Trial Outcomes & Findings for Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients (NCT NCT00522418)

Last Updated: 2015-01-26

Results Overview

QOLIE-89 contains 17 multi-item measures of overall quality of life, emotional well-being, role limitations due to emotional problems, social support, social isolation, energy/fatigue, worry about seizure, medication effects, health discouragement, work/driving/social function, attention/concentration, language, memory, physical function, pain, role limitations due to physical problems, and health perceptions. Range of values 0-100. Higher scores reflect better quality of life; lower ones, worse quality of life.

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

122 participants

Primary outcome timeframe

Mean change from baseline QOLIE-89 Overall Score at 12 months

Results posted on

2015-01-26

Participant Flow

This study was conducted between February 2006 and July 2008 and was prematurely terminated by Cyberonics, Inc. due to a low enrollment rate and not as a result of a safety or efficacy signal. There were 9 screen failures out of 131 screened patients, leaving 122 patients who started the study and are described in the Participant Flow.

Patients were randomized in a 1:1 ratio to the Best Medical Practice With Adjunctive VNS Therapy study group or to the Best Medical Practice Without VNS Therapy study group. VNS Therapy is delivered by an implantable device similar to a pacemaker that sends mild stimulation to the left vagus nerve to help improve seizure control.

Participant milestones

Participant milestones
Measure	VNS Therapy VNS Therapy + Best Medical Practice	Best Medical Practice Best Medical Practice Without VNS Therapy
Overall Study STARTED	59	63
Overall Study Safety Set	54	58
Overall Study Efficacy Set	48	48
Overall Study Baseline and Month 3	47	47
Overall Study Baseline and Month 6	38	45
Overall Study Baseline and Month 9	33	35
Overall Study Baseline and Month 12	31	29
Overall Study COMPLETED	2	5
Overall Study NOT COMPLETED	57	58

Reasons for withdrawal

Reasons for withdrawal
Measure	VNS Therapy VNS Therapy + Best Medical Practice	Best Medical Practice Best Medical Practice Without VNS Therapy
Overall Study Local IRB Consent Violation	5	5
Overall Study Early Study Termination	46	47
Overall Study Noncompliance	2	2
Overall Study Reason Not Specified	3	1
Overall Study Consent Withdraw	1	2
Overall Study Lack of Efficacy	0	1

Baseline Characteristics

Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	VNS Therapy n=48 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=48 Participants Best Medical Practice Without VNS Therapy	Total n=96 Participants Total of all reporting groups
Age, Continuous	38 Years STANDARD_DEVIATION 13 • n=5 Participants	41 Years STANDARD_DEVIATION 11 • n=7 Participants	40 Years STANDARD_DEVIATION 12 • n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	21 Participants n=7 Participants	45 Participants n=5 Participants
Sex: Female, Male Male	24 Participants n=5 Participants	27 Participants n=7 Participants	51 Participants n=5 Participants
Age of Epilepsy Onset	13 years STANDARD_DEVIATION 14 • n=5 Participants	16 years STANDARD_DEVIATION 14 • n=7 Participants	15 years STANDARD_DEVIATION 14 • n=5 Participants
Etiology of Epilepsy Structural/Metabolic	26 participants n=5 Participants	26 participants n=7 Participants	52 participants n=5 Participants
Etiology of Epilepsy Unknown	22 participants n=5 Participants	22 participants n=7 Participants	44 participants n=5 Participants

PRIMARY outcome

Timeframe: Mean change from baseline QOLIE-89 Overall Score at 12 months

Population: Due to early study termination \& only a few patients (n=7) achieving 2 year follow-up, study data for the 24 month time point is not available. However, at the 12 month time point there was an adequate amount of patient study data for analysis. This outcome measure evaluates the data for sixty (60) patients.

Outcome measures

Outcome measures
Measure	VNS Therapy n=31 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=29 Participants Best Medical Practice Without VNS Therapy
Overall Quality of Life in Epilepsy-89 (QOLIE-89) Score in Patients With Baseline & at Least One Post-baseline QOLIE Assessment	5.5 units on a scale Standard Deviation 7.2	1.2 units on a scale Standard Deviation 6.9

SECONDARY outcome

Timeframe: Number of Responders at 12 Months

Response Rate is defined as the percent of participants who are responders. A Responder is defined as participants with a reduction of at least 50% or 75% in seizure frequency from baseline to the seizure count evaluation period.

Outcome measures

Outcome measures
Measure	VNS Therapy n=31 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=29 Participants Best Medical Practice Without VNS Therapy
Response Rate	10 participants	7 participants

SECONDARY outcome

Timeframe: 3, 6, 9, 12, 15, 18, 21, 24 months

Population: This study was conducted between February 2006 and July 2008 and was prematurely terminated by Cyberonics, Inc. due to a low enrollment rate and not as a result of a safety or efficacy signal. Because of early termination and limited data this outcome measure was not tabulated.

Percent of patients that are seizure free as defined by no seizures during the preceding follow-up period.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Mean percent change from baseline in seizure frequency at 12 months

Percent change in total seizuires per week from baseline at 12 months

Outcome measures

Outcome measures
Measure	VNS Therapy n=31 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=29 Participants Best Medical Practice Without VNS Therapy
Mean Percent Change in Seizure Frequency	-19.1 Percent Change Standard Deviation 43.92	-1.0 Percent Change Standard Deviation 56.66

SECONDARY outcome

Timeframe: From the patient's last seizure to the study exit date

Seizure free days is defined as the time from last seizure to study exit date.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Over the last 6 months

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Mean change from baseline CES-D Score at 12 months

The Center for Epidemiologic Studies Depression Scale (CES-D) includes 20 items comprising six scales reflecting major dimensions of depression: depressed mood, feelings of guilt and worthlessness, feelings of helplessness and hopelessness, psychomotor retardation, loss of appetite, and sleep disturbance. Possible range of scores is 0 to 60, higher scores indicate more depressive symptoms.

Outcome measures

Outcome measures
Measure	VNS Therapy n=31 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=29 Participants Best Medical Practice Without VNS Therapy
Change From Baseline in Center for Epidemiologic Studies Depression Scale (CES-D) Score	-2.2 Units on a Scale Standard Deviation 7.0	0.5 Units on a Scale Standard Deviation 8.1

SECONDARY outcome

Timeframe: Mean change from baseline NDDI-E Score at 12 months

The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) is a 6-item questionnaire validated to screen for depression in people with epilepsy. Scores range from 6 to 24, with higher scores indicating more depressive symptoms.

Outcome measures

Outcome measures
Measure	VNS Therapy n=31 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=29 Participants Best Medical Practice Without VNS Therapy
Change From Baseline in Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) Score	-1.0 Units on a Scale Standard Deviation 2.2	-0.2 Units on a Scale Standard Deviation 3.4

SECONDARY outcome

Timeframe: Mean change from baseline CGI-I Score at 12 months

The Clinical Global Impression scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention Scores range from 1-7: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.

Outcome measures

Outcome measures
Measure	VNS Therapy n=31 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=29 Participants Best Medical Practice Without VNS Therapy
Mean Change From Beginning of Intervention Clinical Global Impression-Improvement Scale (CGI-I) Score at 12 Months	-0.8 Units on a Scale Standard Deviation 0.8	-0.3 Units on a Scale Standard Deviation 1.1

SECONDARY outcome

Timeframe: Mean change from baseline AEP Score at 12 months

Adverse Events Profile (AEP) is a 19-item scale used as a systematic measure of adverse effects from antiepileptic drugs (AEDs). Scores range from 19-76; higher scores indicate high prevelance and severity of adverse events.

Outcome measures

Outcome measures
Measure	VNS Therapy n=31 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=29 Participants Best Medical Practice Without VNS Therapy
Change From Baseline in Adverse Event Profile (AEP) Score	-6.0 Units on a scale Standard Deviation 11.4	-3.2 Units on a scale Standard Deviation 6.9

SECONDARY outcome

Timeframe: Change from baseline in number of AEDs at 12 months

Change from baseline in number of AED medications by visit

Outcome measures

Outcome measures
Measure	VNS Therapy n=31 Participants VNS Therapy + Best Medical Practice	Best Medical Practice n=28 Participants Best Medical Practice Without VNS Therapy
Changes in Anti-epileptic Drugs (AEDs)	0 Number of AEDs Taken Interval -1.0 to 1.0	0 Number of AEDs Taken Interval -1.0 to 2.0

SECONDARY outcome

Timeframe: At 12 and 24 months

Percent of participants who were compliant with the protocol.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 12 and 24 months

Number of participants with treatment emergent adverse events, device complications, and premature Study withdrawal.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 12 and 24 months

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 12 and 24 months

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 12 and 24 months

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 12 and 24 months

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 12 and 24 months

Changes in Anti-Epileptic Drugs (AEDs) in patients with less then a 50% reduction in seizures

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 12 and 24 months

Retention rate in patients with less then a 50% reduction in seizures

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Change from baseline up to 12 months

Population: This outcome measure includes patients from both arms, VNS + BMP (N=30) and BMP alone (N=31), with an overall QOLIE-89 at baseline and any other post baseline visit up to 12 months. Subgroup Analysis of population with Baseline Adverse Event Profile Score \>= 40

QOLIE-89 contains 17 multi-item measures of overall quality of life. Range of values 0-100. Higher scores reflect better quality of life; lower ones, worse quality of life. Adverse Events Profile (AEP) is a 19-item scale used as a systematic measure of adverse effects from antiepileptic drugs (AEDs). Scores range from 19-76; higher scores indicate high prevelance and severity of adverse events.

Outcome measures

Outcome measures
Measure	VNS Therapy n=61 Participants VNS Therapy + Best Medical Practice	Best Medical Practice Best Medical Practice Without VNS Therapy
Change From Baseline in QOLIE-89 Measures: Subgroup Analysis of Population With Baseline Adverse Event Profile Score >= 40 VNS Therapy	3.3 Units on a Scale Standard Error 1.14	—
Change From Baseline in QOLIE-89 Measures: Subgroup Analysis of Population With Baseline Adverse Event Profile Score >= 40 Best Medical Practice	0.7 Units on a Scale Standard Error 1.08	—

SECONDARY outcome

Timeframe: Change from baseline up to 12 months

Population: This outcome measure includes patients from both arms VNS + BMP (N=17) and BMP alone (N=17), with an overall QOLIE-89 at baseline and any other baseline visit up to 12 months. Subgroup Analysis of Population With Baseline Adverse Event Profile Score \< 40

Outcome measures

Outcome measures
Measure	VNS Therapy n=34 Participants VNS Therapy + Best Medical Practice	Best Medical Practice Best Medical Practice Without VNS Therapy
Change From Baseline in QOLIE-89 Measures: Subgroup Analysis of Population With Baseline Adverse Event Profile Score < 40 VNS Therapy	3.3 units on a scale Standard Error 1.50	—
Change From Baseline in QOLIE-89 Measures: Subgroup Analysis of Population With Baseline Adverse Event Profile Score < 40 Best Medical Practice	0.5 units on a scale Standard Error 1.52	—

SECONDARY outcome

Timeframe: At 12 and 24 months

The Clinical Global Impression scale (CGI-I)is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention Scores range from 1-7: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.

Outcome measures

Outcome data not reported

Adverse Events

VNS Therapy

Serious events: 5 serious events

Other events: 21 other events

Deaths: 0 deaths

Best Medical Practice

Serious events: 3 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Mark Bunker, Senior Director, Global Medical Affairs

Cyberonics, Inc

Phone: 281-228-7223

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Investigator and Site agree not to publish or otherwise publicaly disclose clinical data generated in connection with the Study, unless approved in advance in writing by Cyberonics. Investigators and Site agree to provide Cyberonics with a copy of any proposed publication, abstract, or presentation relating to the research conducted under this Agreement at least 30 days prior to submission for publication or presentation.
Publication restrictions are in place

Restriction type: OTHER

Measure	VNS Therapy n=54 participants at risk VNS Therapy + Best Medical Practice	Best Medical Practice n=58 participants at risk Best Medical Practice Without VNS Therapy
Musculoskeletal and connective tissue disorders Intervertebral Disc Disorder	0.00% 0/54 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Nervous system disorders Depression	0.00% 0/54 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Nervous system disorders Cerebellar Infarction	0.00% 0/54 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Respiratory, thoracic and mediastinal disorders Laryngospasm	1.9% 1/54 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Renal and urinary disorders Urinary Tract Infection	0.00% 0/54 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
General disorders Fall	1.9% 1/54 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
General disorders Suicide Attempt	1.9% 1/54 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Nervous system disorders Convulsion	1.9% 1/54 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Injury, poisoning and procedural complications Head Injury	1.9% 1/54 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Nervous system disorders Epilepsy	1.9% 1/54 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Musculoskeletal and connective tissue disorders Neck Pain	0.00% 0/54 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Musculoskeletal and connective tissue disorders Pain in Extremity	0.00% 0/54 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Nervous system disorders Paraesthesia	0.00% 0/54 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Surgical and medical procedures Prostate Cancer	1.9% 1/54 • Number of events 2 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Surgical and medical procedures Prostatectomy	1.9% 1/54 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Surgical and medical procedures Renal Stone Removal	0.00% 0/54 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	1.7% 1/58 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Respiratory, thoracic and mediastinal disorders Respiratory Arrest	1.9% 1/54 • Number of events 1 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.
Nervous system disorders Vocal Cord Paralysis	1.9% 1/54 • Number of events 3 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.	0.00% 0/58 • 24 months A total of 122 patients were randomized to receive VNS + BMP or BMP alone. Data from one study site (including 10 randomized patients) was removed from the analysis datasets due to lack of ICF approval by site's local ethics committee. The remaining 112, VNS + BMP (n=54) \& BMP alone (n=58), randomized patients were included in the safety analyses.