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

This study has been terminated.

(Insufficient enrollment)

Sponsor:

Information provided by (Responsible Party):

Cyberonics, Inc.

ClinicalTrials.gov Identifier:

NCT00522418

First received: August 27, 2007

Last updated: October 22, 2012

Last verified: October 2012

History of Changes

Results First Received: April 2, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Conditions:	Epilepsy Partial Epilepsy
Interventions:	Device: Vagal Nerve Simulation (VNS) Therapy Drug: Best Medical Practive

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was started in February 2006 at 41 sites and terminated on July 28, 2008 as a result of a decision by Cyberonics, Inc. The decision to terminate the study was primarily due to insufficient enrollment. The decision was not the result of a safety or efficacy signal.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
VNS Therapy	VNS Therapy + Best Medical Practice
Best Medical Practice	Best Medical Practice Without VNS Therapy

Participant Flow: Overall Study

	VNS Therapy	Best Medical Practice
STARTED	59	63
COMPLETED	2	4
NOT COMPLETED	57	59
Consent Withdraw	1	2
Treatment Failure	0	1
Subject Nonadherence	3	2
Protocol Nonadherence	4	5
Study Termination	47	48
Not Specified	1	1
Lack of Baseline data	1	0

Baseline Characteristics

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Reporting Groups

	Description
VNS Therapy	VNS Therapy + Best Medical Practice
Best Medical Practice	Best Medical Practice Without VNS Therapy
Total	Total of all reporting groups

Baseline Measures

	VNS Therapy	Best Medical Practice	Total
Number of Participants [units: participants]	59	63	122
Age ^[1] [units: Years] Mean ± Standard Deviation	38.1 ± 11.9	41.3 ± 11.5	39.7 ± 11.8
Gender [units: participants]
Female	29	28	57
Male	30	35	65
Epilepsy Etiology [units: participants]
Idiopathic	0	0	0
Symptomatic	30	31	61
Cryptogenic	29	32	61
Simple Partial Seizures ^[2] [units: patients]
No	38	34	72
Yes	17	28	45
Unknown	4	1	5
Age of Epilepsy Onset ^[3] [units: years] Mean ± Standard Deviation	12.5 ± 12.5	15.5 ± 12.5	14.0 ± 12.6
Blood Pressure - Diastolic ^[4] [units: Millimeters of mercury (mmHg)] Mean ± Standard Deviation	77.1 ± 8.0	78.4 ± 8.6	77.8 ± 8.3
Blood Pressure - Systolic ^[4] [units: Millimeters of mercury (mmHg)] Mean ± Standard Deviation	125.2 ± 12.6	125.5 ± 11.7	125.3 ± 12.1
Heart Rate ^[3] [units: Beats per minute] Mean ± Standard Deviation	74.9 ± 7.8	73.0 ± 6.5	73.9 ± 7.2
Height ^[5] [units: centimeters (cm)] Mean ± Standard Deviation	169.7 ± 9.1	171.4 ± 10.9	170.6 ± 10.1
Weight ^[5] [units: kilogram (kg)] Mean ± Standard Deviation	72.4 ± 14.5	76.0 ± 19.4	74.3 ± 17.2

[1]	Age at Randomization
[2]	Data available for 55/59 of VNS Therapy Group and 62/63 of Best Medical Practice Group.
[3]	Data available for 58/59 of VNS Therapy Group and 61/63 of Best Medical Practice Group.
[4]	Data available for 59/59 of VNS Therapy Group and 61/63 of Best Medical Practice Group.
[5]	Data available for 59/59 of VNS Therapy Group and 62/63 of Best Medical Practice Group.

Outcome Measures

Show All Outcome Measures

1. Primary:

Quality of Life in Epilepsy (QOLIE-89) [ Time Frame: Mean score at 21 and 24 months ]

Show Outcome Measure 1

2. Secondary:

Response Rate [ Time Frame: 3, 6 , 9, 12, 15, 18, 21, and 24 months ]

Show Outcome Measure 2

3. Secondary:

Percent of Patients That Are Seizure Free [ Time Frame: 3, 6, 9, 12, 15, 18, 21, 24 months ]

Show Outcome Measure 3

4. Secondary:

Mean Percent Change in Seizure Frequency [ Time Frame: 3, 6, 9, 12, 15, 18, 21, 24 months ]

Show Outcome Measure 4

5. Secondary:

Seizure Free Days [ Time Frame: From the patient's last seizure to the study exit date ]

Show Outcome Measure 5

6. Secondary:

Seizure Free Days Over the Last 6 Months [ Time Frame: Over the last 6 months ]

Show Outcome Measure 6

7. Secondary:

Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 7

8. Secondary:

Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 8

9. Secondary:

Clinical Global Impressions Scale (CGI) [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 9

10. Secondary:

Adverse Event Profile (AEP) [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 10

11. Secondary:

Changes in Anti-epileptic Drugs (AEDs) [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 11

12. Secondary:

Retention Rate [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 12

13. Secondary:

Treatment Emergent Adverse Events, Device Complications, and Premature Study Withdrawal [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 13

14. Secondary:

Quality of Life in Epilepsy - 89 Items(QOLIE-89)in Patients With Less Than a 50% Reduction in Seizures [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 14

15. Secondary:

Centre for Epidemiologic Studies Depression Scale (CES-D) in Patients With Less Then a 50% Reduction [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 15

16. Secondary:

Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) in Patients With Less Then a 50% Reduction in Seizures [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 16

17. Secondary:

Adverse Event Profile (AEP) in Patients With Less Then a 50% Reduction in Seizures [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 17

18. Secondary:

Change in the Number of Anti-epileptic Drugs Prescribed [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 18

19. Secondary:

Percent of Participants Who Were Compliant With the Protocol [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 19

20. Secondary:

Quality of Life in Epilepsy-89 (QOLIE-89) in Patients With a Baseline AEP Score Less Than 40 Versus Those Patients With a Baseline AEP Score Greater Than or Equal to 40 [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 20

21. Secondary:

Clinical Global Impressions Scale (CGI) in Patients With Less Then a 50% Reduction in Seizures [ Time Frame: At 12 and 24 months ]

Show Outcome Measure 21

Serious Adverse Events

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Other Adverse Events

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Time Frame	24 months
Additional Description	Safety data (serious adverse events and adverse events) were collected from visit 2 (randomization)for patients in the Best Medical Practice group (n=63) and in the in the VNS Therapy group (n=59). Therefore, all 122 patients randomized constituted the Safety Population.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
VNS Therapy	VNS Therapy + Best Medical Practice
Best Medical Practice	Best Medical Practice Without VNS Therapy

Other Adverse Events

	VNS Therapy	Best Medical Practice
Total, other (not including serious) adverse events
# participants affected / at risk	21/59	10/63
Cardiac disorders
Arrhythmia ^{† 1}
# participants affected / at risk	2/59 (3.39%)	0/63 (0.00%)
# events	2	0
Ear and labyrinth disorders
Ear Pain ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Tinnitus ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Endocrine disorders
Hypothyroidism ^{† 1}
# participants affected / at risk	0/59 (0.00%)	2/63 (3.17%)
# events	0	2
Eye disorders
Eyelid Disorder ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Glaucoma ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Vision Blurred ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Gastrointestinal disorders
Abdominal Pain ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	2	0
Constipation ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
General disorders
Asthenia ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Chest Pain ^{† 1}
# participants affected / at risk	3/59 (5.08%)	0/63 (0.00%)
# events	3	0
Headache ^{† 1}
# participants affected / at risk	3/59 (5.08%)	1/63 (1.59%)
# events	3	1
Complication of Device Insertion ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Facial Pain ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Local Swelling ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Pyrexia ^{† 1}
# participants affected / at risk	1/59 (1.69%)	1/63 (1.59%)
# events	1	1
Infections and infestations
Localized Infection ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Sinusitis ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Urinary Tract Infection ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Injury, poisoning and procedural complications
Fractured Sacrum ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Fall ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Metabolism and nutrition disorders
Hypercholesterolaemia ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Musculoskeletal and connective tissue disorders
Neck Pain ^{† 1}
# participants affected / at risk	2/59 (3.39%)	0/63 (0.00%)
# events	2	0
Nervous system disorders
Epilepsy ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Hypothesthia ^{† 1}
# participants affected / at risk	3/59 (5.08%)	0/63 (0.00%)
# events	4	0
Mononeuropathy ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Sedation ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Tremor ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Convulsion ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Vocal Cord Paralysis ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	2	0
Psychiatric disorders
Aggression ^{† 1}
# participants affected / at risk	2/59 (3.39%)	0/63 (0.00%)
# events	2	0
Anxiety ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Depression ^{† 1}
# participants affected / at risk	3/59 (5.08%)	0/63 (0.00%)
# events	3	0
Disorientation ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Insomnia ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Psychotic Behavior ^{† 1}
# participants affected / at risk	1/59 (1.69%)	1/63 (1.59%)
# events	1	1
Renal and urinary disorders
Nephrolithiasis ^{† 1}
# participants affected / at risk	2/59 (3.39%)	0/63 (0.00%)
# events	2	0
Respiratory, thoracic and mediastinal disorders
Cough ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Dysphonia ^{† 1}
# participants affected / at risk	8/59 (13.56%)	0/63 (0.00%)
# events	9	0
Dyspnoea ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	2	0
Oropharyngeal Pain ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Throat Tightness ^{† 1}
# participants affected / at risk	2/59 (3.39%)	0/63 (0.00%)
# events	2	0
Skin and subcutaneous tissue disorders
Nail Disorder ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Rash ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1
Scar Pain ^{† 1}
# participants affected / at risk	1/59 (1.69%)	0/63 (0.00%)
# events	1	0
Vascular disorders
Hypertension ^{† 1}
# participants affected / at risk	0/59 (0.00%)	1/63 (1.59%)
# events	0	1

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (14.1)

More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the 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. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
This study was terminated as a result of a decision by Cyberonics, Inc. The decision to terminate the study was primarily due to insufficient enrollment. The decision was not the result of a safety or efficacy signal.

Results Point of Contact:

Name/Title: Senior Director, Global Medical Affairs
Organization: Cyberonics, Inc
phone: 281-228-7223
e-mail: Mark.Bunker@cyberonics.com

Publications:

Gilliam F. Optimizing health outcomes in active epilepsy. Neurology. 2002 Apr 23;58(8 Suppl 5):S9-20. Review.

Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000 Feb 3;342(5):314-9.

Sillanpaa M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998 Jun 11;338(24):1715-22.

Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med. 1985 Jul 18;313(3):145-51.

Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med. 1992 Sep 10;327(11):765-71.

Mattson RH, Cramer JA, Collins JF. Prognosis for total control of complex partial and secondarily generalized tonic clonic seizures. Department of Veterans Affairs Epilepsy Cooperative Studies No. 118 and No. 264 Group. Neurology. 1996 Jul;47(1):68-76.

Schmidt D. The clinical impact of new antiepileptic drugs after a decade of use in epilepsy. Epilepsy Res. 2002 Jun;50(1-2):21-32. Review.

Lhatoo SD, Wong IC, Polizzi G, Sander JW. Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy. Epilepsia. 2000 Dec;41(12):1592-6.

Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology. 1999 Nov 10;53(8):1731-5. Erratum in: Neurology 2000 Apr 25;54(8):1712.

Malow BA, Edwards J, Marzec M, Sagher O, Ross D, Fromes G. Vagus nerve stimulation reduces daytime sleepiness in epilepsy patients. Neurology. 2001 Sep 11;57(5):879-84.

Harden CL, Pulver MC, Ravdin LD, Nikolov B, Halper JP, Labar DR. A Pilot Study of Mood in Epilepsy Patients Treated with Vagus Nerve Stimulation. Epilepsy Behav. 2000 Apr;1(2):93-99.

Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 2000 Dec;42(2-3):203-10.

Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci. 1999 Jan;2(1):94-8.

McLachlan RS, Sadler M, Pillay N, Guberman A, Jones M, Wiebe S, Schneiderman J. Quality of life after vagus nerve stimulation for intractable epilepsy: is seizure control the only contributing factor? Eur Neurol. 2003;50(1):16-9.

Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res. 2001 Nov;47(1-2):17-25. Review.

Gilliam FG, Fessler AJ, Baker G, Vahle V, Carter J, Attarian H. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology. 2004 Jan 13;62(1):23-7.

Responsible Party:	Cyberonics, Inc.
ClinicalTrials.gov Identifier:	NCT00522418 History of Changes
Other Study ID Numbers:	E-100
Study First Received:	August 27, 2007
Results First Received:	April 2, 2010
Last Updated:	October 22, 2012
Health Authority:	Belgium: Institutional Review Board Canada: Ethics Review Committee France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Germany: Ethics Commission Italy: Ethics Committee Netherlands: Medical Ethics Review Committee (METC) Norway:National Committee for Medical and Health Research Ethics Spain: Comité Ético de Investigación Clínica Sweden: Regional Ethical Review Board United Kingdom: Research Ethics Committee

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