at which the number of EEG channels within the 95% confidence interval of relative power reaches a number that is consistent with that during the pre-seizure period. This measure represents the amount of time required following a seizure until the EEG recovers to the pre-seizure state. It is used to objectively estimate patient recovery time. Historical seizures were baseline EEG recordings measured during monitoring prior to implantation. Post-ictal duration is only reported for seizures with Post Ictal Duration (seconds) annotated and >= 20% Heart Rate Rise
Measured: Historical Seizures and Seizures during Epilepsy Monitoring Unit Stay
Changes in Quality of Life on Patient Reported Questionnaire (QOLIE-31-P)
Quality of life data was collected using patient-completed QOLIE-31-P surveys and compared between baseline and follow-up visits. The MIC score for each subscale defines the threshold for Minimally Important Change. If a score exceeds the MIC Score, the improvement from baseline is considered clinically significant. The range for QOLIE-31-P (all sub-scores) is 0-100 with higher scores reflecting greater well-being.Subscale scores were averaged to compute the QOLIE Total Score.
Measured: up to 24 Months Visit
Overall Summary of Seizure Intensity by Subgroup
Quantitative evaluation of EEG was used to characterize the seizures that were treated with Automatic Stimulation. Intensity was evaluated by surveying the average power level from the 10-20 system EEG channel of maximum output during the course of the seizure. Intensity was only reported for seizures with intensity annotated and >= 20% Heart Rate Rise. The relative intensity was calculated by normalizing the power calculations to the pre-seizure state, and thus the reported changes are dimensionless. n= number of seizures
Measured: Historical Seizures and Seizures during Epilepsy Monitoing Unit Stay
Post-stimulation Heart Rate Changes
During a 1 hour period during the EMU stay, the VNS Therapy device was programmed to normal mode stimulation ON time 30 seconds, OFF time 5 minutes. AutoStim and Magnet Mode were programmed OFF. In this hour, 10 to 11 normal mode stimulations can be expected. Around each of these stimulations, ECG data were collected to assess potential stimulation related heart rate changes (during stimulation, after stimulation and after black-out time). A black-out time is a period after stimulation during which no seizure detections can occur, to ensure that potential stimulation related heart rate changes were not seen as ictal tachycardia that would trigger false positive detection. During the trial, the black-out time was programmed to 30 seconds. The heart rate changes for all stimulations and all patients were averaged.
Measured: EMU stay

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Mar 2011Jul 2015

First posted30 Mar 2011 (estimated)
Study startMar 2011
Primary completionJul 2013
Study completionJul 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for EpilepsyStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 31 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01325623
Sponsor's protocol ID: Epilepsy (E)-36
Acronym: E-36
Status last verified: Dec 2015
First submitted: 23 Mar 2011
Last updated: 22 Jan 2016
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Boon P, Vonck K, van Rijckevorsel K, El Tahry R, Elger CE, Mullatti N, Schulze-Bonhage A, Wagner L, Diehl B, Hamer H, Reuber M, Kostov H, Legros B, Noachtar S, Weber YG, Coenen VA, Rooijakkers H, Schijns OE, Selway R, Van Roost D, Eggleston KS, Van Grunderbeek W, Jayewardene AK, McGuire RM. A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation. Seizure. 2015 Nov;32:52-61. doi: 10.1016/j.seizure.2015.08.011. Epub 2015 Sep 21.
PubMed 26552564
Verrier RL, Nearing BD, Olin B, Boon P, Schachter SC. Baseline elevation and reduction in cardiac electrical instability assessed by quantitative T-wave alternans in patients with drug-resistant epilepsy treated with vagus nerve stimulation in the AspireSR E-36 trial. Epilepsy Behav. 2016 Sep;62:85-9. doi: 10.1016/j.yebeh.2016.06.016. Epub 2016 Jul 21.
PubMed 27450311

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 22 Jan 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Seizure Detection and Automatic Magnet Mode Performance Study
ClinicalTrials.gov ID: NCT01325623
Acronym / sponsor ID: E-36 / Epilepsy (E)-36
Conditions: Epilepsy
Keywords: Automatic Magnet Mode (AMM), Vagal Nerve Stimulation
Study type: Interventional
Recruitment status: Completed
Enrolment: 31 participants (actual)
Lead sponsor: Cyberonics, Inc.Industry (pharma, biotech, devices)
Collaborators: PRA Health Sciences
Study start: Mar 2011
Primary completion: Jul 2013 (actual)
Study completion: Jul 2015 (actual)
First posted: 30 Mar 2011 (estimated)
Results: Posted 22 Jan 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The purpose of this study is to confirm cardiac-based seizure detection in Cyberonics Model 106 VNS Therapy System.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Model 106 VNS Therapy System	Other	Device: Model 106 VNS Therapy SystemModel 106 VNS Therapy System includes a new Seizure Detection Algorithm (SDA) and corresponding Automatic Magnet Mode (AMM) feature.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (8 listed)

Patients with a clinical diagnosis of medically refractory epilepsy dominated by partial seizures suitable for implantation with the Model 106 VNS Therapy System.
Patients with a history of increased heart rate (tachycardia) associated with seizure onset based on clinical data obtained from medical history, admission/hospital charts, or prior neurophysiologic evaluations.
Patients willing to undergo an EMU evaluation for a period of at least three days with activation of the AMM feature during that time.
Patients having an average of ≥ 3 seizures per month based upon diary or patient reporting for the 3 months prior to the screening visit.
Patients must have peak-peak R-wave amplitude greater than or equal to 0.40 mV on ECG measured from the proposed electrode location in the neck to the proposed generator location in the chest via surface ECG electrodes in 7 different body positions.

Key exclusion criteria (14 listed)

Patients have had a bilateral or left cervical vagotomy.
Patients currently use, or are expected to use, short-wave diathermy, microwave diathermy, or therapeutic ultrasound diathermy.
A VNS Therapy System implant would (in the investigator's judgment) pose an unacceptable surgical or medical risk for the patient.
Patients expected to require full body magnetic resonance imaging.
Patients have a history of VNS Therapy.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Model 106 VNS Therapy SystemAlso: AspireSR VNS Therapy SystemThe VNS Therapy System is an adjunctive therapy for the treatment of epilepsy. VNS Therapy is available as a scheduled stimulation, this is cyclic stimulation between programmable On- and Off- times (e.g., a 30-second burst every 5 minutes). VNS Therapy is also available as on-demand stimulation, that is, when a magnet is introduced briefly over the implanted device (Magnet Mode). The AspireSR VNS Therapy System includes a new feature, Automatic Magnet Mode or AutoStim. In addition to Normal Mode and Magnet Mode, AspireSR uses a Seizure Detection Algorithm to identify a potential seizure onset based on associated heart rate increases known as ictal tachycardia. The purpose is to deliver stimulation at or near the onset of a seizure.	Device	Model 106 VNS Therapy System

Primary outcome

Summary of Seizures Reported by Investigators and Triple Review
Time frame: Epilepsy Monitoring Unit Stay
Subjects were admitted to the EMU and underwent standard continuous data collection of vEEG and ECG for 3 to 5 days. If a seizure occurred during the EMU stay, clinical investigators annotated the start and stop times, the type of seizure, the presumed seizure onset location, and the lobe of origin as applicable. Following the EMU data collection phase of the trial, the de-identified, continuous electronic records (per patient) from the EMU period were provided to an independent and blinded triple review panel. This panel evaluated the EEG data and annotated seizure onset, seizure offset, and a description of seizure type. In the absence of video, seizure types could only be specified as: partial (particular type not denoted), generalized (non-absence), absence, or partial with secondary generalization.
Observed Sensitivity Based on Heart Rate Increase Associated With Seizures by Randomized SDA Setting
Time frame: Epilepsy Monitoring Unit (EMU) Stay
Sensitivity is the total number of seizures detected divided by the total number of seizures during EMU stay.Data used to support sensitivity analyses included digital ECG/EEG files,corresponding M106 device downloads,and CRF data.Seizure and non-seizure EEG segments were provided to independent reviewers to confirm seizure occurrence and define EEG seizure onset times.Seizure onset times were then compared with observed M106 device detections at the detection threshold setting for AutoStim that the patient was randomized to(SDA 2;60%,SDA 4;40%,SDA 6;20%).Sensitivity is only reported if the heart rate surpassed the programmed detection threshold.Number of participants is total number of subjects who had seizures during the EMU stay. An "Ictal tachycardia Seizure" is a seizure with Ictal Heart rate >= 100 bpm \& at least 55% increase, or 35 bpm increase from baseline) Bootstrap confidence intervals using 3000 bootstrap samples. n=total number of seizures; N= number of participants
Modeled Sensitivity Based on Heart Rate Increase Associated With Seizures by SDA Setting Post-Processed Through Bench-top Device Simulant
Time frame: Epilepsy Monitoring Unit (EMU) Stay
Sensitivity is defined as the total number of seizures detected divided by the total number of seizures during the EMU stay. Data used to support sensitivity analyses included digital ECG/EEG files, corresponding M106 device downloads, and CRF data. Seizure onset times were compared with modeled M106 device detections at the least sensitive setting capable of detecting the seizure based on the corresponding change in heart rate. The participants' surface ECG data collected during the trial and passed through DMSDAT, a validated bench-top simulant of the Automatic Stimulation feature, was used to produce modeled results for each threshold for AutoStim setting (1;70%, 2;60%, 3;50%, 4;40%, 5;30% and 6;20%). Number of participants is total number of subjects who experienced seizures during the EMU stay. Bootstrap confidence intervals using 3000 bootstrap samples.
Potential False Positives Based on Heart Rate Increase Associated With Seizures by Randomized SDA Setting
Time frame: Epilepsy Monitoring Unit (EMU) Stay
Potential false positive rate is defined as the sum across all patients of the total number of potential false positive detections divided by the sum across all patients of the appropriate monitoring time during the EMU stay. Data used to support the potential false positive rate analyses included digital ECG/EEG files retrieved from the EMU evaluation, corresponding M106 device downloads, and triple review results of EEG recordings. The evaluated EMU monitoring time includes a daily 3 minutes stepping exercise during which patients stepped up and down on a step stool at a submaximal effort leve.

12 secondary outcomes

Validation of Cardiac R-Wave Detection
Time frame: At Implant, First Titration Visit, Day 1 EMU and 12 Months
Characterization of Latency Period: Analysis of Observed Latency for True Positive Detections by Randomized SDA Setting
Time frame: Epilepsy Monitoring Unit (EMU) Stay
Human Factors and Usability of the AspireSR® VNS Therapy® System.
Time frame: At implant/recovery up to EMU Discharge (2 to 4 weeks)
Changes From Baseline in Seizure Frequency
Time frame: Up to 24 Month visit
Changes in Seizure Severity Based on Physician Reported Questionnaire (NHS3)
Time frame: up to 24 Months Visit
Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Seizure Severity Questionnaire (SSQ)
Time frame: Up to 24 Month visit
Proportion of Seizures Ending During Stimulation by Type
Time frame: Epilepsy Monitoring Unit (EMU) Stay
Summary of Seizure Duration (Seconds) for All Seizure Types by Subgroup(ITT Population) (Only Seizures With Post Ictal Duration (Seconds) Annotated)
Time frame: Historical Seizures and Seizures during Epilepsy Monitoring Unit Stay
Summary of Post Ictal Duration (Seconds) for All Seizure Types (ITT Population) (Only Seizures With Post Ictal Duration (Seconds) Annotated)
Time frame: Historical Seizures and Seizures during Epilepsy Monitoring Unit Stay
Changes in Quality of Life on Patient Reported Questionnaire (QOLIE-31-P)
Time frame: up to 24 Months Visit
Overall Summary of Seizure Intensity by Subgroup
Time frame: Historical Seizures and Seizures during Epilepsy Monitoing Unit Stay
Post-stimulation Heart Rate Changes
Time frame: EMU stay

Results and safety

Results posted to the registry on 22 Jan 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Enrolled and Treated Population (Safety Population)	31	28

Primary outcome: Summary of Seizures Reported by Investigators and Triple Review

Time frame: Epilepsy Monitoring Unit Stay. Number. Unit: Seizures

Measure	Reported by Investigators n = 30	Reported by Triple Review n = 30	Total n = 30
All Seizure Types	87	124	211
Total Partial	82	51	133
Partial	8	51	59
Simple Partial	26	0	26
Complex Partial	31	0	31
Complex Partial with Secondary Generalization	17	0	17
Primary Generalized	0	43	43
Sub-Clinical	1	0	1

Population analysed: ITT Population: consists of all patients implanted with the AspireSR VNS Therapy System version 2 and who have any EMU record.

Primary outcome: Observed Sensitivity Based on Heart Rate Increase Associated With Seizures by Randomized SDA Setting

Time frame: Epilepsy Monitoring Unit (EMU) Stay. Mean (95% Confidence Interval). Unit: percentage of True Positive Detections

Measure	% Sensitivity n = 18
Ictal Tachycardia Seizures, SDA 2 (n=1; N=1)	100 (NA to NA)
Ictal Tachycardia Seizures, SDA 4 (n=8; N=2)	75 (NA to NA)
Ictal Tachycardia Seizures, SDA 6 (n=2; N=2)	100 (NA to NA)
>= 70% heart rate increase, SDA 4 (n=3; N=2)	66.7 (NA to NA)
>= 60% heart rate increase, SDA 2 (n=1; N=1)	100 (NA to NA)
>= 60% heart rate increase, SDA 4 (n=4; N=2)	50 (NA to NA)
>= 50% heart rate increase, SDA 4 (n=6; N=2)	66.7 (NA to NA)
>= 50% heart rate increase, SDA 6 (n=1; N=1)	100 (NA to NA)

Population analysed: Patients from the ITT population who completed the EMU evaluation and that had at least one reported seizure during the EMU evaluation that was confirmed by triple review; (Investigator Reported Seizures + Triple Review).

Primary outcome: Modeled Sensitivity Based on Heart Rate Increase Associated With Seizures by SDA Setting Post-Processed Through Bench-top Device Simulant

Time frame: Epilepsy Monitoring Unit (EMU) Stay. Mean (95% Confidence Interval). Unit: percentage of True Positive Detections

Measure	% Sensitivity n = 18
>= 70% heart rate increase at SDA 1 (n=5)	100 (NA to NA)
>= 60% heart rate increase at SDA 2 (n=7)	85.7 (70 to 100)
>= 50% heart rate increase at SDA 3 (n=11)	81.8 (57.14 to 100)
>= 40% heart rate increase at SDA 4 (n=19)	89.5 (73.68 to 100)
>= 30% heart rate increase at SDA 5 (n=36)	88.9 (76.67 to 97.37)
>= 20% heart rate increase at SDA 6 (n=53)	92.5 (79.66 to 100)

Primary outcome: Potential False Positives Based on Heart Rate Increase Associated With Seizures by Randomized SDA Setting

Time frame: Epilepsy Monitoring Unit (EMU) Stay. Number (95% Confidence Interval). Unit: Potential False Positive per Hour

Measure	Potential False Positives n = 30
>=60%, SDA 2	0.5 (0.20 to 0.96)
>=40%, SDA 4	2.7 (1.70 to 3.91)
>=20%, SDA 6	7.2 (5.31 to 9.94)

Population analysed: ITT Population: all patients implanted with Model 106 VNS Therapy System Version 2 and who have any EMU record. 10 participants analyzed for \>=60% setting, 12 participants analyzed for \>=40% setting, 8 participants analyzed for \>=20% setting.

12 secondary outcomes are reported in the full results.

Adverse events

Time frame: From baseline up to 24 Months. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
VNS Therapy - Safety Population	10 of 31 (32.3%)	26 of 31 (83.9%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 22 Jan 2016.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 26552564Boon P, Vonck K, van Rijckevorsel K, El Tahry R, Elger CE, Mullatti N, Schulze-Bonhage A, Wagner L, Diehl B, Hamer H, Reuber M, Kostov H, Legros B, Noachtar S, Weber YG, Coenen VA, Rooijakkers H, Schijns OE, Selway R, Van Roost D, Eggleston KS, Van Grunderbeek W, Jayewardene AK, McGuire RM. A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation. Seizure. 2015 Nov;32:52-61. doi: 10.1016/j.seizure.2015.08.011. Epub 2015 Sep 21.
Derived from this study: PubMed 27450311Verrier RL, Nearing BD, Olin B, Boon P, Schachter SC. Baseline elevation and reduction in cardiac electrical instability assessed by quantitative T-wave alternans in patients with drug-resistant epilepsy treated with vagus nerve stimulation in the AspireSR E-36 trial. Epilepsy Behav. 2016 Sep;62:85-9. doi: 10.1016/j.yebeh.2016.06.016. Epub 2016 Jul 21.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Bryan Olin study director

Cyberonics, Inc.

Paul Boon principal investigator

University Ghent

14 sites in 5 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A study testing Model 106 VNS Therapy System in people with Epilepsy, run by Cyberonics, Inc. at 14 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Jan 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in Germany, Belgium, United Kingdom, Netherlands, Norway. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Jan 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Summary of Seizures Reported by Investigators and Triple Review (time frame: Epilepsy Monitoring Unit Stay). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01325623, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jan 2016.