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Abstract

Objective:

To test efficacy and safety of atorvastatin in subjects with clinically isolated syndrome (CIS).

Methods:

Subjects with CIS were enrolled in a phase II, double-blind, placebo-controlled, 14-center randomized trial testing 80 mg atorvastatin on clinical and brain MRI activity. Brain MRIs were performed quarterly. The primary endpoint (PEP) was development of ≥3 new T2 lesions, or one clinical relapse within 12 months. Subjects meeting the PEP were offered additional weekly interferon β-1a (IFNβ-1a).

Results:

Due to slow recruitment, enrollment was discontinued after 81 of 152 planned subjects with CIS were randomized and initiated study drug. Median (interquartile range) numbers of T2 and gadolinium-enhancing (Gd) lesions were 15.0 (22.0) and 0.0 (0.0) at baseline. A total of 53.1% of atorvastatin recipients (n = 26/49) met PEP compared to 56.3% of placebo recipients (n = 18/32) (p = 0.82). Eleven atorvastatin subjects (22.4%) and 7 placebo subjects (21.9%) met the PEP by clinical criteria. Proportion of subjects who did not develop new T2 lesions up to month 12 or to starting IFNβ-1a was 55.3% in the atorvastatin and 27.6% in the placebo group (p = 0.03). Likelihood of remaining free of new T2 lesions was significantly greater in the atorvastatin group compared with placebo (odds ratio [OR] = 4.34, p = 0.01). Likelihood of remaining free of Gd lesions tended to be higher in the atorvastatin group (OR = 2.72, p = 0.11). Overall, atorvastatin was well tolerated. No clear antagonistic effect of atorvastatin plus IFNβ-1a was observed on MRI measures.

Conclusion:

Atorvastatin treatment significantly decreased development of new brain MRI T2 lesion activity, although it did not achieve the composite clinical and imaging PEP.

Classification of Evidence:

This study provided Class II evidence that atorvastatin did not reduce the proportion of patients with CIS meeting imaging and clinical criteria for starting immunomodulating therapy after 12 months, compared to placebo. In an analysis of a secondary endpoint (Class III), atorvastatin was associated with a reduced risk for developing new T2 lesions.

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Supplementary Material

File (coinvestigators.docx)
File (table_e-1.docx)
File (table_e-2.docx)

STUDY FUNDING

This research was performed as a project of the Immune Tolerance Network (ITN020AI, ITN contract number N01-AI-15416), a clinical research consortium sponsored by the National Institute of Allergy and Infectious Diseases. Pfizer provided atorvastatin, placebo, and grant support. Biogen Idec provided IFNβ-1a IM and grant support. E.W. is also supported by the Nancy Davis Foundation. S.S.Z. was also supported for this study by the National Institutes of Health (RO1 AI059709) and the Maisin Foundation.

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Information & Authors

Information

Published In

Neurology®
Volume 78Number 15April 10, 2012
Pages: 1171-1178
PubMed: 22459680

Publication History

Received: May 2, 2011
Accepted: November 17, 2011
Published online: March 28, 2012
Published in print: April 10, 2012

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Disclosure

Dr. Waubant serves on a data safety monitoring board for the NIH and on a scientific advisory board for Actelion Pharmaceuticals Ltd; has received speaker honoraria from Teva Pharmaceutical Industries Ltd.; served as a consultant for Actelion Pharmaceuticals Ltd, Roche, and sanofi-aventis; and receives research support from sanofi-aventis, Biogen Idec, the NIH, the National MS Society, and the Nancy Davis Foundation. Dr. Pelletier serves/has served as a consultant for Synarc Inc., Biogen Idec, Bayer Schering Pharma, Genentech, Inc., Teva Pharmaceutical Industries Ltd., and CNS Imaging Consultant, LLC; serves on the speakers' bureau for Biogen Idec; and receives research support from Biogen Idec, the NIH, and the National Multiple Sclerosis Society. Dr. Mass has received speaker honoraria from Biogen Idec, Novartis, Teva Pharmaceutical Industries Ltd., and Bayer Schering Pharma. Dr. Cohen has served on scientific advisory boards for Biogen Idec, Novartis, EMD Serono, Inc., and Teva Pharmaceutical Industries Ltd.; has received funding for travel from Biogen Idec, sanofi-aventis, and EMD Serono, Inc.; receives publishing royalties for Multiple Sclerosis Therapeutics (Informa Healthcare, 2007); has received speaker honoraria from sanofi-aventis; and receives research support from Biogen Idec, Novartis, Genzyme Corporation, Teva Pharmaceutical Industries Ltd., the Immune Tolerance Network, and the Nancy Davis Center Without Walls. Dr. Kita has received funding for travel from Teva Pharmaceutical Industries Ltd. and Biogen Idec; has received speaker honoraria (paid to institution) from Teva Pharmaceutical Industries Ltd. and Biogen Idec; and receives research support from Biogen Idec, Novartis, Genentech Inc., and Ono Pharmaceutical Co. Ltd. Dr. Cross serves/has served on scientific advisory boards for Eli Lilly and Company, Genentech, Inc., Biogen Idec, Roche, and Coronado BioSciences; serves on the editorial boards of Brain Pathology and the Journal of Neuroimmunology; has received speaker or consulting honoraria from Pfizer Inc, Biogen Idec, sanofi-aventis, Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., Gerson Lehrman Group, and Guidepoint Global, LLC; and receives research support from sanofi-aventis, Acorda Therapeutics Inc., Genentech, Inc., Biogen Idec, Roche, the NIH/NINDS, ICTS Washington University, the National MS Society USA, Consortium of MS Centers, and the Barnes-Jewish Hospital Foundation. Dr. Bar-Or serves on scientific advisory boards for BioMS Medical, DioGenix, Inc., Ono Pharmaceutical Co. Ltd., GlaxoSmithKline, Roche, Guthy Jackson Greater Good Foundation, and NMO Research and Clinical Care Consortium; serves on the editorial boards of Neurology® and Clinical and Experimental Neuroimmunology; has received speaker honoraria from Biogen Idec, Bayhill Therapeutics, Bayer Schering Pharma (Berlex), Eli Lilly and Company, Genentech, Inc., GlaxoSmithKline, Merck Serono, Novartis, Wyeth, sanofi-aventis, and Teva Pharmaceutical Industries Ltd.; and receives/has received research support from BioMS Medical, Merck Serono, Bayhill Therapeutics, Biogen Idec, Genentech, Inc., and Teva Pharmaceutical Industries Ltd. Dr. Vollmer has served on scientific advisory boards for Roche, Elan Corporation, Teva Pharmaceuticals Industries Ltd., Novartis, GlaxoSmithKline, EMD Serono, Inc., Biogen Idec, Abbott, Acorda Therapeutics Inc., Bayhill Therapeutics, Metabolic Solutions Development Co., and Genentech, Inc.; has received speaker honoraria from EMD Serono, Inc., Teva Pharmaceuticals Industries Ltd., Biogen Idec, XenoPort, Inc., and Ono Pharmaceutical Co. Ltd.; has served as a consultant for Biogen Idec, Acorda Therapeutics Inc., Teva Pharmaceutical Industries Ltd., EMD Serono, Inc., Eli Lilly and Company, XenoPort, Inc., IMPAX Laboratories, Inc., GlaxoSmithKline, Daiichi Sankyo, Guidepoint Global, Eisai Inc., Novartis, Ono Pharmaceutical Co. Ltd., and Elan Corporation; has served on speakers' bureaus for Biogen Idec, Teva Pharmaceuticals Industries Ltd., and Athena Diagnostics, Inc.; is listed as author on a pending patent re: Nicotinic attenuation of CNS inflammation and autoimmunity; and has received research support from Teva Pharmaceuticals Industries Ltd., Acorda Therapeutics Inc., Biogen Idec, Daiichi Sankyo, Elan Corporation, Eli Lilly and Company, EMD Serono, Inc., Genzyme Corporation, Biosite, Eisai Inc., Genentech, Inc., Novartis, Ono Pharmaceutical Co. Ltd., Accelerated Cure Project, IMPAX Laboratories, Inc., sanofi-aventis, BioMS Medical, and the Rocky Mountain Multiple Sclerosis Society. Dr. Racke serves on scientific advisory boards for the Accelerated Cure Project and Diogenix, Inc.; serves on the editorial boards of Archives of Neurology, The Neurologist, PPAR Research, and the Journal of Neuroimmunology; serves/has served as a consultant for Eli Lilly and Company, Novartis, Biogen Idec, and Relavesio, Inc.; receives research support from the NIH/NINDS and the National Multiple Sclerosis Society; and research support paid to his institution from Biogen Idec, Novartis, Merck Serono and Teva Pharmaceutical Industries Ltd. Dr. Stüve serves on scientific advisory boards for Novartis, EMD Serono, Inc., sanofi-aventis, and Teva Pharmaceutical Industries Ltd.; serves on editorial boards for Archives of Neurology and Therapeutic Advances in Neurological Disorders; has received honoraria from Teva Pharmaceutical Industries Ltd., Roche, Genzyme Corporation, and Bayer Schering Pharma; and has received research support from Teva Pharmaceutical Industries Ltd., the US Department of Veterans Affairs (Merit Review Grant), and the Doris Duke Charitable Foundation. Dr. Schwid is deceased; disclosures are not included for this author. Dr. Goodman serves on a scientific advisory board for Biogen Idec; has received funding for travel and speaker or consulting honoraria from Acorda Therapeutics Inc., Actelion Pharmaceuticals Ltd, Avanir Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, EMD Serono, Inc., Genentech, Inc., Genzyme Corporation, Novartis, Pfizer Inc, and Teva Pharmaceutical Industries Ltd.; and receives research support from Acorda Therapeutics Inc., Bayer Schering Pharma, Biogen Idec, EMD Serono, Inc., Genentech, Inc., Genzyme Corporation, Novartis, Teva Pharmaceutical Industries Ltd., Takeda Pharmaceutical Company Limited, Ono Pharmaceutical Co. Ltd., the NIH, and the Montel Williams Foundation. Dr. Kachuck serves on scientific advisory boards for Acorda Therapeutics Inc., Teva Pharmaceutical Industries Ltd., EMD Serono, Inc., and Glycominds, Ltd.; has received funding for travel or speaker honoraria from Acorda Therapeutics Inc., Teva Pharmaceutical Industries Ltd., and Glycominds, Ltd.; serves as a consultant for Glycominds, Inc. and Acorda Therapeutics Inc.; serves on the speakers' bureaus for Acorda Therapeutics Inc., Teva Pharmaceutical Industries Ltd., and EMD Serono, Inc.; and receives research support from Teva Pharmaceutical Industries Ltd. and EMD Serono, Inc. Dr. Preiningerova has received speaker honoraria from Biogen Idec, Novartis, Teva Pharmaceutical Industries Ltd. and Acorda Therapeutics Inc.; and has received research support paid to her institution by Acorda Therapeutics Inc., sanofi-aventis, Teva Pharmaceutical Industries Ltd., Biogen Idec, and Novartis. Dr. Weinstock-Guttman serves on a medical advisory board for the National Multiple Sclerosis Society; serves on speakers' bureaus and as a consultant for Biogen Idec, Teva Pharmaceutical Industries Ltd., EMD Serono, Inc, Novartis, Acorda Therapeutics Inc., and Pfizer Inc; serves on the editorial boards of aan.com and Multiple Sclerosis International; and receives research support from Novartis, Acorda Therapeutics Inc., Biogen Idec, EMD Serono, Inc., Teva Pharmaceutical Industries Ltd., Shire plc, Questcor, Cyberonics, Inc., the NIH, and the NMSS. Dr. Calabresi serves on scientific advisory boards for Biogen Idec, Teva Pharmaceutical Industries Ltd., Vertex Pharmaceuticals, Vaccinex, Genzyme Corporation, Abbott, and Novartis; has received funding for travel from Biogen Idec, Teva Pharmaceutical Industries Ltd., Vertex Pharmaceuticals, EMD Serono, Inc., Novartis, and Novo Nordisk; serves on the editorial board of Neurology®; is an author on a patent re: Role of Kv1.3 as neuroprotective; serves/has served as a consultant for Biogen Idec, Teva Pharmaceutical Industries Ltd., Vertex Pharmaceuticals, and Novartis; and receives research support from Vertex Pharmaceuticals, Abbot, Bayer Schering Pharma, EMD Serono, Inc., Teva Pharmaceutical Industries Ltd., Genentech, Inc., Biogen Idec, the NIH/NINDS, the Nancy Davis Foundation, and the National Multiple Sclerosis Society. Dr. Miller has served on scientific advisory boards for sanofi-aventis, Biogen Idec, GlaxoSmithKline, EMD Serono, Inc., Teva Pharmaceutical Industries Ltd., Daiichi Sankyo, Merck Serono, Novartis, Ono Pharmaceutical Co. Ltd., and Acorda Therapeutics Inc.; has served on speakers' bureaus for and received speaker honoraria from Biogen Idec and EMD Serono, Inc.; has received funding for travel or speaker honoraria from sanofi-aventis, Biogen Idec, Avanir, Biomarin, Chelsea Therapeutics, Ono Pharmaceutical Co. Ltd., and Acorda Therapeutics Inc.; serves on the editorial board of Continuum; and has received research support paid to his institution from Acorda Therapeutics Inc., Biogen Idec, Teva Pharmaceutical Industries Ltd., Novartis, Genentech, Inc., Genzyme Corporation, and sanofi-aventis. Dr. Mokhtarani received compensation as an employee of the Immune Tolerance Network. Dr. Iklé has received support paid to his institution through a contract with the NIH/NIAID. S. Murphy has received support paid to her institution through a contract with the NIH/NIAID. H. Kopetskie has received support paid to her institution through a contract with the NIH/NIAID. Dr. Ding, E. Rosenberg, and C. Spencer report no disclosures. Dr. Zamvil serves as Consulting Editor of the Journal of Clinical Investigation, on the editorial board of Neurotherapeutics, and as an Associate Editor for the Journal the Neurological Sciences; has served as a consultant for and received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Genentech, Inc., and EMD Serono, Inc.; has served on speakers' bureaus for Advanced Health Media and Health Logix; and receives research support from the NIH, the National Multiple Sclerosis Society, the Guthy Jackson Charitable Foundation, the Maisin Foundation, and Teva Pharmaceutical Industries Ltd.

Authors

Affiliations & Disclosures

E. Waubant, MD, PhD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
D. Pelletier, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
M. Mass, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
J.A. Cohen, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
M. Kita, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
A. Cross, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
A. Bar-Or, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
T. Vollmer, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
M. Racke, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
O. Stüve, MD, PhD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
S. Schwid, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
A. Goodman, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
N. Kachuck, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
J. Preiningerova, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
B. Weinstock-Guttman, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
P.A. Calabresi, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
A. Miller, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
M. Mokhtarani, MD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
D. Iklé, PhD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
S. Murphy, MS
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
H. Kopetskie
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
L. Ding, MD, PhD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
E. Rosenberg, MA, BSN, RN
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
C. Spencer, BS
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
S.S. Zamvil, MD, PhD
From the University of California (E.W., D.P., C.S., S.S.Z.), San Francisco; Oregon Health & Science University (M.M.), Portland; The Cleveland Clinic Foundation (J.A.C.), Cleveland, OH; Virginia Mason MS Center (M.K.), Seattle, WA; Washington University MS Center (A.C.), St. Louis, MO; Montreal Neurological Institute (A.B.-O.), Montreal, Canada; Barrow Neurological Institute (T.V.), Phoenix, AZ; University of Texas Southwestern Medical Center (M.R., O.S.), Dallas; University of Rochester (S.S., A.G.), Rochester, NY; Keck School of Medicine MS Center (N.K.), University of Southern California, Los Angeles; Yale MS Research Center (J.P.), New Haven, CT; Jacobs Neurological Institute (B.W.-G.), Buffalo, NY; Johns Hopkins University (P.A.C.), Baltimore, MD; Mount Sinai School of Medicine (A.M.), New York, NY; Immune Tolerance Network (M.M.), Seattle, WA; Rho, Inc. (D.I., S.M., H.K.), Chapel Hill, NC; and National Institute of Allergy and Infectious Diseases (L.D., E.R.), Bethesda, MD.
On behalf of the ITN STAyCIS Study Group

Notes

Deceased.
Study funding: Funding information is provided at the end of the article.
Correspondence & reprint requests to Dr. Zamvil: [email protected]

Author Contributions

All authors were involved in the study concept and design, data collection, standardized assessments of subjects, study conduct, data summary and analysis, literature search, and writing of the report. Dr. Waubant was involved in the study concept and design, data collection, standardized assessments of subjects, study conduct, data summary and analysis, literature search, and writing of the report. Dr. Pelletier was involved in the study design, data collection, standardized assessments of subjects, study conduct, MRI central coordination and analysis, data summary and analysis, and writing of the report. Dr. Zamvil was involved in the study concept and design, data collection, standardized assessments of subjects, study conduct, data summary and analysis, literature search, and writing of the report. Drs. Mass, Cohen, Kita, Cross, Bar-Or, Vollmer, Racke, Stüve, Schwid, Goodman, Kachuck, Preiningerova, Weinstock-Guttman, Calabresi, and Miller were involved in the study design and conduct, standardized assessment of subjects, and writing of the report. Dr. Mokhtarani, Dr. Iklé, Dr. Ding, and C. Spencer were involved in the study design and conduct, data collection and analysis, and writing of the report. S. Murphy and H. Kopetskie were involved in data collection and analysis, and writing of the report. E. Rosenberg and the ITN020AI Study Management Team were involved in the study design and conduct, data collection and analysis, and writing of the report.

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