Pilot Trial of Domperidone in Relapsing-Remitting Multiple Sclerosis (RRMS)

Summary

The first major objective of this pilot trial is to demonstrate that it is possible to study myelin repair in relapsing-remitting multiple sclerosis (RRMS) patients with enhancing lesions on MRI by using advanced imaging techniques. To demonstrate that this is possible the investigators will recruit 24 RRMS patients who are being treated with standard disease modifying therapy (DMT) and have new lesions identified on clinically indicated brain MRI scans and measure myelin repair at 16 and 32 weeks using MRI measures of myelin repair. The second major objective is to determine how much repair occurs in participants treated with domperidone compared with those who are not treated. This will allow us to design larger trials to confirm that domperidone improves repair. The study will also confirm the safety and tolerability of domperidone in RRMS, determine circulating prolactin levels during dosing with domperidone 10mg three times daily in people with RRMS, and explore the impact of other clinical factors (such as age) on lesion repair. In addition, blood will be collected to test for metabolomics and the investigators will bank blood for future study of biomarkers that can help the investigators better understand MS. Metabolomics is an experimental test where changes in the pattern of the chemicals in blood cells are compared at different time points (during and after inflammation). There will be random changes but changes that are common in most study participants may help identify chemicals that signal stages in injury or repair. The investigators will also compare the pattern of change in those with the best repair to those with the worst repair. This may help identify a chemical that is associated with better or worse repair and help develop new treatment strategies. There are currently no blood tests that help in the diagnosis of MS, help determine which drug a person will respond to, or help determine a person's expected MS outcome. Any such tests would be considered biomarkers.

Timeline

Start

2015-08

Primary completion

2019-02

Completion

2019-02

Publications

• Background Alonso-Ortiz E, Levesque IR, Pike GB. MRI-based myelin water imaging: A technical review. Magn Reson Med. 2015 Jan;73(1):70-81. doi: 10.1002/mrm.25198. Epub 2014 Mar 6.
• Background Bagnato F, Jeffries N, Richert ND, Stone RD, Ohayon JM, McFarland HF, Frank JA. Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years. Brain. 2003 Aug;126(Pt 8):1782-9. doi: 10.1093/brain/awg182. Epub 2003 Jun 23.
• Background Barkhof F, Bruck W, De Groot CJ, Bergers E, Hulshof S, Geurts J, Polman CH, van der Valk P. Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. Arch Neurol. 2003 Aug;60(8):1073-81. doi: 10.1001/archneur.60.8.1073.
• 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 Bernini GP, Lucarini AR, Franchi F, Salvetti A. Humoral effects of metoclopramide and domperidone in normal subjects and in hypertensive patients. J Endocrinol Invest. 1988 Nov;11(10):711-6. doi: 10.1007/BF03350925.
• Background Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003 Dec 9;61(11):1528-32. doi: 10.1212/01.wnl.0000096175.39831.21.
• Background Filippi M, Rovaris M, Rocca MA, Sormani MP, Wolinsky JS, Comi G; Eurpoean/Canadian Glatiramer Acetate Study Group. Glatiramer acetate reduces the proportion of new MS lesions evolving into "black holes". Neurology. 2001 Aug 28;57(4):731-3. doi: 10.1212/wnl.57.4.731.
• 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 Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol. 2000 Dec;48(6):893-901.
• Background Metz LM, Zhang Y, Yeung M, Patry DG, Bell RB, Stoian CA, Yong VW, Patten SB, Duquette P, Antel JP, Mitchell JR. Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2004 May;55(5):756. doi: 10.1002/ana.20111. No abstract available.
• Background Sloka S, Metz LM, Hader W, Starreveld Y, Yong VW. Reduction of microglial activity in a model of multiple sclerosis by dipyridamole. J Neuroinflammation. 2013 Jul 18;10:89. doi: 10.1186/1742-2094-10-89.
• Background Chandran S, Hunt D, Joannides A, Zhao C, Compston A, Franklin RJ. Myelin repair: the role of stem and precursor cells in multiple sclerosis. Philos Trans R Soc Lond B Biol Sci. 2008 Jan 12;363(1489):171-83. doi: 10.1098/rstb.2006.2019.
• Background Franklin RJ. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci. 2002 Sep;3(9):705-14. doi: 10.1038/nrn917.
• Background Zhao C, Fancy SP, Kotter MR, Li WW, Franklin RJ. Mechanisms of CNS remyelination--the key to therapeutic advances. J Neurol Sci. 2005 Jun 15;233(1-2):87-91. doi: 10.1016/j.jns.2005.03.008.
• Background Gregg C, Shikar V, Larsen P, Mak G, Chojnacki A, Yong VW, Weiss S. White matter plasticity and enhanced remyelination in the maternal CNS. J Neurosci. 2007 Feb 21;27(8):1812-23. doi: 10.1523/JNEUROSCI.4441-06.2007.
• Background Xiao L, Xu H, Zhang Y, Wei Z, He J, Jiang W, Li X, Dyck LE, Devon RM, Deng Y, Li XM. Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes. Mol Psychiatry. 2008 Jul;13(7):697-708. doi: 10.1038/sj.mp.4002064. Epub 2007 Aug 7.
• Background Mi S, Pepinsky RB, Cadavid D. Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. CNS Drugs. 2013 Jul;27(7):493-503. doi: 10.1007/s40263-013-0068-8.
• Background Nerozzi D, Magnani A, Dastoli C, Ferri E, Capesciotti G, Antonozzi I, Frajese G, Meltzer HY. Prolactin responses to domperidone in chronic schizophrenia. Psychiatry Res. 1992 May;42(2):159-69. doi: 10.1016/0165-1781(92)90079-i.
• Background Knoppert DC, Page A, Warren J, Seabrook JA, Carr M, Angelini M, Killick D, Dasilva OP. The effect of two different domperidone doses on maternal milk production. J Hum Lact. 2013 Feb;29(1):38-44. doi: 10.1177/0890334412438961. Epub 2012 May 3.
• Background Mallik S, Samson RS, Wheeler-Kingshott CA, Miller DH. Imaging outcomes for trials of remyelination in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014 Dec;85(12):1396-404. doi: 10.1136/jnnp-2014-307650. Epub 2014 Apr 25.
• Zhang Y, Liu WQ, Hosseinpour Z, Pike GB, Cerchiaro G, Greenfield J, Yong VW, Metz LM. Feasibility study to assess lesion repair in relapsing-remitting multiple sclerosis: A randomized controlled pilot clinical trial of domperidone add-on treatment. Mult Scler Relat Disord. 2024 May;85:105525. doi: 10.1016/j.msard.2024.105525. Epub 2024 Feb 27.

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