VNS Therapy Automatic Magnet Mode Outcomes Study in Epilepsy Patients Exhibiting Ictal Tachycardia (E-37)

Seizure events were recorded during the EMU stay (only Automatic Stimulation Mode aka AutoStim ON) using vEEG and ECG to evaluate tachycardia detection algorithm performance. The threshold for the AutoStim feature (20-70%) was programmed for each subject, based upon the historical ictal elevation in heart rate for that subject, requiring the corresponding heart rate elevation above that of a moving baseline window.

Number of seizures observed and reported by investigators during the EMU stay (several subjects had more than one type of seizure) were collected and also reviewed by three (3) independent and blinded reviewers for confirmation. Additionally, the reviewers identified new seizures while reviewing the study EMU stay vEEG.

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 and non-seizure EEG segments were provided to independent reviewers to confirm seizure occurrence and define electrographic seizure onset times. Seizure onset times were then compared with observed M106 device detections at the least sensitive setting capable of detecting the seizure based on the corresponding change in heart rate. Threshold for AutoStim setting (1;70%, 2;60%, 3;50%, 4;40%, 5;30% and 6;20%). No subjects were assigned to settings 3 and 6 that had seizures with a corresponding heart rate increase of >= 50% and >= 20%, respectively. Number of participants is total number of subjects who experienced seizures during the EMU stay.

Bootstrap confidence intervals using 3000 bootstrap samples.

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.

Each day in the EMU, subjects exercised for up to 3 minutes stepping up and down at a submaximal effort level on a step stool. Subject's resting heart rate was compared with the calculated 85% of the patient's age-predicted maximum heart rate. This calculated heart rate was then used as termination criteria for the step test.

Non-Seizure Detection Rate (previously known as Potential False Positive Rate) is defined as the total number of non-seizure detections summed for the group divided by the total evaluable monitoring time during the EMU. The non-seizure detection rate per hour was calculated at the various tachycardia detection settings for all subjects during EMU and during exercise activities (stair stepper).

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.

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.

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 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 and 18 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.

Adult subjects (18 years and older) completed the Quality of Life in Epilepsy-Patient-Weighted (QOLIE-31-P) survey questionnaire at screening and safety follow-up visits. The range for QOLIE-31-P (Sub-domains) scale is 0-100. The higher the score the better quality of life.

Mean QOLIE-31-P scores at 3, 6, 12 and 18 months were compared to baseline. MIC Thresholds as defined in Simon Borghs, Christine de la Loge, Joyce A. Cramer, defining minimally important change in QOLIE-31-P scores.

Seizure frequency was calculated at 3, 6,12 and 18 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 proportion of patients that achieved ≥50% seizure reduction per month from baseline by visit.

AED load were collected and measured from baseline.The AED load is calculated as the sum of all ratios of the total daily dose of each medication taken on the day of the visit over the defined daily dose of the medication for the main indication according to the WHO database.

Positive median value indicates increased drug load.

All adverse events (AEs) occurring during the study were collected and incidence rates tabulated by System Organ Class and Preferred Term utilizing MedDRA version 16.1 dictionary. The incidence profile was used to assess differences in near term tolerability rates relative to standard VNS Therapy.

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, the first day of EMU, the end of EMU, and the 6 month follow-up visit.

Overall Usability was calculated as percentage of the users who found the overall usability of system to be "easy-2" or extremely easy-1".

At baseline and each follow-up visit, subjects completed a healthcare utilization questionnaire to report the number of unplanned inpatient hospitalizations, emergency room visits, outpatient hospitalizations, physician office visits.

At baseline and each follow-up visit, subjects completed a healthcare utilization questionnaire to report the number of nights spent at the hospital.

At baseline and each follow-up visit, subjects completed a healthcare utilization questionnaire to report the number of days per week of missed work because of health reasons.

At baseline and each follow-up visit, subjects completed a healthcare utilization questionnaire to report the number of hours per week caregivers spent caring for patients.

At baseline and each follow-up visit, subjects completed a healthcare utilization questionnaire to report the number of phone calls to physicians.