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.