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Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial.
Neurology. 2015 Apr 14; 84(15):1582-91.Neur

Abstract

OBJECTIVE

To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS).

METHODS

Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population.

RESULTS

Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo-fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients. Within each placebo-fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported.

CONCLUSION

Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching.

CLASSIFICATION OF EVIDENCE

This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

Authors+Show Affiliations

From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland. lkappos@uhbs.ch.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.From the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; St. Michael's Hospital (P.O.'C.), Toronto, Canada; Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Department of Neurology (C.P.), VU University Medical Center, Amsterdam, Netherlands; Ludwig-Maximilians University of Munich and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany; Department of Neurology (K.S.), Medical University of Lodz, Poland; Novartis Pharmaceuticals Corporation (S.R., G.F.), East Hanover, NJ; and Novartis Pharma AG (R.S., P.v.R., L.Z.-A.), Basel, Switzerland.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25795646

Citation

Kappos, Ludwig, et al. "Long-term Effects of Fingolimod in Multiple Sclerosis: the Randomized FREEDOMS Extension Trial." Neurology, vol. 84, no. 15, 2015, pp. 1582-91.
Kappos L, O'Connor P, Radue EW, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;84(15):1582-91.
Kappos, L., O'Connor, P., Radue, E. W., Polman, C., Hohlfeld, R., Selmaj, K., Ritter, S., Schlosshauer, R., von Rosenstiel, P., Zhang-Auberson, L., & Francis, G. (2015). Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology, 84(15), 1582-91. https://doi.org/10.1212/WNL.0000000000001462
Kappos L, et al. Long-term Effects of Fingolimod in Multiple Sclerosis: the Randomized FREEDOMS Extension Trial. Neurology. 2015 Apr 14;84(15):1582-91. PubMed PMID: 25795646.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. AU - Kappos,Ludwig, AU - O'Connor,Paul, AU - Radue,Ernst-Wilhelm, AU - Polman,Chris, AU - Hohlfeld,Reinhard, AU - Selmaj,Krzysztof, AU - Ritter,Shannon, AU - Schlosshauer,Rolf, AU - von Rosenstiel,Philipp, AU - Zhang-Auberson,Lixin, AU - Francis,Gordon, Y1 - 2015/03/20/ PY - 2014/06/15/received PY - 2014/12/19/accepted PY - 2015/3/22/entrez PY - 2015/3/22/pubmed PY - 2015/6/16/medline SP - 1582 EP - 91 JF - Neurology JO - Neurology VL - 84 IS - 15 N2 - OBJECTIVE: To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population. RESULTS: Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo-fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients. Within each placebo-fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported. CONCLUSION: Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS. SN - 1526-632X UR - https://www.unboundmedicine.com/medline/citation/25795646/Long_term_effects_of_fingolimod_in_multiple_sclerosis:_the_randomized_FREEDOMS_extension_trial_ L2 - http://www.neurology.org/cgi/pmidlookup?view=long&amp;pmid=25795646 DB - PRIME DP - Unbound Medicine ER -