Injectable drugs |
|
20 mg s.c. once daily |
CIS |
PreCISe (phase 3)6868. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Oct;374(9700):1503-11. https://doi.org/10.1016/S0140-6736(09)61259-9
https://doi.org/10.1016/S0140-6736(09)61...
|
Placebo |
45% |
– |
– |
|
|
|
Glatiramer acetate |
RRMS |
Copolymer 1 MS Study (phase 3)8787. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP et al; The Copolymer 1 Multiple Sclerosis Study Group. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology. 1995 Jul;45(7):1268-76. https://doi.org/10.1212/WNL.45.7.1268
https://doi.org/10.1212/WNL.45.7.1268...
|
Placebo |
– |
29% |
28% |
Yes |
Yes |
Yes |
|
40 mg s.c. three times a week |
RRMS |
GALA (phase 3)8888. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013 Jun;73(6):705-13. https://doi.org/10.1002/ana.23938
https://doi.org/10.1002/ana.23938...
|
Placebo |
– |
34% |
N.S. |
Yes |
Yes |
Yes |
Interferon beta-1 a i.m. |
30 mcg i.m. once a week |
CIS |
CHAMPS (phase 3)6565. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000 Sep;343(13):898-904. https://doi.org/10.1056/NEJM200009283431301
https://doi.org/10.1056/NEJM200009283431...
|
Placebo |
30% |
– |
– |
|
|
|
RRMS |
The MSCRG study (phase 3)8484. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al.; The Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996 Mar;39(3):285-94. https://doi.org/10.1002/ana.410390304
https://doi.org/10.1002/ana.410390304...
|
Placebo |
– |
18% |
37% |
Yes |
Yes |
Yes |
Interferon beta-1 a s.c. |
22 mcg s.c. three times a week |
CIS |
ETOMS (phase 3)6666. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernández O, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001 May;357(9268):1576-82. https://doi.org/10.1016/S0140-6736(00)04725-5
https://doi.org/10.1016/S0140-6736(00)04...
|
Placebo |
24% |
23% |
N.S. |
Yes |
Yes |
Yes |
RRMS |
PRISMS (phase 3)8585. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998 Nov;352(9139):1498-504. https://doi.org/10.1016/S0140-6736(98)03334-0
https://doi.org/10.1016/S0140-6736(98)03...
|
Placebo |
– |
29% |
32% |
44 mcg s.c. three times a week |
CIS |
REFLEX (phase 3)6969. Comi G, De Stefano N, Freedman MS, Barkhof F, Polman CH, Uitdehaag BM et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012 Jan;11(1):33-41. https://doi.org/10.1016/S1474-4422(11)70262-9
https://doi.org/10.1016/S1474-4422(11)70...
|
Placebo |
51% |
– |
– |
Yes |
Yes |
Yes |
RRMS |
PRISMS (phase 3)8585. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998 Nov;352(9139):1498-504. https://doi.org/10.1016/S0140-6736(98)03334-0
https://doi.org/10.1016/S0140-6736(98)03...
|
Placebo |
– |
32% |
38% |
|
CIS |
BENEFIT (phase 3)6767. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006 Oct;67(7):1242-9. https://doi.org/10.1212/01.wnl.0000237641.33768.8d
https://doi.org/10.1212/01.wnl.000023764...
|
Placebo |
46% |
– |
– |
|
|
|
Interferon beta-1 b |
250 mcg s.c. every other day |
RRMS |
The IFNB MS Study (phase 3)8686. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993 Apr;43(4):655-61. https://doi.org/10.1212/WNL.43.4.655
https://doi.org/10.1212/WNL.43.4.655...
|
Placebo |
– |
34% |
N.S. |
Yes |
Yes |
Yes |
SPMS |
European Study on IFN β-1 b In SPMS (phase 3)110110. European Study Group on Interferon β-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet. 1998;352(9139):1491-7. https://doi.org/10.1016/S0140-6736(98)10039-9
https://doi.org/10.1016/S0140-6736(98)10...
|
Placebo |
– |
31% |
22% |
Pegylated Interferon beta-1 a |
125 mcg s.c. once every two weeks |
RRMS |
ADVANCE (phase 3)8989. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J et al. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014 Jul;13(7):657-65. https://doi.org/10.1016/S1474-4422(14)70068-7
https://doi.org/10.1016/S1474-4422(14)70...
|
Placebo |
– |
36% |
38% |
Yes |
Yes |
Yes |
Oral drugs |
Cladribine |
3.5 mg/kg body weight p.o. (cumulative over two years) - see the study or label for detailed schedule |
CIS |
ORACLE MS (phase 3)8282. Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Hartung HP et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67. https://doi.org/10.1016/S1474-4422(14)70005-5
https://doi.org/10.1016/S1474-4422(14)70...
|
Placebo |
67% |
– |
– |
|
|
|
RRMS |
CLARITY (phase 3)9696. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010 Feb;362(5):416-26. https://doi.org/10.1056/NEJMoa0902533
https://doi.org/10.1056/NEJMoa0902533...
|
Placebo |
– |
58% |
33% |
No |
No |
Yes |
Dimethyl fumarate |
240 mg p.o. twice daily |
RRMS |
DEFINE (phase 3)9090. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep;367(12):1098-107. https://doi.org/10.1056/NEJMoa1114287
https://doi.org/10.1056/NEJMoa1114287...
|
Placebo |
– |
53% |
38% |
Yes |
Yes |
Yes |
CONFIRM (phase 3)9191. 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 Sep;367(12):1087-97. https://doi.org/10.1056/NEJMoa1206328
https://doi.org/10.1056/NEJMoa1206328...
|
Placebo |
– |
44% |
21% |
Fingolimod |
0.5 mg p.o. once daily |
RRMS |
FREEDOMS (phase 3)9797. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb;362(5):387-401. https://doi.org/10.1056/NEJMoa0909494
https://doi.org/10.1056/NEJMoa0909494...
|
Placebo |
– |
55% |
27% |
Yes |
Yes |
Yes |
FREEDOMS 2 (phase 3)9898. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Jun;13(6):545-56. https://doi.org/10.1016/S1474-4422(14)70049-3
https://doi.org/10.1016/S1474-4422(14)70...
|
Placebo |
– |
48% |
N.S. |
|
|
CIS |
TOPIC (phase 3)7070. Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Oct;13(10):977-86. https://doi.org/10.1016/S1474-4422(14)70191-7
https://doi.org/10.1016/S1474-4422(14)70...
|
Placebo |
43% |
32% |
30% |
|
|
|
Teriflunomide |
14 mg p.o. once daily |
RRMS |
TEMSO (phase 3)9292. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011 Oct;365(14):1293-303. https://doi.org/10.1056/NEJMoa1014656
https://doi.org/10.1056/NEJMoa1014656...
|
Placebo |
– |
32% |
30% |
Yes |
Yes |
Yes |
|
|
TOWER (phase 3)9393. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson T, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Mar;13(3):247-56. https://doi.org/10.1016/S1474-4422(13)70308-9
https://doi.org/10.1016/S1474-4422(13)70...
|
Placebo |
– |
36% |
32% |
|
|
|
|
Alemtuzumab |
12 mg i.v. once a day for 5 days at baseline + 12 mg i.v. once a day for three days after 12 months |
RRMS |
CARE-MS I (phase 3)9494. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov;380(9856):1819-28. https://doi.org/10.1016/S0140-6736(12)61769-3
https://doi.org/10.1016/S0140-6736(12)61...
|
Interferon beta-1 a 44 meg s.c. |
– |
55% |
30% |
Yes |
Yes |
Yes |
CARE-MS 2 (phase 3)9595. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov;380(9856):1829-39. https://doi.org/10.1016/S0140-6736(12)61768-1
https://doi.org/10.1016/S0140-6736(12)61...
|
Interferon beta-1 a 44 mcg s.c. |
– |
49% |
42% |
|
Cyclophosphamide |
750 mg/m2 body surface area i.v. every four weeks In the first year; variable Intervals thereafter, according to each study protocol |
RRMS |
Controlled Pilot Trial of Monthly Cyclophosphamide In MS (phase 2)105105. Killian JM, Bressler RB, Armstrong RM, Huston DP. Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis. Arch Neurol. 1988 Jan;45(1):27-30. https://doi.org/10.1001/archneur.1988.00520250033014
https://doi.org/10.1001/archneur.1988.00...
|
Placebo |
– |
N.S.
|
– |
No |
No |
No |
SPMS |
PROMESS (phase 3)125125. Brochet B, Deloire MSA, Perez P, Loock T, Baschet L, Debouverie M et al; PROMESS study investigators. Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis. PLOS One. 2017 Jan; 12(1):e0168834. https://doi.org/10.1371/journal.pone.0168834
https://doi.org/10.1371/journal.pone.016...
|
Methylprednisolone i.v. every four weeks |
– |
N.S.
|
N.S.
|
|
|
|
Intravenous Immunoglobulin |
0.15-0.20 g/kg body weight i.v. once a month |
RRMS |
AIMSS (phase 2)106106. Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet. 1997 Mar;349(9052):589-93. https://doi.org/10.1016/S0140-6736(96)09377-4
https://doi.org/10.1016/S0140-6736(96)09...
|
Placebo |
– |
59% |
N.S. |
No |
No |
No |
Infusion drugs |
Mitoxantrone |
12 mg/m2 i.v. every three months |
Worsening RRMS and SPMS |
MIMS (phase 3)107107. Hartung HP, Gonsette R, König N, Kwiecinski H, Guseo A, Morrissey SP et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002 Dec;360(9350):2018-25. https://doi.org/10.1016/S0140-6736(02)12023-X
https://doi.org/10.1016/S0140-6736(02)12...
|
Placebo |
– |
66% |
64% |
No |
Yes |
Yes |
|
Natalizumab |
300 mg i.v. every four weeks |
RRMS |
AFFIRM (phase 3)9999. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar;354(9):899-910. https://doi.org/10.1056/NEJMoa044397
https://doi.org/10.1056/NEJMoa044397...
|
Placebo |
– |
68% |
42% |
Yes |
Yes |
Yes |
|
|
RRMS |
OPERA I (phase 3)100100. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B et al. Ocrelizumab versus Interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017 Jan;376(3):221-34. https://doi.org/10.1056/NEJMoa1601277
https://doi.org/10.1056/NEJMoa1601277...
|
Interferon beta-1 a 44 mcg s.c. |
– |
46% |
43% |
|
|
|
Ocrelizumab |
600 mg i.v. every 24 weeks |
OPERA II (phase 3)100100. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B et al. Ocrelizumab versus Interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017 Jan;376(3):221-34. https://doi.org/10.1056/NEJMoa1601277
https://doi.org/10.1056/NEJMoa1601277...
|
Interferon beta-1 a 44 mcg s.c. |
– |
47% |
37% |
Yes |
Yes |
Yes |
|
|
PPMS |
ORATORIO (phase 3)112112. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan;376(3):209-20. https://doi.org/10.1056/NEJMoa1606468
https://doi.org/10.1056/NEJMoa1606468...
|
Placebo |
– |
– |
24% |
|
|
|
|
Rituximab |
1000 mg i.v. on days 1 and 15; repeated every 6 months, or at variable Intervals according to CD19+ lymphocyte counts |
RRMS |
HERMES (phase 2)108108. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008 Feb;358(7):676-88. https://doi.org/10.1056/NEJMoa0706383
https://doi.org/10.1056/NEJMoa0706383...
|
Placebo |
– |
50% |
– |
No |
No |
No |
Other |
Autologous hematopoietic stem cell transplantation |
N/A |
Severe RRMS and SPMS |
ASTIMS (phase 2)109109. Mancardi GL, Sormani MP, Gualandi F, Saiz A, Carreras E, Merelli E et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. 2015 Mar;84(10):981-8. https://doi.org/10.1212/WNL.0000000000001329
https://doi.org/10.1212/WNL.000000000000...
|
Mitoxantrone |
– |
64% |
N.S. |
– |
– |
– |