drugset / Trial / NCT02104661
Protective Role of Oxcarbazepine in Multiple Sclerosis
Phase 2
Completed
30 enrolled
Queen Mary University of London
Barnet and Chase Farm Hospitals NHS Trust · collabBarts & The London NHS Trust · collabMid and South Essex NHS Foundation Trust · collabNational Multiple Sclerosis Society · collabNovartis Pharmaceuticals · collabRoyal Free Hospital NHS Foundation Trust · collabSt George's Healthcare NHS Trust · collabUniversity College, London · collab
RandomizedParallel-groupQuadruple-blindTreatment
Summary
People with multiple sclerosis (MS) have nerve loss even without acute inflammatory relapses, as obvious in the progressive phase of disease. Drugs that may prevent nerve loss work better in earlier stages when it is difficult to measure progressive disability. But it is now possible to measure the nerve loss as neurofilament light (NFL) in the cerebrospinal fluid (CSF). This is a trial of a neuroprotective drug, oxcarbazepine, which showed benefit in an animal model of multiple sclerosis. The investigators will use an innovative outcome, a reduction in the content of NFL in the CSF, as well as the usual clinical disability and imaging methods, to measure the success of the oxcarbazepine as a neuroprotective agent in MS. The use of NFL, a surrogate marker of neurodegeneration, allows a blinded and accurate outcome.
Timeline
- Start
- 2014-10
- Primary completion
- 2018-01-31
- Completion
- 2018-01-31
Publications
- Background Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278-85. doi: 10.1056/NEJM199801293380502.
- Background Leray E, Yaouanq J, Le Page E, Coustans M, Laplaud D, Oger J, Edan G. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010 Jul;133(Pt 7):1900-13. doi: 10.1093/brain/awq076. Epub 2010 Apr 27.
- Background Petzold A, de Boer JF, Schippling S, Vermersch P, Kardon R, Green A, Calabresi PA, Polman C. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2010 Sep;9(9):921-32. doi: 10.1016/S1474-4422(10)70168-X.
- Background Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, Waldmann H, Compston DA. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108. doi: 10.1007/s00415-005-0934-5. Epub 2005 Jul 27.
- Background Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008 Nov;9(11):839-55. doi: 10.1038/nrn2480.
- Background Stys PK. General mechanisms of axonal damage and its prevention. J Neurol Sci. 2005 Jun 15;233(1-2):3-13. doi: 10.1016/j.jns.2005.03.031.
- Background Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009 May;5(5):256-66. doi: 10.1038/nrneurol.2009.41.
- Background Altmann DR, Jasperse B, Barkhof F, Beckmann K, Filippi M, Kappos LD, Molyneux P, Polman CH, Pozzilli C, Thompson AJ, Wagner K, Yousry TA, Miller DH. Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis. Neurology. 2009 Feb 17;72(7):595-601. doi: 10.1212/01.wnl.0000335765.55346.fc. Epub 2008 Nov 12.
- Background Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, Chataway J, Hughes RA, Miller DH. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 2010 Jul;9(7):681-8. doi: 10.1016/S1474-4422(10)70131-9. Epub 2010 Jun 8.
- Background Ebers GC, Heigenhauser L, Daumer M, Lederer C, Noseworthy JH. Disability as an outcome in MS clinical trials. Neurology. 2008 Aug 26;71(9):624-31. doi: 10.1212/01.wnl.0000313034.46883.16. Epub 2008 May 14.
- Background Lycke JN, Karlsson JE, Andersen O, Rosengren LE. Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1998 Mar;64(3):402-4. doi: 10.1136/jnnp.64.3.402.
- Background Malmestrom C, Haghighi S, Rosengren L, Andersen O, Lycke J. Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology. 2003 Dec 23;61(12):1720-5. doi: 10.1212/01.wnl.0000098880.19793.b6.
- Background Salzer J, Svenningsson A, Sundstrom P. Neurofilament light as a prognostic marker in multiple sclerosis. Mult Scler. 2010 Mar;16(3):287-92. doi: 10.1177/1352458509359725. Epub 2010 Jan 19.
- Background Petzold A, Eikelenboom MJ, Keir G, Grant D, Lazeron RH, Polman CH, Uitdehaag BM, Thompson EJ, Giovannoni G. Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11. doi: 10.1136/jnnp.2004.043315.
- Background Semra YK, Seidi OA, Sharief MK. Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability. J Neuroimmunol. 2002 Jan;122(1-2):132-9. doi: 10.1016/s0165-5728(01)00455-6.
- Background Petzold A, Baker D, Pryce G, Keir G, Thompson EJ, Giovannoni G. Quantification of neurodegeneration by measurement of brain-specific proteins. J Neuroimmunol. 2003 May;138(1-2):45-8. doi: 10.1016/s0165-5728(03)00092-4.
- Background Norgren N, Rosengren L, Stigbrand T. Elevated neurofilament levels in neurological diseases. Brain Res. 2003 Oct 10;987(1):25-31. doi: 10.1016/s0006-8993(03)03219-0.
- Background Kuhle J, Leppert D, Petzold A, Regeniter A, Schindler C, Mehling M, Anthony DC, Kappos L, Lindberg RL. Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis. Neurology. 2011 Apr 5;76(14):1206-13. doi: 10.1212/WNL.0b013e31821432ff. Epub 2011 Feb 23.
- Background Petzold A, Rejdak K, Plant GT. Axonal degeneration and inflammation in acute optic neuritis. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1178-80. doi: 10.1136/jnnp.2003.017236.
- Background Gunnarsson M, Malmestrom C, Axelsson M, Sundstrom P, Dahle C, Vrethem M, Olsson T, Piehl F, Norgren N, Rosengren L, Svenningsson A, Lycke J. Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol. 2011 Jan;69(1):83-9. doi: 10.1002/ana.22247. Epub 2010 Dec 8.
- Background Gnanapavan S, Grant D, Morant S, Furby J, Hayton T, Teunissen CE, Leoni V, Marta M, Brenner R, Palace J, Miller DH, Kapoor R, Giovannoni G. Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression. PLoS One. 2013 Aug 1;8(8):e70019. doi: 10.1371/journal.pone.0070019. Print 2013.
- Background Al-Izki S et al. Selective targeting of neuroprotection to MS lesions: sodium channel blockers in experimental autoimmune encephalomyelitis. In: Multiple Sclerosis Journal.; 2011:S53-S276
- Background Koch MW, Polman SK. Oxcarbazepine versus carbamazepine monotherapy for partial onset seizures. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006453. doi: 10.1002/14651858.CD006453.pub2.
- Background May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of oxcarbazepine. Clin Pharmacokinet. 2003;42(12):1023-42. doi: 10.2165/00003088-200342120-00002.
- Background Lidster K et al. Neuroprotection in a novel optic neuritis model. In: Multiple Sclerosis Journal.; 2011:S227-S505 17
- Background Solaro C, Restivo D, Mancardi GL, Tanganelli P. Oxcarbazepine for treating paroxysmal painful symptoms in multiple sclerosis: a pilot study. Neurol Sci. 2007 Jun;28(3):156-8. doi: 10.1007/s10072-007-0811-3. Epub 2007 Jun 30.
- Background Lu CH, Kalmar B, Malaspina A, Greensmith L, Petzold A. A method to solubilise protein aggregates for immunoassay quantification which overcomes the neurofilament "hook" effect. J Neurosci Methods. 2011 Feb 15;195(2):143-50. doi: 10.1016/j.jneumeth.2010.11.026. Epub 2010 Dec 4.
- Background Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444-52. doi: 10.1212/wnl.33.11.1444.
- Background Hobart J, Lamping D, Fitzpatrick R, Riazi A, Thompson A. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain. 2001 May;124(Pt 5):962-73. doi: 10.1093/brain/124.5.962.
- Background Hobart J. The Multiple Sclerosis Impact Scale (MSIS-29). In: Quality of Life Measurement in Neurodegenerative and Related Conditions. Cambridge University Press; 2011:pp. 24-40
- Background Sumowski JF, Wylie GR, Deluca J, Chiaravalloti N. Intellectual enrichment is linked to cerebral efficiency in multiple sclerosis: functional magnetic resonance imaging evidence for cognitive reserve. Brain. 2010 Feb;133(Pt 2):362-74. doi: 10.1093/brain/awp307. Epub 2009 Dec 14.
- Background Henderson AP, Trip SA, Schlottmann PG, Altmann DR, Garway-Heath DF, Plant GT, Miller DH. A preliminary longitudinal study of the retinal nerve fiber layer in progressive multiple sclerosis. J Neurol. 2010 Jul;257(7):1083-91. doi: 10.1007/s00415-010-5467-x. Epub 2010 Feb 9.
- Background Black JA, Liu S, Carrithers M, Carrithers LM, Waxman SG. Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann Neurol. 2007 Jul;62(1):21-33. doi: 10.1002/ana.21172.
- Background Teunissen CE, Iacobaeus E, Khademi M, Brundin L, Norgren N, Koel-Simmelink MJ, Schepens M, Bouwman F, Twaalfhoven HA, Blom HJ, Jakobs C, Dijkstra CD. Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis. Neurology. 2009 Apr 14;72(15):1322-9. doi: 10.1212/WNL.0b013e3181a0fe3f.
- Background Fisniku LK, Chard DT, Jackson JS, Anderson VM, Altmann DR, Miszkiel KA, Thompson AJ, Miller DH. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol. 2008 Sep;64(3):247-54. doi: 10.1002/ana.21423.
- Background Roosendaal SD, Bendfeldt K, Vrenken H, Polman CH, Borgwardt S, Radue EW, Kappos L, Pelletier D, Hauser SL, Matthews PM, Barkhof F, Geurts JJ. Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability. Mult Scler. 2011 Sep;17(9):1098-106. doi: 10.1177/1352458511404916. Epub 2011 May 17.
- Background Furby J, Hayton T, Altmann D, Brenner R, Chataway J, Smith KJ, Miller DH, Kapoor R. A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis. J Neurol. 2010 Sep;257(9):1508-16. doi: 10.1007/s00415-010-5563-y. Epub 2010 May 1.
- Background Chard DT, Jackson JS, Miller DH, Wheeler-Kingshott CA. Reducing the impact of white matter lesions on automated measures of brain gray and white matter volumes. J Magn Reson Imaging. 2010 Jul;32(1):223-8. doi: 10.1002/jmri.22214.
- Background Rocca MA, Horsfield MA, Sala S, Copetti M, Valsasina P, Mesaros S, Martinelli V, Caputo D, Stosic-Opincal T, Drulovic J, Comi G, Filippi M. A multicenter assessment of cervical cord atrophy among MS clinical phenotypes. Neurology. 2011 Jun 14;76(24):2096-102. doi: 10.1212/WNL.0b013e31821f46b8.
- Background Furby J, Hayton T, Anderson V, Altmann D, Brenner R, Chataway J, Hughes R, Smith K, Miller D, Kapoor R. Magnetic resonance imaging measures of brain and spinal cord atrophy correlate with clinical impairment in secondary progressive multiple sclerosis. Mult Scler. 2008 Sep;14(8):1068-75. doi: 10.1177/1352458508093617. Epub 2008 Jul 16.
- Background Kalkers NF, Barkhof F, Bergers E, van Schijndel R, Polman CH. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult Scler. 2002 Dec;8(6):532-3. doi: 10.1191/1352458502ms849xx.
- Background Horsfield MA, Sala S, Neema M, Absinta M, Bakshi A, Sormani MP, Rocca MA, Bakshi R, Filippi M. Rapid semi-automatic segmentation of the spinal cord from magnetic resonance images: application in multiple sclerosis. Neuroimage. 2010 Apr 1;50(2):446-55. doi: 10.1016/j.neuroimage.2009.12.121. Epub 2010 Jan 7.
- Background Kearney H, Yiannakas MC, Abdel-Aziz K, Wheeler-Kingshott CA, Altmann DR, Ciccarelli O, Miller DH. Improved MRI quantification of spinal cord atrophy in multiple sclerosis. J Magn Reson Imaging. 2014 Mar;39(3):617-23. doi: 10.1002/jmri.24194. Epub 2013 Apr 30.
- Background Inglese M, Madelin G, Oesingmann N, Babb JS, Wu W, Stoeckel B, Herbert J, Johnson G. Brain tissue sodium concentration in multiple sclerosis: a sodium imaging study at 3 tesla. Brain. 2010 Mar;133(Pt 3):847-57. doi: 10.1093/brain/awp334. Epub 2010 Jan 27.
- Background Paling D et al. Total sodium concentration is increased in lesions and normal appearing white matter in Multiple Sclerosis. In: ISMRM.; 2012
- Background Schneider T, Wheeler-Kingshott CA, Alexander DC. In-vivo estimates of axonal characteristics using optimized diffusion MRI protocols for single fibre orientation. Med Image Comput Comput Assist Interv. 2010;13(Pt 1):623-30. doi: 10.1007/978-3-642-15705-9_76.
- Background Schneider T. Mapping the axon diameter index in the corpus callosum is clinically feasible. In: ISMRM.; 2012
- Background Henderson AP, Trip SA, Schlottmann PG, Altmann DR, Garway-Heath DF, Plant GT, Miller DH. An investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography. Brain. 2008 Jan;131(Pt 1):277-87. doi: 10.1093/brain/awm285. Epub 2007 Dec 4.
- Background Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704.
- Background Andersohn F, Schade R, Willich SN, Garbe E. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology. 2010 Jul 27;75(4):335-40. doi: 10.1212/WNL.0b013e3181ea157e.
- Background Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Edith Chan AW, Amor S, Perkins V, Gerritsen WH, Ummenthum K, Peferoen-Baert R, van der Valk P, Montoya A, Joel SP, Garthwaite J, Giovannoni G, Selwood DL, Baker D. Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain. 2014 Jan;137(Pt 1):92-108. doi: 10.1093/brain/awt324. Epub 2013 Nov 27.
- Background Davis A, Dobson R, Kaninia S, Espasandin M, Berg A, Giovannoni G, Schmierer K. Change practice now! Using atraumatic needles to prevent post lumbar puncture headache. Eur J Neurol. 2014 Feb;21(2):305-11. doi: 10.1111/ene.12307. Epub 2013 Dec 9.
- Background Petzold A, Altintas A, Andreoni L, Bartos A, Berthele A, Blankenstein MA, Buee L, Castellazzi M, Cepok S, Comabella M, Constantinescu CS, Deisenhammer F, Deniz G, Erten G, Espino M, Fainardi E, Franciotta D, Freedman MS, Giedraitis V, Gilhus NE, Giovannoni G, Glabinski A, Grieb P, Hartung HP, Hemmer B, Herukka SK, Hintzen R, Ingelsson M, Jackson S, Jacobsen S, Jafari N, Jalosinski M, Jarius S, Kapaki E, Kieseier BC, Koel-Simmelink MJ, Kornhuber J, Kuhle J, Kurzepa J, Lalive PH, Lannfelt L, Lehmensiek V, Lewczuk P, Livrea P, Marnetto F, Martino D, Menge T, Norgren N, Papuc E, Paraskevas GP, Pirttila T, Rajda C, Rejdak K, Ricny J, Ripova D, Rosengren L, Ruggieri M, Schraen S, Shaw G, Sindic C, Siva A, Stigbrand T, Stonebridge I, Topcular B, Trojano M, Tumani H, Twaalfhoven HA, Vecsei L, Van Pesch V, Vanderstichele H, Vedeler C, Verbeek MM, Villar LM, Weissert R, Wildemann B, Yang C, Yao K, Teunissen CE. Neurofilament ELISA validation. J Immunol Methods. 2010 Jan 31;352(1-2):23-31. doi: 10.1016/j.jim.2009.09.014. Epub 2009 Oct 24.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Oxcarbazepine | Small molecule | 150 mg | — |