Natalizumab improves walking and upper-limb disability compared with placebo in patients with secondary progressive multiple sclerosis: an integrated, post hoc area under the outcome-time curve analysis from the ASCEND trial
ECTRIMS Online Library. Giovannoni G. 10/26/17; 202484; 131
Gavin Giovannoni
Gavin Giovannoni
Contributions
Abstract

Abstract: 131

Type: Oral

Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Background: While natalizumab did not meet the primary multicomponent endpoint of reducing disability progression in mostly nonrelapsing secondary progressive multiple sclerosis (SPMS) patients in ASCEND, results have shown that natalizumab significantly delays upper limb disability progression and is associated with greater levels of disability improvement than placebo, suggesting that natalizumab treatment benefits in this population may be a combination of reduced sustained worsening and increased sustained improvement.
Objective: This post hoc analysis of ASCEND used area-under-the-curve (AUC) methodology to examine natalizumab treatment effects on integrated disability worsening and improvement as measured by the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT).
Methods: ASCEND, a multicenter, randomized, double-blind phase 3 trial, enrolled natalizumab-naive patients diagnosed with SPMS ≥2 years prior with disability progression unrelated to clinical relapses in the past year. Patients received IV 300 mg natalizumab (n=439) or placebo (n=448) for 2 years. AUC trapezoidal analysis was used to compare changes from baseline in EDSS scores and percentage changes from baseline in T25FW and 9HPT times for natalizumab- vs placebo-treated patients.
Results: Significant improvements from baseline to week 96 with natalizumab relative to placebo were observed in the median (range) AUC of T25FW (natalizumab, 19.18 [−121.5, 725.5]; placebo, 24.5 [−130.8, 2129.6]; P=0.020) and 9HPT (average hand: natalizumab, −1.59 [−66.3, 226.7]; placebo, 2.58 [−81.1, 834.8]; P=0.006) but not EDSS (natalizumab, 0 [−4.2, 4.1]; placebo, 0 [−5.1, 4.2]; P=0.733). These results correspond to 28% and 77% reductions in T25FW and 9HPT mean AUC, respectively, for natalizumab vs placebo. The negative median AUC for natalizumab patients on the 9HPT suggests the majority of natalizumab-treated patients experienced an overall favorable disability experience relative to baseline on upper limb function.
Conclusion: This post hoc analysis of ASCEND used AUC methodology to integrate disability worsening with improvement outcomes. These results show natalizumab significantly improved the overall disability experience for walking and upper limb function compared with placebo in mostly nonrelapsing SPMS patients with advanced disability. Consistent with the primary results from ASCEND, natalizumab treatment effects were greatest for upper limb function.
Disclosure: GG: steering committees for AbbVie, Atara Bio, Biogen, Novartis, Roche, Teva; consultancy fees from Biogen, Canbex, Genzyme-Sanofi, GlaxoSmithKline, Merck Serono, Novartis, Roche, Synthon.
MSF: honoraria or consulting fees from Bayer HealthCare, Biogen, Chugai, EMD Canada, Hoffmann-La Roche, Merck Serono, Novartis, Sanofi Genzyme, Teva Canada Innovation; participation in company advisory boards or boards of directors for Actelion, Bayer HealthCare, Biogen, Hoffmann-La Roche, Merck Serono, Novartis, Opexa, Sanofi Genzyme; participation in a company-sponsored speakers' bureau for Genzyme.
HPH: personal compensation for consulting services and/or speaking at scientific symposia from Biogen, GeNeuro, Genzyme, Merck Serono, Novartis, Octapharma, Opexa, Roche, Teva.
EH: research support from Biogen; honoraria from Actelion, Biogen, Celgene, Merck Serono, Novartis, Sanofi Genzyme.
DJ: research funding from Biogen, Genentech; personal compensation for speaking or consulting services from Acorda, Bayer, Biogen, Genentech, GlaxoSmithKline, Novartis, Questcor, Serono, Teva.
RK: personal compensation for consultancies, lectures, participation in advisory boards, and/or support for travel to medical meetings from Biogen, Genzyme, Karo Bio, Novartis, Roche, Teva.
AM: research funding from Acorda, Biogen, Genentech, Genzyme, Novartis, Questcor, Roche, Sanofi; personal compensation for consulting services from Accordant Health Services, Acorda, Alkermes, Biogen, EMD Serono, Genentech, GlaxoSmithKline, Novartis, Roche, Sanofi Genzyme, Teva.
FS: compensation for service on scientific advisory boards, on steering committees of clinical trials, and as a consultant for and/or received support for congress participation, speaker honoraria, or research support for his laboratory from Biogen, EMD Serono, Genzyme, Merck, Novartis, Roche, Sanofi, Teva.
QD, NC, DS, PRH: employees of and may hold stock and/or stock options in Biogen.

Abstract: 131

Type: Oral

Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Background: While natalizumab did not meet the primary multicomponent endpoint of reducing disability progression in mostly nonrelapsing secondary progressive multiple sclerosis (SPMS) patients in ASCEND, results have shown that natalizumab significantly delays upper limb disability progression and is associated with greater levels of disability improvement than placebo, suggesting that natalizumab treatment benefits in this population may be a combination of reduced sustained worsening and increased sustained improvement.
Objective: This post hoc analysis of ASCEND used area-under-the-curve (AUC) methodology to examine natalizumab treatment effects on integrated disability worsening and improvement as measured by the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT).
Methods: ASCEND, a multicenter, randomized, double-blind phase 3 trial, enrolled natalizumab-naive patients diagnosed with SPMS ≥2 years prior with disability progression unrelated to clinical relapses in the past year. Patients received IV 300 mg natalizumab (n=439) or placebo (n=448) for 2 years. AUC trapezoidal analysis was used to compare changes from baseline in EDSS scores and percentage changes from baseline in T25FW and 9HPT times for natalizumab- vs placebo-treated patients.
Results: Significant improvements from baseline to week 96 with natalizumab relative to placebo were observed in the median (range) AUC of T25FW (natalizumab, 19.18 [−121.5, 725.5]; placebo, 24.5 [−130.8, 2129.6]; P=0.020) and 9HPT (average hand: natalizumab, −1.59 [−66.3, 226.7]; placebo, 2.58 [−81.1, 834.8]; P=0.006) but not EDSS (natalizumab, 0 [−4.2, 4.1]; placebo, 0 [−5.1, 4.2]; P=0.733). These results correspond to 28% and 77% reductions in T25FW and 9HPT mean AUC, respectively, for natalizumab vs placebo. The negative median AUC for natalizumab patients on the 9HPT suggests the majority of natalizumab-treated patients experienced an overall favorable disability experience relative to baseline on upper limb function.
Conclusion: This post hoc analysis of ASCEND used AUC methodology to integrate disability worsening with improvement outcomes. These results show natalizumab significantly improved the overall disability experience for walking and upper limb function compared with placebo in mostly nonrelapsing SPMS patients with advanced disability. Consistent with the primary results from ASCEND, natalizumab treatment effects were greatest for upper limb function.
Disclosure: GG: steering committees for AbbVie, Atara Bio, Biogen, Novartis, Roche, Teva; consultancy fees from Biogen, Canbex, Genzyme-Sanofi, GlaxoSmithKline, Merck Serono, Novartis, Roche, Synthon.
MSF: honoraria or consulting fees from Bayer HealthCare, Biogen, Chugai, EMD Canada, Hoffmann-La Roche, Merck Serono, Novartis, Sanofi Genzyme, Teva Canada Innovation; participation in company advisory boards or boards of directors for Actelion, Bayer HealthCare, Biogen, Hoffmann-La Roche, Merck Serono, Novartis, Opexa, Sanofi Genzyme; participation in a company-sponsored speakers' bureau for Genzyme.
HPH: personal compensation for consulting services and/or speaking at scientific symposia from Biogen, GeNeuro, Genzyme, Merck Serono, Novartis, Octapharma, Opexa, Roche, Teva.
EH: research support from Biogen; honoraria from Actelion, Biogen, Celgene, Merck Serono, Novartis, Sanofi Genzyme.
DJ: research funding from Biogen, Genentech; personal compensation for speaking or consulting services from Acorda, Bayer, Biogen, Genentech, GlaxoSmithKline, Novartis, Questcor, Serono, Teva.
RK: personal compensation for consultancies, lectures, participation in advisory boards, and/or support for travel to medical meetings from Biogen, Genzyme, Karo Bio, Novartis, Roche, Teva.
AM: research funding from Acorda, Biogen, Genentech, Genzyme, Novartis, Questcor, Roche, Sanofi; personal compensation for consulting services from Accordant Health Services, Acorda, Alkermes, Biogen, EMD Serono, Genentech, GlaxoSmithKline, Novartis, Roche, Sanofi Genzyme, Teva.
FS: compensation for service on scientific advisory boards, on steering committees of clinical trials, and as a consultant for and/or received support for congress participation, speaker honoraria, or research support for his laboratory from Biogen, EMD Serono, Genzyme, Merck, Novartis, Roche, Sanofi, Teva.
QD, NC, DS, PRH: employees of and may hold stock and/or stock options in Biogen.

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