BACKGROUND: Multipotent adult progenitor cells are a bone marrow-derived, 
allogeneic, cell therapy product that modulates the immune system, and 
represents a promising therapy for acute stroke. We aimed to identify the 
highest, well-tolerated, and safest single dose of multipotent adult progenitor 
cells, and if they were efficacious as a treatment for stroke recovery.
METHODS: We did a phase 2, randomised, double-blind, placebo-controlled, 
dose-escalation trial of intravenous multipotent adult progenitor cells in 33 
centres in the UK and the USA. We used a computer-generated randomisation 
sequence and interactive voice and web response system to assign patients aged 
18-83 years with moderately severe acute ischaemic stroke and a National 
Institutes of Health Stroke Scale (NIHSS) score of 8-20 to treatment with 
intravenous multipotent adult progenitor cells (400 million or 1200 million 
cells) or placebo between 24 h and 48 h after symptom onset. Patients were 
ineligible if there was a change in NIHSS of four or more points during at least 
a 6 h period between screening and randomisation, had brainstem or lacunar 
infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or 
had a history of splenectomy. In group 1, patients were enrolled and randomly 
assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for 
safety through 7 days. In group 2, patients were randomly assigned in a 3:1 
ratio to receive 1200 million cells or placebo and assessed for safety through 
the first 7 days. In group 3, patients were enrolled, randomly assigned, and 
stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 
1:1 ratio within 24-48 h. Patients, investigators, and clinicians were masked to 
treatment assignment. The primary safety outcome was dose-limiting toxicity 
effects. The primary efficacy endpoint was global stroke recovery, which 
combines dichotomised results from the modified Rankin scale, change in NIHSS 
score from baseline, and Barthel index at day 90. Analysis was by intention to 
treat (ITT) including all patients in groups 2 and 3 who received the 
investigational agent or placebo. This study is registered with 
ClinicalTrials.gov, number NCT01436487.
FINDINGS: The study was done between Oct 24, 2011, and Dec 7, 2015. After safety 
assessments in eight patients in group 1, 129 patients were randomly assigned 
(67 to receive multipotent adult progenitor cells and 62 to receive placebo) in 
groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 
patients who received multipotent adult progenitor cells and 61 patients who 
received placebo. There were no dose-limiting toxicity events in either group. 
There were no infusional or allergic reactions and no difference in 
treatment-emergent adverse events between the groups (64 [99%] of 65 patients in 
the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo 
group). There was no difference between the multipotent adult progenitor cell 
group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 
[95% CI 0·55-2·09], p=0·83).
INTERPRETATION: Administration of multipotent adult progenitor cells was safe 
and well tolerated in patients with acute ischaemic stroke. Although no 
significant improvement was observed at 90 days in neurological outcomes with 
multipotent adult progenitor cells treatment, further clinical trials evaluating 
the efficacy of the intervention in an earlier time window after stroke (<36 h) 
are planned.
FUNDING: Athersys Inc.