Trial Outcomes & Findings for VNS Therapy Automatic Magnet Mode Outcomes Study in Epilepsy Patients Exhibiting Ictal Tachycardia (E-37) (NCT NCT01846741)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

20 participants

Primary outcome timeframe

Up to 18 Month Visit-End of Study

Results posted on

2015-11-24

Participant Flow

Eligible subjects were at least 12 years old, good general health suitable for VNS implant with refractory (drug-resistant) partial onset seizures and a history of ictal tachycardia, defined as heart rate above 100 beats per minute (bpm) during a seizure and at least a 55% increase or 35 bpm increase from baseline.

A total of (22) subjects were screened; (2) did not meet study criteria, (20) were treated/implanted with the AspireSR® VNS Therapy® System.

Participant milestones

Participant milestones
Measure	VNS Therapy - ITT Population Subjects who were implanted with the AspireSR® VNS Therapy® System. The intent-to-treat (ITT) population is defined as all subjects with the VNS Therapy system implanted and the device had been turned on.
Baseline Visit STARTED	22
Baseline Visit COMPLETED	20
Baseline Visit NOT COMPLETED	2
Implantation to 18-Month/End of Study STARTED	20
Implantation to 18-Month/End of Study COMPLETED	20
Implantation to 18-Month/End of Study NOT COMPLETED	0

Reasons for withdrawal

Reasons for withdrawal
Measure	VNS Therapy - ITT Population Subjects who were implanted with the AspireSR® VNS Therapy® System. The intent-to-treat (ITT) population is defined as all subjects with the VNS Therapy system implanted and the device had been turned on.
Baseline Visit Subject did not meet entry criteria	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	VNS Therapy (ITT Population) n=20 Participants Subjects who were implanted with the AspireSR® VNS Therapy® System.
Age, Continuous	35.6 Years STANDARD_DEVIATION 14.1 • n=5 Participants
Age, Customized	31 years n=5 Participants
Age, Customized 18-29 years	9 years n=5 Participants
Age, Customized 30-39 years	5 years n=5 Participants
Age, Customized 40-49 years	2 years n=5 Participants
Age, Customized 50-59 years	2 years n=5 Participants
Age, Customized 60 years or older	2 years n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants
Race/Ethnicity, Customized White	15 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	3 participants n=5 Participants
Cognitive Status Normal	14 participants n=5 Participants
Cognitive Status Minimal Impairment	6 participants n=5 Participants
Time from diagnosis to VNS therapy	17 years n=5 Participants
Previous brain or Epilepsy surgery No	12 participants n=5 Participants
Previous brain or Epilepsy surgery Yes	8 participants n=5 Participants
Etiology Idiopathic Partial	8 participants n=5 Participants
Etiology Symptomatic Partial	10 participants n=5 Participants
Etiology Cryptogenic	2 participants n=5 Participants
Family history of seizures No	12 participants n=5 Participants
Family history of seizures Yes	8 participants n=5 Participants
Seizures with auras in past 2 months No	7 participants n=5 Participants
Seizures with auras in past 2 months Yes	13 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 18 Month Visit-End of Study

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Epilepsy Monitoring Unit (EMU) Stay

Population: ITT Population: Consists of all patients in the safety population who have any EMU performance recorded data and experienced any seizures.

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=16 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=16 Participants EMU Seizures Identified Post EMU	Total n=16 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Summary of Seizures Reported by Investigators and Triple Review Unclassified	0 Number of Seizures	4 Number of Seizures	4 Number of Seizures	—	—	—
Summary of Seizures Reported by Investigators and Triple Review All Seizure Types	84 Number of Seizures	5 Number of Seizures	89 Number of Seizures	—	—	—
Summary of Seizures Reported by Investigators and Triple Review Total Partial Seizures	76 Number of Seizures	0 Number of Seizures	76 Number of Seizures	—	—	—
Summary of Seizures Reported by Investigators and Triple Review Simple Partial	37 Number of Seizures	0 Number of Seizures	37 Number of Seizures	—	—	—
Summary of Seizures Reported by Investigators and Triple Review Complex Partial	38 Number of Seizures	0 Number of Seizures	38 Number of Seizures	—	—	—
Summary of Seizures Reported by Investigators and Triple Review Secondarily Generalized	1 Number of Seizures	0 Number of Seizures	1 Number of Seizures	—	—	—
Summary of Seizures Reported by Investigators and Triple Review Sub-Clinical	8 Number of Seizures	1 Number of Seizures	9 Number of Seizures	—	—	—

SECONDARY outcome

Timeframe: Epilepsy Monitoring Unit (EMU) Stay

Population: ITT Population (Investigator Reported Seizures + Triple Review). N= represents total number of seizures.

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=16 Participants All Seizures Identified (During EMU)	Reported by Triple Review EMU Seizures Identified Post EMU	Total Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Observed >= 70% heart rate increase at Setting 1 (n=1)	0 Percent of True Positive Seizures Confidence interval was not calculated where the mean sensitivity equals to 100%, or where number of patients within the setting is less than or equal to 2 (acceleration cannot be calculated)	—	—	—	—	—
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Observed >= 60% heart rate increase at Setting 2 (n=9)	100 Percent of True Positive Seizures Confidence interval was not calculated where the mean sensitivity equals to 100%, or where number of patients within the setting is less than or equal to 2 (acceleration cannot be calculated)	—	—	—	—	—
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Observed >= 40% heart rate increase at Setting 4 (n=1)	100 Percent of True Positive Seizures Confidence interval was not calculated where the mean sensitivity equals to 100%, or where number of patients within the setting is less than or equal to 2 (acceleration cannot be calculated)	—	—	—	—	—
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Observed >= 30% heart rate increase at Setting 5 (n=2)	50 Percent of True Positive Seizures Confidence interval was not calculated where the mean sensitivity equals to 100%, or where number of patients within the setting is less than or equal to 2 (acceleration cannot be calculated)	—	—	—	—	—

SECONDARY outcome

Timeframe: Epilepsy Monitoring Unit (EMU) Stay

Population: ITT Population (Investigator Reported Seizures + Triple Review). N= represents total number of seizures.

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=16 Participants All Seizures Identified (During EMU)	Reported by Triple Review EMU Seizures Identified Post EMU	Total Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Modeled >= 70% heart rate increase at Setting 1 (n=8)	87.5 Percent of True Positive Seizures Interval 77.0 to 100.0	—	—	—	—	—
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Modeled >= 60% heart rate increase at Setting 2 (n=12)	100 Percent of True Positive Seizures Confidence interval was not calculated where the mean sensitivity equals to 100%	—	—	—	—	—
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Modeled >= 50% heart rate increase at Setting 3 (n=20)	95 Percent of True Positive Seizures Interval 91.0 to 100.0	—	—	—	—	—
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Modeled >= 40% heart rate increase at Setting 4 (n=23)	100 Percent of True Positive Seizures Confidence interval was not calculated where the mean sensitivity equals to 100%	—	—	—	—	—
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Modeled >= 30% heart rate increase at Setting 5 (n=31)	100 Percent of True Positive Seizures Confidence interval was not calculated where the mean sensitivity equals to 100%	—	—	—	—	—
Assess Performance of the Tachycardia Detection Algorithm (Sensitivity) During an EMU Stay Based on ITT Population-Modeled >= 20% heart rate increase at Setting 6 (n=38)	100 Percent of True Positive Seizures Confidence interval was not calculated where the mean sensitivity equals to 100%	—	—	—	—	—

SECONDARY outcome

Timeframe: Epilepsy Monitoring Unit (EMU) Stay

Population: ITT Population. 5 participants analyzed for \>=70%, 4 for \>=60% setting, 8 for \>=50% setting, 2 for \>=40% setting, 1 for the \>=30% setting.

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).

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Non-seizure Related Stimulation Rate Per Hour During EMU Stay and Stair Stepper Exercise Periods >=70%, n=5	0.4 detections per hour Interval 0.1 to 1.0	1.6 detections per hour Interval 0.0 to 6.4	—	—	—	—
Assess Non-seizure Related Stimulation Rate Per Hour During EMU Stay and Stair Stepper Exercise Periods >=60%, n=4	0.8 detections per hour Interval 0.3 to 1.4	4.0 detections per hour Interval 0.0 to 9.9	—	—	—	—
Assess Non-seizure Related Stimulation Rate Per Hour During EMU Stay and Stair Stepper Exercise Periods >=50%, n=8	1.2 detections per hour Interval 0.8 to 1.6	6.2 detections per hour Interval 2.0 to 12.2	—	—	—	—
Assess Non-seizure Related Stimulation Rate Per Hour During EMU Stay and Stair Stepper Exercise Periods >=40%, n=2	0.6 detections per hour Confidence intervals were not calculated where number of subjects within the setting is less than or equal to 2 (acceleration can not be calculated)	6.6 detections per hour Confidence intervals were not calculated where number of subjects within the setting is less than or equal to 2 (acceleration can not be calculated)	—	—	—	—
Assess Non-seizure Related Stimulation Rate Per Hour During EMU Stay and Stair Stepper Exercise Periods >= 30%, n=1	4.6 detections per hour Confidence intervals were not calculated where number of subjects within the setting is less than or equal to 2 (acceleration can not be calculated)	5.0 detections per hour Confidence intervals were not calculated where number of subjects within the setting is less than or equal to 2 (acceleration can not be calculated)	—	—	—	—

SECONDARY outcome

Timeframe: Epilepsy Monitoring Unit (EMU) Stay

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=31 Seizures Treated All Seizures Identified (During EMU)	Reported by Triple Review n=12 Seizures Treated EMU Seizures Identified Post EMU	Total n=1 Seizures Treated Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=12 Seizures Treated During AutoStim Course in The EMU	Sub-Clinical Seizures n=4 Seizures Treated During AutoStim Course in The EMU	Unknown Seizures n=2 Seizures Treated During AutoStim Course in The EMU
Assess Characterization of Seizures (Duration and Cessation)	61.3 Percent of Seizures Ended During Stim	41.7 Percent of Seizures Ended During Stim	0 Percent of Seizures Ended During Stim	83.3 Percent of Seizures Ended During Stim	75.0 Percent of Seizures Ended During Stim	50.0 Percent of Seizures Ended During Stim

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total n=20 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assesses Changes in Seizure Severity Based on Physician Reported Questionnaire (NHS3) Baseline to 3 Months; n=17,2,9	-2.0 units on a scale Interval -9.5 to 2.0	-3.5 units on a scale Interval -4.0 to -3.0	0.0 units on a scale Interval -2.0 to 3.0	—	—	—
Assesses Changes in Seizure Severity Based on Physician Reported Questionnaire (NHS3) Baseline to 6 Months; n=17,4,11	-0.5 units on a scale Interval -12.0 to 3.0	-1.0 units on a scale Interval -9.0 to 2.0	0.0 units on a scale Interval -2.0 to 1.0	—	—	—
Assesses Changes in Seizure Severity Based on Physician Reported Questionnaire (NHS3) Baseline to 12 Months; n=18,6,10	-1.0 units on a scale Interval -12.0 to 3.0	-3.0 units on a scale Interval -7.0 to 3.0	0.0 units on a scale Interval -2.0 to 2.0	—	—	—
Assesses Changes in Seizure Severity Based on Physician Reported Questionnaire (NHS3) Baseline to 18 Months; n=15, 6, 9	-3.0 units on a scale Interval -5.0 to 4.0	-2.5 units on a scale Interval -6.0 to -1.0	0.0 units on a scale Interval -6.0 to 10.0	—	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total n=20 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=20 Participants During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Questionnaire (SSQ) SSQ Total Score n=19,20,20,17 MIC=0.48	1.349 Units on a Scale Standard Deviation 1.488	1.442 Units on a Scale Standard Deviation 1.736	1.469 Units on a Scale Standard Deviation 1.908	1.711 Units on a Scale Standard Deviation 1.389	—	—
Assess Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Questionnaire (SSQ) Activity During Seizure; n=15,17,16, 15 MIC=0.5	1.567 Units on a Scale Standard Deviation 2.890	1.294 Units on a Scale Standard Deviation 2.840	1.469 Units on a Scale Standard Deviation 2.895	1.200 Units on a Scale Standard Deviation 2.242	—	—
Assess Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Questionnaire (SSQ) Overall Recovery; n=19,20,19,17 MIC=0.39	1.298 Units on a Scale Standard Deviation 2.215	1.489 Units on a Scale Standard Deviation 2.570	1.942 Units on a Scale Standard Deviation 2.817	1.922 Units on a Scale Standard Deviation 1.862	—	—
Assess Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Questionnaire (SSQ) Overall Severity; n=19,20,20,17 MIC=0.48	1.246 Units on a Scale Standard Deviation 2.137	1.383 Units on a Scale Standard Deviation 2.238	1.767 Units on a Scale Standard Deviation 2.717	1.765 Units on a Scale Standard Deviation 1.711	—	—
Assess Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Questionnaire (SSQ) Postictal Emotional Recovery n=19,20,19,17MIC=0.34	1.351 Units on a Scale Standard Deviation 2.430	1.733 Units on a Scale Standard Deviation 2.494	1.825 Units on a Scale Standard Deviation 2.838	1.922 Units on a Scale Standard Deviation 2.631	—	—
Assess Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Questionnaire (SSQ) Postictal Physical Recovery; n=19,20,19,17MIC=0.48	1.123 Units on a Scale Standard Deviation 2.803	1.450 Units on a Scale Standard Deviation 3.789	2.088 Units on a Scale Standard Deviation 3.778	2.098 Units on a Scale Standard Deviation 2.710	—	—
Assess Changes in Seizures Severity, Intensity & Post-Ictal Recovery Based on Patient Completed Questionnaire (SSQ) Postictal Cognitive Recovery;n=19,20,19,17MIC=0.42	1.421 Units on a Scale Standard Deviation 3.166	1.283 Units on a Scale Standard Deviation 3.436	1.912 Units on a Scale Standard Deviation 3.878	1.745 Units on a Scale Standard Deviation 2.917	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total n=20 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=20 Participants During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) QOLIE Overall Total Score; n=20,20,19,18 MIC=5.19	11.0 Units on a Scale Standard Deviation 18.8	11.8 Units on a Scale Standard Deviation 19.1	13.3 Units on a Scale Standard Deviation 23.6	14.4 Units on a Scale Standard Deviation 24.1	—	—
Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) Energy/Fatigue; n=20,20,20,19 MIC=5.25	2.7 Units on a Scale Standard Deviation 25.6	4.0 Units on a Scale Standard Deviation 22.7	8.8 Units on a Scale Standard Deviation 26.1	6.1 Units on a Scale Standard Deviation 32.4	—	—
Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) Emotional well being; n=20,20,20,18 MIC=4.76	7.7 Units on a Scale Standard Deviation 25.4	8.7 Units on a Scale Standard Deviation 27.7	10.1 Units on a Scale Standard Deviation 33.5	3.0 Units on a Scale Standard Deviation 36.5	—	—
Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) Social Functioning; n=19,20,20,18 MIC=3.95	11.0 Units on a Scale Standard Deviation 25.9	11.0 Units on a Scale Standard Deviation 18.2	9.6 Units on a Scale Standard Deviation 25.6	12.5 Units on a Scale Standard Deviation 30.1	—	—
Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) Cognitive Functioning; n=20,20,20,19 MIC=5.34	19.2 Units on a Scale Standard Deviation 24.6	19.0 Units on a Scale Standard Deviation 24.4	16.6 Units on a Scale Standard Deviation 30.4	16.3 Units on a Scale Standard Deviation 32.7	—	—
Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) Medication Effects; n=19,20,19,19 MIC=5.0	10.3 Units on a Scale Standard Deviation 33.1	8.1 Units on a Scale Standard Deviation 30.0	10.4 Units on a Scale Standard Deviation 37.5	16.7 Units on a Scale Standard Deviation 33.2	—	—
Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) Seizure Worry; n=20,20,20,19 MIC=7.42	16.4 Units on a Scale Standard Deviation 32.2	16.9 Units on a Scale Standard Deviation 28.6	20.9 Units on a Scale Standard Deviation 27.6	23.3 Units on a Scale Standard Deviation 29.2	—	—
Assess Changes From Baseline in Quality of Life Based on Patient Completed Questionnaire (QOLIE-31-P) Overall Quality of Life; n=20,20,19,17 MIC=6.42	10.6 Units on a Scale Standard Deviation 24.7	14.6 Units on a Scale Standard Deviation 27.8	13.1 Units on a Scale Standard Deviation 30.6	19.1 Units on a Scale Standard Deviation 29.5	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Changes From Baseline in Seizure Frequency At 3-Month Visit; n=5,4	25 Percentage of Participants Interval 8.66 to 49.1	20 Percentage of Participants Interval 5.73 to 43.66	—	—	—	—
Assess Changes From Baseline in Seizure Frequency At 6-Month Visit; n=7,7	35 Percentage of Participants Interval 15.39 to 59.22	35 Percentage of Participants Interval 15.39 to 59.22	—	—	—	—
Assess Changes From Baseline in Seizure Frequency At 12-Month Visit; n=10,10	50 Percentage of Participants Interval 27.2 to 72.8	50 Percentage of Participants Interval 27.2 to 72.8	—	—	—	—
Assess Changes From Baseline in Seizure Frequency At 18-Month Visit; n=11,11	55 Percentage of Participants Interval 31.53 to 76.94	55 Percentage of Participants Interval 31.53 to 76.94	—	—	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review EMU Seizures Identified Post EMU	Total Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Percent Changes in Antiepileptic Drug (AED) Load From Baseline At 3 months	0 Percent Change Interval 0.0 to 30.0	—	—	—	—	—
Assess Percent Changes in Antiepileptic Drug (AED) Load From Baseline At 6 months	0 Percent Change Interval -24.96 to 30.0	—	—	—	—	—
Assess Percent Changes in Antiepileptic Drug (AED) Load From Baseline At 12 months	3.35 Percent Change Interval -59.55 to 52.74	—	—	—	—	—
Assess Percent Changes in Antiepileptic Drug (AED) Load From Baseline At 18 Months	0 Percent Change Interval -59.55 to 42.0	—	—	—	—	—

SECONDARY outcome

Timeframe: From initial titration visit (approximately 2 weeks after implantation) up to End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review EMU Seizures Identified Post EMU	Total Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Convulsion	6 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Dysphonia	6 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Oropharyngeal Pain	3 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Stress	3 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Urinary Tract Infection	2 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Contusion	2 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Dysphagia	2 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Headache	2 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Tooth Fracture	2 Number of Participants	—	—	—	—	—
Assess All Adverse Events to Outline the Tolerability Profile of the AspireSR® VNS Therapy® System Umblical Hernia	2 Number of Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to 6 Month Visit

Population: ITT Population

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".

Outcome measures

Outcome measures
Measure	Reported By Investigators n=18 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=18 Participants EMU Seizures Identified Post EMU	Total n=20 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=18 Participants During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Evaluation of Human Factors and Usability of the AspireSR® VNS Therapy® System.	89 Percentage of Participants Rated 1 or 2	83 Percentage of Participants Rated 1 or 2	95 Percentage of Participants Rated 1 or 2	100 Percentage of Participants Rated 1 or 2	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total n=20 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=20 Participants During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Changes in Healthcare Utilization: Inpatient Hospital Visits, Emergency Room Visits, Outpatient Hospitalizations and Physician Office Visits. Inpatient Hospital visits, n=20, 20, 20, 20	0 Visits Interval 0.0 to 0.0	0 Visits Interval 0.0 to 1.0	0 Visits Interval 0.0 to 1.0	0 Visits Interval 0.0 to 1.0	—	—
Assess Changes in Healthcare Utilization: Inpatient Hospital Visits, Emergency Room Visits, Outpatient Hospitalizations and Physician Office Visits. Emergency Room Visits, n=20, 20, 20, 20	0 Visits Interval 0.0 to 1.0	0 Visits Interval 0.0 to 2.0	0 Visits Interval 0.0 to 4.0	0 Visits Interval 0.0 to 2.0	—	—
Assess Changes in Healthcare Utilization: Inpatient Hospital Visits, Emergency Room Visits, Outpatient Hospitalizations and Physician Office Visits. Outpatient Hospital Visits, n=20, 20, 20, 19	0 Visits Interval 0.0 to 1.0	0 Visits Interval 0.0 to 1.0	0 Visits Interval 0.0 to 3.0	0 Visits Interval 0.0 to 1.0	—	—
Assess Changes in Healthcare Utilization: Inpatient Hospital Visits, Emergency Room Visits, Outpatient Hospitalizations and Physician Office Visits. Physician Office Visits, n=20, 20, 20, 20	0 Visits Interval 0.0 to 4.0	0 Visits Interval 0.0 to 4.0	0 Visits Interval 0.0 to 4.0	0 Visits Interval 0.0 to 8.0	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total n=20 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=20 Participants During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Changes in Healthcare Utilization: Number of Nights Spent at the Hospital	0 Nights Interval 0.0 to 0.0	0 Nights Interval 0.0 to 1.0	0 Nights Interval 0.0 to 1.0	0 Nights Interval 0.0 to 3.0	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total n=20 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=20 Participants During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Changes in Healthcare Utilization: Days Per Week Patients and Caregivers Could Not Work #of DD/WK Could not work or Play(Pt),n=18,18,19,20	0 Days Per Week Interval 0.0 to 3.0	0 Days Per Week Interval 0.0 to 7.0	0 Days Per Week Interval 0.0 to 3.0	0 Days Per Week Interval 0.0 to 7.0	—	—
Assess Changes in Healthcare Utilization: Days Per Week Patients and Caregivers Could Not Work #of DD/WK Could not Work(Caregiver),n=18, 20,17,15	0 Days Per Week Interval 0.0 to 7.0	0 Days Per Week Interval 0.0 to 7.0	0 Days Per Week Interval 0.0 to 7.0	0 Days Per Week Interval 0.0 to 7.0	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Reported By Investigators n=19 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total n=17 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=15 Participants During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Changes in Healthcare Utilization: Number of Hours Per Week Caregivers Spent Caring for Patients.	2.0 Hours Per Week Interval 0.0 to 100.0	1.0 Hours Per Week Interval 0.0 to 56.0	4.0 Hours Per Week Interval 0.0 to 168.0	2.0 Hours Per Week Interval 0.0 to 168.0	—	—

SECONDARY outcome

Timeframe: Up to 18 Month Visit-End of Study

Population: ITT Population

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

Outcome measures

Outcome measures
Measure	Reported By Investigators n=20 Participants All Seizures Identified (During EMU)	Reported by Triple Review n=20 Participants EMU Seizures Identified Post EMU	Total n=20 Participants Seizures Reported by Investigators and Triple Reviewers	Simple Partial Seizures n=19 Participants During AutoStim Course in The EMU	Sub-Clinical Seizures During AutoStim Course in The EMU	Unknown Seizures During AutoStim Course in The EMU
Assess Changes in Healthcare Utilization: Number of Phone Calls to Physician	0 Phone Calls Interval 0.0 to 5.0	0 Phone Calls Interval 0.0 to 3.0	0 Phone Calls Interval 0.0 to 7.0	0 Phone Calls Interval 0.0 to 10.0	—	—

Adverse Events

VNS Therapy - Safety Population

Serious events: 3 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	VNS Therapy - Safety Population n=20 participants at risk All adverse events were collected from baseline up to the end of study for all subjects treated/implanted with the AspireSR® VNS Therapy® system. Only the most common AEs (\> 5%) are reported in the AE data table.
Surgical and medical procedures Incision wound cellulitis	5.0% 1/20 • After Implantation up to 18 months-End of Study
Surgical and medical procedures Post-procedural hematoma	5.0% 1/20 • After Implantation up to 18 months-End of Study
Nervous system disorders Altered State of Consciousness	5.0% 1/20 • After Implantation up to 18 months-End of Study
Injury, poisoning and procedural complications Subdural Hematoma	5.0% 1/20 • After Implantation up to 18 months-End of Study

Other adverse events

Other adverse events
Measure	VNS Therapy - Safety Population n=20 participants at risk All adverse events were collected from baseline up to the end of study for all subjects treated/implanted with the AspireSR® VNS Therapy® system. Only the most common AEs (\> 5%) are reported in the AE data table.
Respiratory, thoracic and mediastinal disorders Dysphonia	35.0% 7/20 • After Implantation up to 18 months-End of Study
Nervous system disorders Convulsion	30.0% 6/20 • After Implantation up to 18 months-End of Study
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	15.0% 3/20 • After Implantation up to 18 months-End of Study
Psychiatric disorders Stress	15.0% 3/20 • After Implantation up to 18 months-End of Study
Infections and infestations Urinary Tract Infection	10.0% 2/20 • After Implantation up to 18 months-End of Study
Gastrointestinal disorders Nausea	10.0% 2/20 • After Implantation up to 18 months-End of Study
Injury, poisoning and procedural complications Procedural Pain	10.0% 2/20 • After Implantation up to 18 months-End of Study
Injury, poisoning and procedural complications Tooth Fracture	10.0% 2/20 • After Implantation up to 18 months-End of Study
Gastrointestinal disorders Vomiting	10.0% 2/20 • After Implantation up to 18 months-End of Study
Gastrointestinal disorders Dysphagia	10.0% 2/20 • After Implantation up to 18 months-End of Study
Nervous system disorders Headache	10.0% 2/20 • After Implantation up to 18 months-End of Study
Injury, poisoning and procedural complications Contusion	10.0% 2/20 • After Implantation up to 18 months-End of Study
Gastrointestinal disorders Umblical Hernia	10.0% 2/20 • After Implantation up to 18 months-End of Study

Additional Information

Bita Najimipour, Clinical Study Manager

Cyberonics, Inc.

Phone: (281) 228-7370

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted for sponsor's review if such publication contains Confidential Information or will adversely affect any intellectual property or proprietary right of the sponsor. The sponsor can require changes to the communication, but cannot extend the embargo set forth in the study agreement.
Publication restrictions are in place

Restriction type: OTHER