Background: Pediatric multiple sclerosis (MS) is rare: only 1.5-5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS. Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13-17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR). Results: Twenty participants [median (range) age, 17 (14-18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16-24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0-6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction (n = 20; 95% confidence interval: 66.8-92.8; p < 0.0001) vs. the year before DMF initiation. Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment.

Biogen Cambridge MA United States

Dasman Diabetes Institute Dasman Kuwait and Amiri Hospital Sharq Kuwait

Department of Pediatric Neurology and Developmental Medicine Hauner Children's Hospital University of Munich Munich Germany

Department of Pediatrics and Pediatric Neurology University Medical Center Göttingen Göttingen Germany

Klinika Neurologii Rozwojowej Uniwersyteckie Centrum Kliniczne Gdansk Poland

Loma Linda University Children's Health Loma Linda CA United States

Neurologicka klinika Fakultni nemocnice Hradec Kralove Hradec Kralove Czechia

See more in PubMed

Renoux C, Vukusic S, Mikaeloff Y, Edan G, Clanet M, Dubois B, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med. (2007) 356:2603–13. 10.1056/NEJMoa067597 PubMed DOI

Harding KE, Liang K, Cossburn MD, Ingram G, Hirst CL, Pickersgill TP, et al. . Long-term outcome of paediatric-onset multiple sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. (2013) 84:141–7. 10.1136/jnnp-2012-303996 PubMed DOI

Ghezzi A, Deplano V, Faroni J, Grasso MG, Liguori M, Marrosu G, et al. . Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler. (1997) 3:43–6. 10.1177/135245859700300105 PubMed DOI

Chitnis T, Glanz B, Jaffin S, Healy B. Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler. (2009) 15:627–31. 10.1177/1352458508101933 PubMed DOI

Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. (2014) 13:936–48. 10.1016/S1474-4422(14)70093-6 PubMed DOI PMC

Duquette P, Murray TJ, Pleines J, Ebers GC, Sadovnick D, Weldon P, et al. . Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr. (1987) 111:359–63. 10.1016/S0022-3476(87)80454-7 PubMed DOI

Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D. Early onset multiple sclerosis: a longitudinal study. Neurology. (2002) 59:1006–10. 10.1212/WNL.59.7.1006 PubMed DOI

Sindern E, Haas J, Stark E, Wurster U. Early onset MS under the age of 16: clinical and paraclinical features. Acta Neurol Scand. (1992) 86:280–4. 10.1111/j.1600-0404.1992.tb05086.x PubMed DOI

Multiple Sclerosis International Federation Atlas of MS 2013: Mapping Multiple Sclerosis Around the World. (2013). Available online at: https://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf (accessed November 16, 2017).

Benson LA, Healy BC, Gorman MP, Baruch NF, Gholipour T, Musallam A, et al. . Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years. Mult Scler Relat Disord. (2014) 3:186–93. 10.1016/j.msard.2013.06.004 PubMed DOI

Gorman MP, Healy BC, Polgar-Turcsanyi M, Chitnis T. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol. (2009) 66:54–9. 10.1001/archneurol.2008.505 PubMed DOI

Marrie RA, O'Mahony J, Maxwell C, Ling V, Till C, Barlow-Krelina E, et al. . Factors associated with health care utilization in pediatric multiple sclerosis. Mult Scler Relat Disord. (2019) 38:101511. 10.1016/j.msard.2019.101511 PubMed DOI

Pohl D, Waubant E, Banwell B, Chabas D, Chitnis T, Weinstock-Guttman B, et al. . Treatment of pediatric multiple sclerosis and variants. Neurology. (2007) 68:S54–65. 10.1212/01.wnl.0000259407.40023.ab PubMed DOI

Ghezzi A, Banwell B, Boyko A, Amato MP, Anlar B, Blinkenberg M, et al. . The management of multiple sclerosis in children: a European view. Mult Scler. (2010) 16:1258–67. 10.1177/1352458510375568 PubMed DOI

Waubant E, Banwell B, Wassmer E, Sormani MP, Amato MP, Hintzen R, et al. . Clinical trials of disease-modifying agents in pediatric MS: opportunities, challenges, and recommendations from the IPMSSG. Neurology. (2019) 92:e2538–49. 10.1212/WNL.0000000000007572 PubMed DOI PMC

Ghezzi A, Amato MP, Makhani N, Shreiner T, Gärtner J, Tenembaum S. Pediatric multiple sclerosis: conventional first-line treatment and general management. Neurology. (2016) 87:S97–102. 10.1212/WNL.0000000000002823 PubMed DOI

Simone M, Chitnis T. Use of disease-modifying therapies in pediatric MS. Curr Treat Options Neurol. (2016) 18:36. 10.1007/s11940-016-0420-7 PubMed DOI

European Medicines Agency Assessment Report. Rebif: International Non-proprietary Name: INTERFERON BETA-1A. (2013). Available online at: https://www.ema.europa.eu/en/documents/variation-report/rebif-h-c-136-ii-0103-epar-assessment-report-variation_en.pdf (accessed February 12, 2018).

Chitnis T, Ghezzi A, Bajer-Kornek B, Boyko A, Giovannoni G, Pohl D. Pediatric multiple sclerosis: escalation and emerging treatments. Neurology. (2016) 87:S103–9. 10.1212/WNL.0000000000002884 PubMed DOI

Ghezzi A, Moiola L, Pozzilli C, Brescia-Morra V, Gallo P, Grimaldi LM, et al. . Natalizumab in the pediatric MS population: results of the Italian registry. BMC Neurol. (2015) 15:174. 10.1186/s12883-015-0433-y PubMed DOI PMC

Dale RC, Brilot F, Duffy LV, Twilt M, Waldman AT, Narula S, et al. . Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. (2014) 83:142–50. 10.1212/WNL.0000000000000570 PubMed DOI PMC

Feng J, Rensel M. Review of the safety, efficacy and tolerability of fingolimod in the treatment of pediatric patients with relapsing-remitting forms of multiple sclerosis (RRMS). Pediatr Health Med Ther. (2019) 10:141–6. 10.2147/PHMT.S220817 PubMed DOI PMC

Chitnis T, Arnold DL, Banwell B, Brück W, Ghezzi A, Giovannoni G, et al. . Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med. (2018) 379:1017–27. 10.1056/NEJMoa1800149 PubMed DOI

Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. (2012) 367:1087–97. 10.1056/NEJMoa1206328 PubMed DOI

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. (2012) 367:1098–107. 10.1056/NEJMoa1114287 PubMed DOI

Saida T, Yamamura T, Kondo T, Yun J, Yang M, Li J, et al. . A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries. BMC Neurol. (2019) 19:5. 10.1186/s12883-018-1220-3 PubMed DOI PMC

Gold R, Arnold DL, Bar-Or A, Hutchinson M, Kappos L, Havrdova E. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: interim analysis of ENDORSE, a randomized extension study. Mult Scler. (2017) 23:253–65. 10.1177/1352458516649037 PubMed DOI PMC

Biogen Data on File Cambridge, MA: (2020).

Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos. (2009) 37:1819–25. 10.1124/dmd.109.028209 PubMed DOI

Makhani N, Schreiner T. Oral dimethyl fumarate in children with multiple sclerosis: a dual-center study. Pediatr Neurol. (2016) 57:101–4. 10.1016/j.pediatrneurol.2016.01.010 PubMed DOI

Alroughani R, Das R, Penner N, Pultz J, Taylor C, Eraly S. Safety and efficacy of delayed-release dimethyl fumarate in pediatric patients with relapsing multiple sclerosis (FOCUS). Pediatr Neurol. (2018) 83:19–24. 10.1016/j.pediatrneurol.2018.03.007 PubMed DOI

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. . Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. (2011) 69:292–302. 10.1002/ana.22366 PubMed DOI PMC

Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, et al. . International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. (2013) 19:1261–7. 10.1177/1352458513484547 PubMed DOI

Fox RJ, Chan A, Gold R, Phillips JT, Selmaj K, Chang I, et al. . Characterizing absolute lymphocyte count profiles in dimethyl fumarate-treated patients with MS: patient management considerations. Neurol Clin Pract. (2016) 6:220–9. 10.1212/CPJ.0000000000000238 PubMed DOI PMC

Lanzillo R, Moccia M, Palladino R, Signoriello E, Carotenuto A, Maniscalco GT, et al. . Clinical predictors of dimethyl fumarate response in multiple sclerosis: a real life multicentre study. Mult Scler Relat Disord. (2020) 38:101871. 10.1016/j.msard.2019.101871 PubMed DOI

Gold R, Arnold DL, Bar-Or A, Fox RJ, Kappos L, Chen C. Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years' follow-up of DEFINE, CONFIRM, and ENDORSE. Ther Adv Neurol Disord. (2020) 13:1756286420915005. 10.1177/1756286420915005 PubMed DOI PMC

Min J, Cohan S, Alvarez E, Sloane J, Phillips JT, van der Walt A, et al. . Real-world characterization of dimethyl fumarate-related gastrointestinal events in multiple sclerosis: management strategies to improve persistence on treatment and patient outcomes. Neurol Ther. (2019) 8:109–19. 10.1007/s40120-019-0127-2 PubMed DOI PMC

McKay KA, Hillert J, Manouchehrinia A. Long-term disability progression of pediatric-onset multiple sclerosis. Neurology. (2019) 92:e2764–73. 10.1212/WNL.0000000000007647 PubMed DOI PMC

Bar-Or A, Hintzen RQ, Dale RC, Rostasy K, Bruck W, Chitnis T. Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases. Neurology. (2016) 87:S12–9. 10.1212/WNL.0000000000002821 PubMed DOI

Banwell B, Bar-Or A, Cheung R, Kennedy J, Krupp LB, Becker DJ. Abnormal T-cell reactivities in childhood inflammatory demyelinating disease and type 1 diabetes. Ann Neurol. (2008) 63:98–111. 10.1002/ana.21244 PubMed DOI

McLaughlin KA, Chitnis T, Newcombe J, Franz B, Kennedy J, McArdel S, et al. . Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J Immunol. (2009) 183:4067–76. 10.4049/jimmunol.0801888 PubMed DOI PMC

Bove R, Chitnis T. The role of gender and sex hormones in determining the onset and outcome of multiple sclerosis. Mult Scler. (2014) 20:520–6. 10.1177/1352458513519181 PubMed DOI

Waubant E, Chabas D, Okuda DT, Glenn O, Mowry E, Henry RG, et al. . Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults. Arch Neurol. (2009) 66:967–71. 10.1001/archneurol.2009.135 PubMed DOI

Huppke P, Huppke B, Ellenberger D, Rostasy K, Hummel H, Stark W, et al. . Therapy of highly active pediatric multiple sclerosis. Mult Scler. (2019) 25:72–80. 10.1177/1352458517732843 PubMed DOI

Wassmer E, Chitnis T, Pohl D, Amato MP, Banwell B, Ghezzi A, et al. . International Pediatric MS Study Group Global Members Symposium report. Neurology. (2016) 87:S110–6. 10.1212/WNL.0000000000002880 PubMed DOI PMC

McKay KA, Manouchehrinia A, Berrigan L, Fisk JD, Olsson T, Hillert J. Long-term cognitive outcomes in patients with pediatric-onset vs adult-onset multiple sclerosis. JAMA Neurol. (2019) 76:1028–34. 10.1001/jamaneurol.2019.1546 PubMed DOI PMC

Carotenuto A, Moccia M, Costabile T, Signoriello E, Paolicelli D, Simone M, et al. . Associations between cognitive impairment at onset and disability accrual in young people with multiple sclerosis. Sci Rep. (2019) 9:18074. 10.1038/s41598-019-54153-7 PubMed DOI PMC

Johnen A, Elpers C, Riepl E, Landmeyer NC, Krämer J, Polzer P, et al. . Early effective treatment may protect from cognitive decline in paediatric multiple sclerosis. Eur J Paediatr Neurol. (2019) 23:783–91. 10.1016/j.ejpn.2019.08.007 PubMed DOI

Deiva K, Huppke P, Banwell B, Chitnis T, Gärtner J, Krupp L, et al. . Consistent control of disease activity with fingolimod versus IFN β-1a in paediatric-onset multiple sclerosis: further insights from PARADIGMS. J Neurol Neurosurg Psychiatry. (2020) 91:58–66. 10.1136/jnnp-2019-321124 PubMed DOI PMC