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

Study Overview
=================
Brief Summary
-----------------
Obtain baseline clinical outcome data (Stage 1) upon which to base a subsequent study (Stage 2) of the Model 106 VNS implantable pulse generator

Detailed Description
-----------------
Prospective, observational, un-blinded, 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, and 6-month follow-up. After the 6-month follow-up, patients will continue follow-up for safety for approximately two years or until final regulatory approval of the product.

Official Title
-----------------
VNS Therapy Automatic Magnet Mode Outcomes Study in Epilepsy Patients Exhibiting Ictal Tachycardia

Conditions
-----------------
Epilepsy

Intervention / Treatment
-----------------
* Device: M106 VNS Therapy System


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with a clinical diagnosis of medically refractory epilepsy with partial onset seizures suitable for implantation with the VNS Therapy System. 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 must be at least 12 years old. Patients must be in good general health and ambulatory. Patient or guardian must be willing and able to complete informed consent/assent. Exclusion Criteria: Patients have had a bilateral or left cervical vagotomy. Patients currently using, 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 (MRI). Patients have a history of implantation of the VNS Therapy. Patients with an IQ known or estimated to be < 70, history of depression requiring hospitalization, 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 1 year of study enrollment. Patients with known clinically meaningful cardiovascular arrhythmias as well as patients with clinically meaningful cardiovascular arrhythmias determined by a 24-hour Holter recording obtained during the baseline period. Patients dependent on alcohol or narcotic drugs as defined by DSM IV-TR within the past 2 years. Patients with a history of psychogenic non-epileptic seizures. Women who are pregnant. Women of childbearing age must take a pregnancy test and agree to use an approved method of contraception during the study. Patients currently enrolled in another investigational study.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Model 106 VNS Therapy System<br> | Device: M106 VNS Therapy System<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the Effect Size Associated With Objective Measures and Patient Self-reports of Clinical Outcomes Including Seizure Frequency, Seizure Severity, Seizure Duration, Seizure Intensity, and Post-ictal Duration. | The purpose for determining the effect size was to power a stage 2 study. At the conclusion of stage 1 of the E-37 study, it was determined that another study would not be necessary as it would not provide incremental clinical benefit information above what has already been collected. Therefore, computation of effect size was not necessary. | Up to 18 Month Visit-End of Study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Seizures Reported by Investigators and Triple Review | 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. | Epilepsy Monitoring Unit (EMU) Stay | 
| Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Observed | 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. | Epilepsy Monitoring Unit (EMU) Stay | 
| Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Modeled | 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. | Epilepsy Monitoring Unit (EMU) Stay | 
| Assess Non-seizure Related Stimulation Rate Per Hour During EMU Stay and Stair Stepper Exercise Periods | 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). | Epilepsy Monitoring Unit (EMU) Stay | 
| Assess Characterization of Seizures (Duration and Cessation) | 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. | Epilepsy Monitoring Unit (EMU) Stay | 
| Assesses 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. | Up to 18 Month Visit-End of Study | 
| Assess Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed 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 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. | Up to 18 Month Visit-End of Study | 
| Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) | 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. | Up to 18 Month Visit-End of Study | 
| Assess Changes From Baseline in Seizure Frequency | 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. | Up to 18 Month Visit-End of Study | 
| Assess Percent Changes in Antiepileptic Drug (AED) Load From Baseline | 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. | Up to 18 Month Visit-End of Study | 
| Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System | 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. | From initial titration visit (approximately 2 weeks after implantation) up to End of Study | 
| Evaluation of 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, 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. | Up to 6 Month Visit | 
| Assess Changes in Healthcare Utilization: Inpatient Hospital Visits, Emergency Room Visits, Outpatient Hospitalizations and Physician Office Visits. | 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. | Up to 18 Month Visit-End of Study | 
| Assess Changes in Healthcare Utilization: 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 nights spent at the hospital. | Up to 18 Month Visit-End of Study | 
| Assess Changes in Healthcare Utilization: Days Per Week Patients and Caregivers Could Not Work | 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. | Up to 18 Month Visit-End of Study | 
| Assess Changes in Healthcare Utilization: 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 hours per week caregivers spent caring for patients. | Up to 18 Month Visit-End of Study | 
| Assess Changes in Healthcare Utilization: Number of Phone Calls to Physician | At baseline and each follow-up visit, subjects completed a healthcare utilization questionnaire to report the number of phone calls to physicians. | Up to 18 Month Visit-End of Study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Automatic Magnet Mode (AMM), Vagus Nerve Stimulation (VNS)