Neurology. 2016 Nov 8;87(19):1985-1992. Epub 2016 Oct 12.
Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients.
Giovannoni G1,
Cohen JA2,
Coles AJ2,
Hartung HP2,
Havrdova E2,
Selmaj KW2,
Margolin DH2,
Lake SL2,
Kaup SM2,
Panzara MA2,
Compston DA2;
CARE-MS II Investigators.
Arnold D, Cohen JA, Coles A, Compston A, Confavreux C, Fox E, Hartung HP, Havrdova E, Selmaj K, Weiner H, Panitch H, Clifford D, Antel J, Barkhof F, Snydman D, DeGroot L, Cines D, D'Agostino R, Greenberg B, Krauss J, Limmroth V, Markowitz C, Naismith R, Tabby D, Deri NH, Boundy K, Broadley S, Dreyer MD, Hodgkinson S, King JO, Macdonell R, Racp F, McCombe PA, Paine MA, Reddel S, Schwartz R, Vucic S, Karl Vass MD, Dominique Dive P, Dubois BD, Sindic C, Callegaro D, Ferreira ML, Barreto Martins MM, Tilbery C, Charles Ayotte, Brunet DG, Freedman MS, Grand'Maison F, Jacques FH, Kremenchutzky M, Traboulsee AL, Licia Antonelli MD, Brinar V, Habek M, Piskać SK, Trkanjec Z, Vladić A, Ivana Kovarova, Rektor I, Talab R, Vachova M, Petersen T, Ravnborg M, Sørensen PS, Michel Clanet, Clavelou P, de Seze J, Debouverie M, Edan G, Lubetzki C, Moreau T, Vermersch P, Baum K, Haas J, Hemmer B, Herrlinger U, Köhler W, Ochs G, Stangel M, Tumani H, Urban PP, Zettl UK, Ziemssen T, Anat Achiron, Karni A, Dembinsky AV, Bertolotto A, Capra R, Comi G, Durelli L, Ghezzi A, Mancardi GL, Marrosu MG, Pozzilli C, Caballero NS, Mendoza CV, Violante Villanueva JA, Raymond M M Hupperts, van Munster E, Wojciech Kozubski, Selmaj K, Stelmasiak Z, Barantsevich ER, DMedSc, Belova AN, Boyko AN, Gusev EI, Malkova NA, Perfiliev SV, Poverennova IE, Skoromets AA, Stolyarov ID, Yakupov EZ, Zavalishin IA, Dinčić E, Drulović J, Nadj Č, Tončev G, González RA, Ayuso GI, Fernández Ó, Montalbán X, Jan Lycke, Svenningsson A, Kobys TO, Nehrych TI, Voloshyna NP, Giovannoni G, Rog DJ, Scolding NJ, Sharrack B, Abou Zeid NE, Agius MA, Doan-Do Bass A, Bigley GK Jr, Bomprezzi R, Boster A, Boutwell CM, Braley TJ, Cascione MC, Clauser G, Cooper JA, Crayton HJ, Dunn J, Edwards KR, Elias S, Evans BK, Fletcher MH, Ford CC, Frohman EM, Gazda SK, Giancarlo T, Gitt JS, Glyman SA, Goodman A, Gottschalk C, Gottesman MH, Grazioli EM, Gudesblatt M, Gupta AS, Herbert J, Honeycutt WD, Hughes BL, Hunter SF, Janus TJ, Javed A, Jones DE, Jubelt B, Henson LJ, Khan OA, Kita M, Kirzinger S, Krieger S, Krolczyk SJ, LaGanke CC, Lallana EC, Lathi ES, Lava NS, Lynch SG, Machanic BI, Markovic-Plese S, Mattson DH, Mikol DD, Miller A, Miller TA, Minagar A, Mitchell GW, Moses H Jr, Negroski D, Pardo G, Picone MA, Preiningerova J, Rammohan KW, Riley CS, Riskind PN, Rizvi SA, Rossen M, Rothstein TL, Rowe VD 3rd, Royal W 3rd, Schaeffer JD, Sheppard CA, Shubin RA, Silliman SL, Singer BA, Stein LS, Steingo B, Sullivan HC, Thoits TK, Thrower BW, Twyman CL, Vaishnav AG, Vincent SG, Vollmer T, Waldman SR, Weiner LP, Wendt JK, Wingerchuk DM, Wray SE, Wynn DR.
- 1
- From Queen Mary University of London (G.G.), Barts and The London School of Medicine, UK; Mellen Center (J.A.C.), Cleveland Clinic, OH; Department of Clinical Neurosciences (A.J.C., D.A.S.C.), University of Cambridge, UK; Department of Neurology and Center for Neuropsychiatry (H.-P.H.), Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology and Center for Clinical Neuroscience (E.H.), First Medical Faculty, Charles University in Prague, Czech Republic; Department of Neurology (K.W.S.), Medical University of Łódź, Poland; Sanofi Genzyme (D.H.M., S.L.L., M.A.P.), Cambridge, MA; and Evidence Scientific Solutions (S.M.K.), Philadelphia, PA (at the time the work was conducted). g.giovannoni@qmul.ac.uk.
- 2
- From Queen Mary University of London (G.G.), Barts and The London School of Medicine, UK; Mellen Center (J.A.C.), Cleveland Clinic, OH; Department of Clinical Neurosciences (A.J.C., D.A.S.C.), University of Cambridge, UK; Department of Neurology and Center for Neuropsychiatry (H.-P.H.), Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology and Center for Clinical Neuroscience (E.H.), First Medical Faculty, Charles University in Prague, Czech Republic; Department of Neurology (K.W.S.), Medical University of Łódź, Poland; Sanofi Genzyme (D.H.M., S.L.L., M.A.P.), Cambridge, MA; and Evidence Scientific Solutions (S.M.K.), Philadelphia, PA (at the time the work was conducted).
Abstract
OBJECTIVE:
To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.
METHODS:
Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.
RESULTS:
Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.
CONCLUSIONS:
In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.
CLASSIFICATION OF EVIDENCE:
This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.
© 2016 American Academy of Neurology.
Figure 1Expanded Disability Status Scale (EDSS)–based improvement or worsening
(A) Distribution of confirmed EDSS change from baseline to month 24 shown in half-point increments for alemtuzumab patients compared with subcutaneous interferon-β-1a (SC IFN-β-1a) patients. (B) Odds for improvement vs remaining stable or worsening with respect to the different functional systems of the EDSS at month 24. CI = confidence interval; OR = odds ratio of being improved vs stable or worsened.
Neurology. 2016 Nov 8;87(19):1985-1992.
Figure 2Proportions of patients demonstrating 6-month confirmed disability improvement (CDI)
Kaplan-Meier estimates of risk for 6-month CDI with stratification by baseline Expanded Disability Status Scale (EDSS). Only patients with baseline EDSS ≥2.0 were included in the analyses of CDI; 154 (alemtuzumab, n = 105; subcutaneous interferon-β-1a [SC IFN-β-1a], n = 49) patients were excluded from the analysis for not meeting this criterion.
Neurology. 2016 Nov 8;87(19):1985-1992.
Figure 3Multiple Sclerosis Functional Composite (MSFC)–based disability outcomes
(A) Patients with ≥15% worsening in MSFC scorea and mean (95% confidence interval [CI]) changes in (B) 9-Hole Peg Test, (C) Timed 25-Foot Walk, (D) Paced Auditory Serial Addition Test–3 (PASAT-3), and (E) 4-dimensional composite score, MSFC plus Sloan low-contrast letter acuity (SLCLA) (1.25% contrast). a Increase from baseline of ≥15% on ≥1 component sustained for at least 6 months. p Values are from proportional hazards regression with robust variance estimation and covariate adjustment for geographic region. Changes from baseline on MSFC Z scores analyzed using Wei-Lachin test and mixed model for repeated measures analyses with a time by treatment interaction and covariate adjustment for geographic region and baseline score. Wei-Lachin test statistics were 2.87 (9-Hole Peg Test), 1.61 (Timed 25-Foot Walk Test), 1.44 (PASAT-3), and 2.57 (MSFC + SLCLA). The Sloan chart was not administered to patients at Russian and Ukrainian sites because Sloan charts use Latin alphabetic characters that may have been unfamiliar to individuals in these countries (alemtuzumab, n = 47; subcutaneous interferon-β-1a [SC IFN-β-1a], n = 23). *p < 0.001 and **p < 0.05, between-treatment differences; †p < 0.05, within-treatment change from baseline.
Neurology. 2016 Nov 8;87(19):1985-1992.
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