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

An Open Prospective Randomised Long-Term Effectiveness Study, Comparing Best Medical Practice With or Without Adjunctive VNS Therapy in Patients 16 Years and Older With Pharmaco-resistant Partial Epilepsy

This is a post-market medical device study. This study will compare best medical practice with or without adjunctive VNS Therapy in patients who are 16 years and older with pharmacoresistant partial epilepsy.

Study Overview

• Status: Terminated
• Conditions: Epilepsy; Partial Epilepsy
• Intervention / Treatment: Device: Vagal Nerve Simulation (VNS) Therapy; Drug: Best Medical Practive

Detailed Description

This is a post-market medical device study. This study will compare best medical practice with or without adjunctive VNS Therapy in patients who are 16 years and older with pharmaco-resistant partial epilepsy. The Sponsor, Cyberonics, provides funding for this study. Patients are followed for 26 months, 24 of those months are following the initiation of treatment. No study sites will be permitted to enroll study subjects until Institutional Review Board (IRB)/Ethics Committee (EC) approval has been received.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • ULB-Hôpital Erasme, Centre de référence pour le traitement de l'épilepsie réfractaire - Neurologie
  • Gent, Belgium, 9000
    • UZ Gent, Department of Neurology, 1K12/A
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y6J4
      • Foothills Hospital, Neurology Department
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • QEII Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • Hopital Notre Dame
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute, Clinical Research
• France
  • Grenoble, France, 38043
    • CHU Grenoble, Neurology Department
  • Lille, France, 59037
    • Hopital Roger Salengro, Service de Neurologie
  • Lyon, France, 69003
    • Hôpital Neurologique, Untité d'épileptologie
  • Montpellier, France, 34295
    • Hôpital Gui De Chauliac, Service Explorations Neurologiques et Epileptologie
  • Paris, France, 75674
    • Hôpital Sainte-Anne, Service de Neurochirurgie
  • Strasbourg, France, 67091
    • Service d'exploration des épilepsies
  • Tours, France, 37044
    • CHU Tours, Service de neurologie
• Germany
  • Bonn, Germany, 53105
    • Universitätskliniken Bonn, Klinik für Epileptologie
  • Erlangen, Germany, 91054
    • Universitätsklinik Erlangen, Zentrum für Epilepsie ZEE
  • Greifswald, Germany, 17487
    • Klinik der Ernst-Moritz-Arndt-Universität, Neurologische Klinik
  • Kehl-Kork, Germany, 77694
    • Epilepsiezentrum Kork
  • Marburg, Germany, 35039
    • Klinikum der Philips-Universität Marburg, Fachbereich, 20 - Medizin / Klinik Neurologie / Epilepsie Zentrum
  • Radeberg, Germany, 01465
    • Sächsisches Epilepsiezentrum Radeberg, Epilepsiezentrum Kleinwachau
• Italy
  • Ancona, Italy, 60100
    • Azienda Ospedaliero Universitaria - Ospedali Riuniti Umberto I - Lancisi - Salesi, NeuroPsichiatria Infantile
  • Bologna, Italy, 40123
    • Universita di Bologna, Clinica Neurologica
  • Firenze, Italy, 50100
    • Azienda Ospendaliero-Universitaria, Caressi Dep Neuroscience
  • Milano, Italy, 20142
    • Ospedale San Paolo, Centro Epilessia
  • Monserrato, Italy, 09042
    • Universita degli Studi di Cagliari - Policlinico Monserrato, Clinica Neurologica
  • Pisa, Italy, 56126
    • Universita di Pisa, Clinica Neurologica
  • Pontedera, Italy, 56025
    • Ospedale F. Lotti, NeuroFisioPatalogia
  • Reggio Calabria, Italy, 89100
    • Azienda Ospedaliera "Bianchi Melacrino Morelli", Centro Regionale Epilessie
  • Roma, Italy, 00168
    • Università Cattolica Del Sacro Cuore, Istituto di NeuroChirurgia
  • Torino, Italy, 10126
    • Centro Epilessia, Dipartimento di Neuroscienze
• Netherlands
  • Blaricum, Netherlands, 1261, AN
    • Tergooiziekenhuizen, Dienst Neurologie
  • Enschede, Netherlands, 7513 R
    • Medisch Spectrum Twente, Dienst Neurologie
  • Heemstede, Netherlands, 8025 BV
    • Stichting Epilepsie Instituut Nederland, Dienst Neurologie
  • Oosterhout, Netherlands, 4901 ZG
    • Kempenhaeghe, Dienst Neurologie
  • Rotterdam, Netherlands, 3078 HT
    • Medisch Centrum Rijnmond-Zuid, locatie Clara, Dienst Neurologie
• Norway
  • Sandvika, Norway, 1306
    • Spesialsykehuset for Epilepsi, Dep of Neurodiagnostics
• Spain
  • Madrid, Spain, 28034
    • Hospital Ruber Internacional, Servicio de neurología
  • Santiago de Compostela, Spain, 15706
    • Hospital Clínico de Santiago
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario, Servicio de neurología
  • Valencia, Spain, 46014
    • Hospital General de Valencia, Neurology/Neurophisiology
  • Valencia, Spain, 46930
    • Hospital General Basico De La Defensa de Valencia, Servicio de neurología
• Sweden
  • Goteborg, Sweden, 41345
    • Institute of Neuroscience and Physiology, Clinical Neuroscience and Rehabilitation
  • Lund, Sweden, 221 85
    • Universitetssjukhuset i Lund, Neurologiska kliniken
  • Umea, Sweden, 901 85
    • Norrlands Universitetssjukhus, Neurocentrum
  • Uppsala, Sweden, 751 85
    • Akademiska sjukhuset, Neurocentrum
• United Kingdom
  • Cambridge, United Kingdom, CB2 2QQ
    • Addenbrookes Hospital, Dept of Neurosurgery
  • Fazakerley, United Kingdom, L97LJ
    • Walton Centre, Dept of Neurosciences, Clinical Sciences Centre
  • London, United Kingdom, SE5 9RS
    • Kings College Hospital, Dept of Neurosurgery
  • London, United Kingdom, WC1N3B
    • National Hospital For Neurology and Neurosurgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient has confirmed partial onset seizures.
• Seizure activity is not adequately controlled by patient's current AED regimen.
• Patient is between 16 and 75 years of age.
• Patient is able to give accurate seizure counts and health outcomes information. Patient is able to complete study instruments with minimal assistance.
• Patient has previously failed at least 3 AEDs in single or combination use.
• During baseline evaluation period, patient should take at least 1 AED.
• Patient should have confirmed epilepsy for a minimum of 2 years.
• Patient's AED regimen is stable for at least 1 month prior to enrolment.
• Patient has at least 1 objective partial onset seizure per month during the 2 months prior to enrolment.
• Patient or legal guardian understands study procedures and has voluntarily signed an informed consent in accordance with institutional and local regulatory policies.

Exclusion Criteria:

• Patient has pseudoseizures or a history of pseudoseizures.
• Patient has idiopathic generalised epilepsy or unclassified epilepsy.
• Patient has ever received direct brain stimulation (cerebella or thalamic) for treatment of epilepsy.
• Patient has had a unilateral or bilateral cervical vagotomy.
• Patient has a history of non-compliance with the completion of a seizure diary.
• Patient has taken an investigational drug within a period of 3 months prior to inclusion.
• Patient is currently using another investigational medical device.
• Patient has a significant cardiac or pulmonary condition currently under treatment.
• Patient has previously undergone brain surgery.
• Patient has a demand cardiac pacemaker, implantable defibrillator, or other implantable stimulator.
• Patient currently lives more than 2 hours from the study site or plans to relocate to a location more than 2 hours from the study site within one year of enrolment in the Study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VNS Therapy; VNS Therapy + Best Medical Practice	Device: Vagal Nerve Simulation (VNS) Therapy; VNS Therapy + Best Medical Practice including anti-epileptic drugs
Active Comparator: Best Medical Practice	Drug: Best Medical Practive; Best Medical Practice including anti-Epileptic Drugs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Quality of Life in Epilepsy-89 (QOLIE-89) Score in Patients With Baseline & at Least One Post-baseline QOLIE Assessment	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.	Mean change from baseline QOLIE-89 Overall Score at 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	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.	Number of Responders at 12 Months
Percent of Patients That Are Seizure Free	Percent of patients that are seizure free as defined by no seizures during the preceding follow-up period.	3, 6, 9, 12, 15, 18, 21, 24 months
Mean Percent Change in Seizure Frequency	Percent change in total seizuires per week from baseline at 12 months	Mean percent change from baseline in seizure frequency at 12 months
Seizure Free Days	Seizure free days is defined as the time from last seizure to study exit date.	From the patient's last seizure to the study exit date
Seizure Free Days Over the Last 6 Months		Over the last 6 months
Change From Baseline in Center for Epidemiologic Studies Depression Scale (CES-D) Score	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.	Mean change from baseline CES-D Score at 12 months
Change From Baseline in Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) Score	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.	Mean change from baseline NDDI-E Score at 12 months
Mean Change From Beginning of Intervention Clinical Global Impression-Improvement Scale (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.	Mean change from baseline CGI-I Score at 12 months
Change From Baseline in Adverse Event Profile (AEP) Score	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.	Mean change from baseline AEP Score at 12 months
Changes in Anti-epileptic Drugs (AEDs)	Change from baseline in number of AED medications by visit	Change from baseline in number of AEDs at 12 months
Retention Rate	Percent of participants who were compliant with the protocol.	At 12 and 24 months
Treatment Emergent Adverse Events, Device Complications, and Premature Study Withdrawal	Number of participants with treatment emergent adverse events, device complications, and premature Study withdrawal.	At 12 and 24 months
Quality of Life in Epilepsy - 89 Items(QOLIE-89)in Patients With Less Than a 50% Reduction in Seizures	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.	At 12 and 24 months
Centre for Epidemiologic Studies Depression Scale (CES-D) in Patients With Less Then a 50% Reduction	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.	At 12 and 24 months
Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) in Patients With Less Then a 50% Reduction in Seizures	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.	At 12 and 24 months
Adverse Event Profile (AEP) in Patients With Less Then a 50% Reduction in Seizures	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.	At 12 and 24 months
Change in the Number of Anti-epileptic Drugs Prescribed	Changes in Anti-Epileptic Drugs (AEDs) in patients with less then a 50% reduction in seizures	At 12 and 24 months
Percent of Participants Who Were Compliant With the Protocol	Retention rate in patients with less then a 50% reduction in seizures	At 12 and 24 months
Change From Baseline in QOLIE-89 Measures: 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.	Change from baseline up to 12 months
Change From Baseline in QOLIE-89 Measures: 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.	Change from baseline up to 12 months
Clinical Global Impressions Scale (CGI) in Patients With Less Then a 50% Reduction in Seizures	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.	At 12 and 24 months

Collaborators and Investigators

• Sponsor: Cyberonics, Inc.
• Investigators: Principal Investigator: Phillippe Ryvlin, MD, Hopital Neurologique, Lyon, France; Study Director: Sophie Leyman, MD, Cyberonics Europe

Publications and helpful links

General Publications

• Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000 Feb 3;342(5):314-9. doi: 10.1056/NEJM200002033420503.
• 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. doi: 10.1038/4600.
• Gilliam F. Optimizing health outcomes in active epilepsy. Neurology. 2002 Apr 23;58(8 Suppl 5):S9-20. doi: 10.1212/wnl.58.8_suppl_5.s9.
• 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. doi: 10.1212/wnl.62.1.23.
• 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. doi: 10.1056/NEJM199806113382402.
• 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. doi: 10.1056/NEJM198507183130303.
• 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. doi: 10.1056/NEJM199209103271104.
• 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. doi: 10.1212/wnl.47.1.68.
• 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. doi: 10.1016/s0920-1211(02)00065-7.
• 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. doi: 10.1111/j.1499-1654.2000.001592.x.
• 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. doi: 10.1212/wnl.53.8.1731. 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. doi: 10.1212/wnl.57.5.879.
• 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. doi: 10.1006/ebeh.2000.0046.
• 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. doi: 10.1016/s0920-1211(00)00181-9.
• 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. doi: 10.1159/000070853.
• 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. doi: 10.1016/s0920-1211(01)00286-8.
• Ryvlin P, Gilliam FG, Nguyen DK, Colicchio G, Iudice A, Tinuper P, Zamponi N, Aguglia U, Wagner L, Minotti L, Stefan H, Boon P, Sadler M, Benna P, Raman P, Perucca E. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia. 2014 Jun;55(6):893-900. doi: 10.1111/epi.12611. Epub 2014 Apr 22. Erratum In: Epilepsia. 2014 Sep;55(9):1476. Epilepsia. 2015 Jun;56(6):983.

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): July 1, 2008

Study Registration Dates

• First Submitted: August 27, 2007
• First Submitted That Met QC Criteria: August 27, 2007
• First Posted (Estimate): August 29, 2007

Study Record Updates

• Last Update Posted (Estimate): January 26, 2015
• Last Update Submitted That Met QC Criteria: January 9, 2015
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: Epilepsy; VNS Therapy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Epilepsies, Partial
• Other Study ID Numbers: E-100