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Seizure Detection and Automatic Magnet Mode Performance Study (E-36)

This study has been completed.
Sponsor:
Collaborator:
PRA Health Sciences
Information provided by (Responsible Party):
Cyberonics, Inc.
ClinicalTrials.gov Identifier:
NCT01325623
First received: March 23, 2011
Last updated: December 21, 2015
Last verified: December 2015
  Purpose
The purpose of this study is to confirm cardiac-based seizure detection in Cyberonics Model 106 VNS Therapy System.

Condition Intervention
Epilepsy
Device: Model 106 VNS Therapy System

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Seizure Detection and Automatic Magnet Mode Performance Study

Resource links provided by NLM:


Further study details as provided by Cyberonics, Inc.:

Primary Outcome Measures:
  • Summary of Seizures Reported by Investigators and Triple Review [ Time Frame: Epilepsy Monitoring Unit Stay ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Validation of Cardiac R-Wave Detection [ Time Frame: At Implant, First Titration Visit, Day 1 EMU and 12 Months ] [ Designated as safety issue: No ]
    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.

  • Characterization of Latency Period: Analysis of Observed Latency for True Positive Detections by Randomized SDA Setting [ Time Frame: Epilepsy Monitoring Unit (EMU) Stay ] [ Designated as safety issue: No ]
    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.

  • Human Factors and Usability of the AspireSR® VNS Therapy® System. [ Time Frame: At implant/recovery up to EMU Discharge (2 to 4 weeks) ] [ Designated as safety issue: No ]

    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".


  • Changes From Baseline in Seizure Frequency [ Time Frame: Up to 24 Month visit ] [ Designated as safety issue: No ]
    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.

  • Changes in Seizure Severity Based on Physician Reported Questionnaire (NHS3) [ Time Frame: up to 24 Months Visit ] [ Designated as safety issue: No ]

    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.


  • Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Seizure Severity Questionnaire (SSQ) [ Time Frame: Up to 24 Month visit ] [ Designated as safety issue: No ]

    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


  • Proportion of Seizures Ending During Stimulation by Type [ Time Frame: Epilepsy Monitoring Unit (EMU) Stay ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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

  • Changes in Quality of Life on Patient Reported Questionnaire (QOLIE-31-P) [ Time Frame: up to 24 Months Visit ] [ Designated as safety issue: No ]
    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.

  • Overall Summary of Seizure Intensity by Subgroup [ Time Frame: Historical Seizures and Seizures during Epilepsy Monitoing Unit Stay ] [ Designated as safety issue: No ]
    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

  • Post-stimulation Heart Rate Changes [ Time Frame: EMU stay ] [ Designated as safety issue: No ]
    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.


Enrollment: 31
Study Start Date: March 2011
Study Completion Date: July 2015
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Model 106 VNS Therapy System
Model 106 VNS Therapy System includes a new Seizure Detection Algorithm (SDA) and corresponding Automatic Magnet Mode (AMM) feature.
Device: Model 106 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.
Other Name: AspireSR VNS Therapy System

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01325623

Locations
Belgium
Hôpital Erasme
Anderlecht, Belgium
Cliniques Universitaires Saint-Luc
Brussels, Belgium
Universitair Ziekenhuis Gent
Ghent, Belgium
Germany
Epilepsie-Zentrum Bethel
Bielefeld, Germany
Universitätsklinikum Bonn
Bonn, Germany
Universitätsklinikum Erlangen
Erlangen, Germany
Albert-Ludwigs-Universität
Freiburg, Germany
Ludwig-Maximilians-Universität München
Munich, Germany
Universitätsklinikum Tübingen
Tübingen, Germany
Netherlands
Kempenhaege
Heeze, Netherlands
Norway
Oslo University Hospital
Oslo, Norway
United Kingdom
King's College Hospital
London, United Kingdom
The National Hospital for Neurology and Neurosurgery
London, United Kingdom
Royal Hallamshire Hospital
Sheffield, United Kingdom
Sponsors and Collaborators
Cyberonics, Inc.
PRA Health Sciences
Investigators
Study Director: Bryan Olin Cyberonics, Inc.
Principal Investigator: Paul Boon Universitair Ziekenhuis Gent
  More Information

Publications:
Responsible Party: Cyberonics, Inc.
ClinicalTrials.gov Identifier: NCT01325623     History of Changes
Other Study ID Numbers: Epilepsy (E)-36 
Study First Received: March 23, 2011
Results First Received: December 21, 2015
Last Updated: December 21, 2015
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by Cyberonics, Inc.:
Automatic Magnet Mode (AMM)
Vagal Nerve Stimulation

Additional relevant MeSH terms:
Seizures
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms

ClinicalTrials.gov processed this record on December 07, 2016