TY - JOUR
T1 - Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND)
T2 - a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension
AU - ASCEND investigators
AU - Kapoor, Raju
AU - Ho, Pei Ran
AU - Campbell, Nolan
AU - Chang, Ih
AU - Deykin, Aaron
AU - Forrestal, Fiona
AU - Lucas, Nisha
AU - Yu, Bei
AU - Arnold, Douglas L.
AU - Freedman, Mark S.
AU - Goldman, Myla D.
AU - Hartung, Hans Peter
AU - Havrdová, Eva Kubala
AU - Jeffery, Douglas
AU - Miller, Aaron
AU - Sellebjerg, Finn
AU - Cadavid, Diego
AU - Mikol, Dan
AU - Steiner, Deborah
AU - Bartholomé, Emmanuel
AU - D'Hooghe, Marie
AU - Pandolfo, Massimo
AU - Van Wijmeersch, Bart
AU - Bhan, Virender
AU - Blevins, Gregg
AU - Brunet, Donald
AU - Devonshire, Virginia
AU - Duquette, Pierre
AU - Freedman, Mark
AU - Grand'Maison, François
AU - Jacques, François
AU - Lapierre, Yves
AU - Lee, Liesly
AU - Morrow, Sarah
AU - Yeung, Michael
AU - Dufek, Michal
AU - Havrdová, Eva Kubala
AU - Kanovsky, Petr
AU - Stetkarova, Ivana
AU - Talabova, Marika
AU - Frederiksen, Jette
AU - Kant, Matthias
AU - Petersen, Thor
AU - Ravnborg, Mads
AU - Sellebjerg, Finn
AU - Airas, Laura
AU - Elovaara, Irina
AU - Eralinna, Juha Pekka
AU - Sarasoja, Taneli
AU - Yadav, Vijayshree
N1 - Funding Information:
RK has received support from the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (UCLH/UCL) and personal compensation for consultancies, lectures, participation in advisory boards, and support for travel to medical meetings from Biogen, Genzyme, Karo Bio, Novartis, Roche, and Teva. UCL Hospitals received payment for investigation and follow-up of participants in the ASCEND trial. P-RH, NC, IC, AD, FF, NL, BY, and DS are employees of and hold stock or stock options, or both, in Biogen. DLA has served on advisory boards, received speaker honoraria, served as a consultant for, or received research support from, Adelphi, Biogen, Genentech, MedDay, Novartis Pharma AG, Pfizer, Receptos/Celgene, Roche, and Sanofi, and holds stock in NeuroRx Research. MSF has received honoraria or consulting fees from Actelion, Bayer HealthCare, Clene Nanomedicine, Hoffman-La Roche, Merck Serono, Sanofi, Genzyme, and Teva Canada Innovation; participated in company advisory boards, steering committees, or boards of directors for Actelion, Bayer HealthCare, Chugai, EMD Serono, and Sanofi Genzyme; received travel support from Biogen; and received grants for research from Sanofi Genzyme. MDG has received personal compensation for consulting services from Acorda Therapeutics, Adamas, AtlasD, EMD Serono, Endece, Genzyme, Novartis, and Serepta; honorarium from the American Academy of Neurology; and research support from Biogen, Novartis Pharmaceuticals, NMSS, and NINDS. H-PH has received personal compensation for consulting services and speaking at scientific symposia from Biogen, GeNeuro, Genzyme, Merck Serono, Novartis, Octapharma, Opexa, Roche, and Teva. EKH has received research support from Biogen and The Czech Ministry of Education (project PROGRESQ27/LF1) and honoraria from Actelion, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. DJ has received research funding from Biogen, Genentech, and Novartis, and personal compensation for speaking or consulting services from Acorda, Bayer, Biogen, Genentech, Mallinkrodt, Novartis, Sanofi Genzyme, Serono, and Teva. AM has received research funding from Biogen, Genentech, Genzyme, Novartis, Roche, and Sanofi and personal compensation for consulting services from Accordant Health Services, Adamas, Biogen, Celgene, Genentech, Mallinkrodt, Mapi-Pharma, Novartis, and Roche. FS has served on scientific advisory boards, on steering committees of clinical trials, or as a consultant for, or received support for, congress participation, speaker honoraria, or research support for his laboratory from Biogen, Genzyme, Merck Serono, Novartis, and Sanofi. DC was an employee of Biogen at the time of this analysis and is now an employee of Fulcrum Therapeutics. DM was an employee of Biogen at the time of this analysis and is now an employee of Amgen. Fulcrum Therapeutics, and Amgen were not in any way associated with this study.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/5
Y1 - 2018/5
N2 - Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen.
AB - Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen.
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U2 - 10.1016/S1474-4422(18)30069-3
DO - 10.1016/S1474-4422(18)30069-3
M3 - Article
C2 - 29545067
AN - SCOPUS:85043460798
VL - 17
SP - 405
EP - 415
JO - The Lancet Neurology
JF - The Lancet Neurology
SN - 1474-4422
IS - 5
ER -