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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.LN

Abstract

BACKGROUND

Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients.

METHODS

We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients-those aged 18-55 years with relapsing-remitting multiple sclerosis-to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134.

FINDINGS

Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in patients given placebo and 0·21 (0·17-0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]).

INTERPRETATION

Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis.

FUNDING

Novartis Pharma AG.

Authors+Show Affiliations

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: pcalabr1@jhmi.edu.Medical Image Analysis Center, University Hospital, Basel, Switzerland.Department of Neurology, University of California, San Francisco, CA, USA.The Multiple Sclerosis and Movement Disorders Center, Cornerstone Health Care, Winston-Salem, NC, USA.Department of Neurology, University of Miami, Miami, FL, USA.Department of Neurology, University of Chicago Medical Center, Chicago, IL, USA.Department of Neurology, University of Colorado Denver, Aurora, CO, USA.Department of Neurology, University of California at Davis, Davis, CA, USA; Department of Veterans Affairs Northern California Health Care System (VANCHCS), Mather, CA, USA.Department of Neurology, University Hospital, Basel, Switzerland.Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.Novartis Pharma AG, Basel, Switzerland.Department of Neurology, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, NY, USA.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24685276

Citation

Calabresi, Peter A., 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." The Lancet. Neurology, vol. 13, no. 6, 2014, pp. 545-56.
Calabresi PA, Radue EW, Goodin D, 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;13(6):545-56.
Calabresi, P. A., Radue, E. W., Goodin, D., Jeffery, D., Rammohan, K. W., Reder, A. T., Vollmer, T., Agius, M. A., Kappos, L., Stites, T., Li, B., Cappiello, L., von Rosenstiel, P., & Lublin, F. D. (2014). Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet. Neurology, 13(6), 545-56. https://doi.org/10.1016/S1474-4422(14)70049-3
Calabresi PA, 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;13(6):545-56. PubMed PMID: 24685276.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. AU - Calabresi,Peter A, AU - Radue,Ernst-Wilhelm, AU - Goodin,Douglas, AU - Jeffery,Douglas, AU - Rammohan,Kottil W, AU - Reder,Anthony T, AU - Vollmer,Timothy, AU - Agius,Mark A, AU - Kappos,Ludwig, AU - Stites,Tracy, AU - Li,Bingbing, AU - Cappiello,Linda, AU - von Rosenstiel,Philipp, AU - Lublin,Fred D, Y1 - 2014/03/28/ PY - 2014/4/2/entrez PY - 2014/4/2/pubmed PY - 2014/7/9/medline SP - 545 EP - 56 JF - The Lancet. Neurology JO - Lancet Neurol VL - 13 IS - 6 N2 - BACKGROUND: Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients. METHODS: We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients-those aged 18-55 years with relapsing-remitting multiple sclerosis-to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134. FINDINGS: Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in patients given placebo and 0·21 (0·17-0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]). INTERPRETATION: Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis. FUNDING: Novartis Pharma AG. SN - 1474-4465 UR - https://www.unboundmedicine.com/medline/citation/24685276/Safety_and_efficacy_of_fingolimod_in_patients_with_relapsing_remitting_multiple_sclerosis__FREEDOMS_II_:_a_double_blind_randomised_placebo_controlled_phase_3_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1474-4422(14)70049-3 DB - PRIME DP - Unbound Medicine ER -