Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial
Abstract
Background In animal models of acute ischaemic stroke, blocking of the leukocyte-endothelium adhesion by antagonism of α4 integrin reduces infarct volumes and improves outcomes. We assessed the effect of one dose of natalizumab, an antibody against the leukocyte adhesion molecule α4 integrin, in patients with acute ischaemic stroke.Methods In this double-blind, phase 2 study, patients with acute ischaemic stroke (aged 18-85 years) from 30 US and European clinical sites were randomly assigned (1:1) to 300 mg intravenous natalizumab or placebo with stratification by treatment window and baseline infarct size. Patients, investigators, and study staff were masked to treatment assignments. The primary endpoint was the change in infarct volume from baseline to day 5 and was assessed in the modified intention-to-treat population. Secondary endpoints were the change in infarct volume from baseline to day 30, and from 24 h to days 5 and 30; the National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at days 5 (or discharge), 30, and 90; and modified Rankin Scale (mRS) and Barthel Index (BI) at days 5 (or discharge), 30, and 90. This trial is registered with ClinicalTrials.gov, number NCT01955707.Findings Between Dec 16, 2013, and April 9, 2015, 161 patients were randomly assigned to natalizumab (n=79) or placebo (n=82). Natalizumab did not reduce infarct volume growth from baseline to day 5 compared with placebo (median absolute growth 28 mL [range -8 to 303] vs 22 mL [-11 to 328]; relative growth ratio 1·09 [90% CI 0·91-1·30], p=0·78) or to day 30 (4 mL [-43 to 121] vs 4 mL [-28 to 180]; 1·05 [0·88-1·27], p=0·68), from 24 h to day 5 (8 mL [-30 to 177] vs 7 mL [-13 to 204]; 1·00 [0·89-1·12], p=0·49), and from 24 h to day 30 (-5 mL [-93 to 81] vs -5 mL [-48 to 48]; 0·98 [0·87-1·11], p=0·40). No difference was noted between the natalizumab and placebo groups in the NIHSS (score ≤1 or ≥8 point improvement) from baseline at 24 h, day 5 (or discharge), day 30 (27 [35%] vs 36 [44%]; odds ratio 0·69 [90% CI 0·39-1·21], p=0·86), and day 90 (36 [47%] vs 37 [46%]; 1·10 [0·63-1·93], p=0·39). More patients in the natalizumab group than in the placebo group had mRS scores of 0 or 1 at day 30 (13 [18%] vs seven [9%]; odds ratio 2·88 [90% CI 1·20-6·93], p=0·024) and day 90 (18 [25%] vs 16 [21%]; 1·48 [0·74-2·98], p=0·18); and BI (score ≥95) at day 90 (34 [44%] vs 26 [33%]; 1·91 [1·07-3·41], p=0·033) but not significantly at day 5 or day 30 (26 [34%] vs 26 [32%]; 1·13 [0·63-2·00], p=0·37). Natalizumab and placebo groups had similar incidences of adverse events (77 [99%] of 78 patients vs 81 [99%] of 82 patients), serious adverse events (36 [46%] vs 38 [46%]), and deaths (14 [18%] vs 13 [16%]). Two patients in the natalizumab group died because of adverse events assessed as related to treatment by the investigator (pneumonia, and septic shock and multiorgan failure).Interpretation Natalizumab administered up to 9 h after stroke onset did not reduce infarct growth. Treatment-associated benefits on functional outcomes might warrant further investigation.Funding Biogen.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A number of preclinical and clinical trials have failed to improve ischemic stroke outcomes or lesion size by preventing leukocyte diapedesis, indicating that our knowledge of the inflammatory response to this condition is incomplete.
“To date, a number of preclinical and clinical trials have failed to improve ischemic stroke outcomes or lesion size by preventing leukocyte diapedesis (142, 147), indicating that our knowledge of the inflammatory response to this condition is incomplete.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [147]
Cites
The immunology of stroke: from mechanisms to translation
Iadecola, C., & Anrather, J. (2011) · Nature Medicine · doi:10.1038/nm.2399 · Cited by 2,596 · see citing works
The Science of Stroke: Mechanisms in Search of Treatments
Moskowitz, M. A., Lo, E. H., & Iadecola, C. (2010) · Neuron · doi:10.1016/j.neuron.2010.07.002 · Cited by 1,930 · see citing works
Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin
Yednock, T. A., Cannon, C., Fritz, L. C., Sánchez‐Madrid, F., Steinman, L., & Karin, N. (1992) · Nature · doi:10.1038/356063a0 · Cited by 1,737 · see citing works
A controlled trial of natalizumab for relapsing multiple sclerosis.
Miller, D. H., Khan, O., Sheremata, W., Blumhardt, L., Rice, G., Libonati, M., Willmer-Hulme, A., Dalton, C., Miszkiel, K., & O'Connor, P. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa020696 · Cited by 1,265 · see citing works
Use of the Barthel Index and Modified Rankin Scale in Acute Stroke Trials
Sulter, G., Steen, C., & Keyser, J. D. (1999) · Stroke · doi:10.1161/01.str.30.8.1538 · Cited by 1,119 · see citing works
Shichita, T., Sugiyama, Y., Ooboshi, H., Sugimori, H., Nakagawa, R., Takada, I., Iwaki, T., Okada, Y., Iida, M., Cua, D. J., et al. (2009) · Nature Medicine · doi:10.1038/nm.1999 · Cited by 842 · see citing works
Natalizumab for Active Crohn's Disease
Ghosh, S. K., Goldin, E., Gordon, F. H., Malchow, H. A., Rask-Madsen, J., Rutgeerts, P. J., Vyhnálek, P., Zádorová, Z., Palmer, T., & Donoghue, S. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa020732 · Cited by 811 · see citing works
Role of T Lymphocytes and Interferon-γ in Ischemic Stroke
Yilmaz, G., Arumugam, T. V., Stokes, K. Y., & Granger, D. N. (2006) · Circulation · doi:10.1161/circulationaha.105.593046 · Cited by 722 · see citing works
The immunology of acute stroke
Chamorro, Á., Meisel, A., Planas, A. M., Urra, X., van de Beek, D., & Veltkamp, R. C. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.98 · Cited by 707 · see citing works
Self-citationUse of anti-ICAM-1 therapy in ischemic stroke
Enlimomab Acute Stroke Trial Investigators (2001) · Neurology · doi:10.1212/wnl.57.8.1428 · Cited by 546 · see citing works
Cerebral microinfarcts: the invisible lesions
Smith, E. E., Schneider, J. A., Wardlaw, J. M., & Greenberg, S. M. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70307-6 · Cited by 456 · see citing works
Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN)
Krams, M., Lees, K. R., Hacke, W., Grieve, A. P., Orgogozo, J., & Ford, G. A. (2003) · Stroke · doi:10.1161/01.str.0000092527.33910.89 · Cited by 431 · see citing works
Liesz, A., Zhou, W., Mracsko, E. Z., Karcher, S., Bauer, H., Schwarting, S., Sun, L., Bruder, D., Stegemann‐Koniszewski, S., Cerwenka, A., et al. (2011) · Brain · doi:10.1093/brain/awr008 · Cited by 410 · see citing works
Self-citationT- and B-Cell-Deficient Mice with Experimental Stroke have Reduced Lesion Size and Inflammation
Hum, P. D., Subramanian, S., Parker, S. M., Afentoulis, M. E., Kaler, L. J., Vandenbark, A. A., & Offner, H. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600482 · Cited by 355 · see citing works
Underlying Structure of the National Institutes of Health Stroke Scale
Lyden, P. D., Lü, M., Jackson, C., Marler, J. R., Kothari, R., Brott, T. G., & Zivin, J. A. (1999) · Stroke · doi:10.1161/01.str.30.11.2347 · Cited by 354 · see citing works
B-Lymphocyte-Mediated Delayed Cognitive Impairment following Stroke
Doyle, K. P., Quach, L. N., Solé, M., Axtell, R. C., Nguyen, T. V., Soler-Llavina, G. J., Jurado, S., Han, J., Steinman, L., Longo, F. M., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4098-14.2015 · Cited by 338 · see citing works
MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS
Miller, D. H., Soon, D. T. L., Fernando, K., MacManus, D. G., Barker, G. J., Yousry, T. A., Fisher, E., O'Connor, P. W., Phillips, J. T., Polman, C. H., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000260064.77700.fd · Cited by 332 · see citing works
Gordon, F. H., Lai, C., Hamilton, M., Allison, M. C., Srivastava, E. D., Fouweather, M. G., Donoghue, S., Greenlees, C., Subhani, J., Amlot, P. L., et al. (2001) · Gastroenterology · doi:10.1053/gast.2001.26260 · Cited by 314 · see citing works
Stroke Impact Scale-16: A brief assessment of physical function
Duncan, P. W., Lai, S. M., Bode, R. K., Perera, S., DeRosa, J., & the GAIN Americas Investigators (2003) · Neurology · doi:10.1212/01.wnl.0000041493.65665.d6 · Cited by 299 · see citing works
Llovera, G., Hofmann, K., Roth, S., Salas-Perdomo, A., Ferrer-Ferrer, M., Perego, C., Zanier, E. R., Mamrak, U., Rex, A., Party, H., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa9853 · Cited by 250 · see citing works
Innate Inflammatory Responses in Stroke: Mechanisms and Potential Therapeutic Targets
Kim, J. Y., Kawabori, M., & Yenari, M. A. (2014) · Current Medicinal Chemistry · doi:10.2174/0929867321666131228205146 · Cited by 250 · see citing works
Use of Montreal Cognitive Assessment in Patients With Stroke
Chiti, G., & Pantoni, L. (2014) · Stroke · doi:10.1161/strokeaha.114.004590 · Cited by 185 · see citing works
Mortality and Cost of Pneumonia After Stroke for Different Risk Groups
Wilson, R. D. (2010) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2010.05.002 · Cited by 182 · see citing works
Natalizumab: α4-integrin antagonist selective adhesion molecule inhibitors for MS
Rudick, R. A., & Sandrock, A. W. (2004) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.4.4.571 · Cited by 169 · see citing works
Antibody to the α4 Integrin Decreases Infarct Size in Transient Focal Cerebral Ischemia in Rats
Becker, K. J., Kindrick, D. L., Relton, J. K., Harlan, J., & Winn, R. K. (2001) · Stroke · doi:10.1161/01.str.32.1.206 · Cited by 168 · see citing works
Self-citationLong-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study
O'Connor, P. W., Goodman, A. D., Kappos, L., LUBLIN, F. D., Polman, C. H., Rudick, R. A., Hauswirth, K., Cristiano, L. M., Forrestal, F., & Duda, P. W. (2014) · Neurology · doi:10.1212/wnl.0000000000000541 · Cited by 136 · see citing works
Salvadori, E., Pasi, M., Poggesi, A., Chiti, G., Inzitari, D., & Pantoni, L. (2013) · Journal of Neurology · doi:10.1007/s00415-013-6962-7 · Cited by 119 · see citing works
Kimura, K., Minematsu, K., Kazui, S., & Yamaguchi, T. (2005) · Cerebrovascular Diseases · doi:10.1159/000083252 · Cited by 118 · see citing works
Natalizumab for relapsing remitting multiple sclerosis
Pucci, E., Giuliani, G., Solari, A., Simi, S., Minozzi, S., Pietrantonj, C. D., & Galea, I. (2011) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007621.pub2 · Cited by 101 · see citing works
Relton, J. K., Sloan, K. E., Frew, E. M., Whalley, E. T., Adams, S. P., & Lobb, R. R. (2001) · Stroke · doi:10.1161/01.str.32.1.199 · Cited by 94 · see citing works
Blocking of α4 Integrin Does Not Protect From Acute Ischemic Stroke in Mice
Langhauser, F., Kraft, P., Göb, E., Leinweber, J., Schuhmann, M. K., Lorenz, K., Gelderblom, M., Bittner, S., Meuth, S. G., Wiendl, H., et al. (2014) · Stroke · doi:10.1161/strokeaha.114.005000 · Cited by 87 · see citing works
Pasi, M., Salvadori, E., Poggesi, A., Inzitari, D., & Pantoni, L. (2013) · Journal of Neurology · doi:10.1007/s00415-012-6819-5 · Cited by 59 · see citing works
Expression of α4-integrins on human neutrophils
Kirveskari, J. P., Bono, P., Granfors, K., et al. (2000) · Journal of Leukocyte Biology · doi:10.1189/jlb.68.2.243 · Cited by 24 · see citing works
Expression of alpha4-integrins on human neutrophils.
Kirveskari, J. P., Bono, P., Granfors, K., et al. (2000) · PubMed · Cited by 21 · see citing works
Impact of infections on long-term outcome after severe middle cerebral artery infarction
Ulm, L., Harms, H., Ohlraun, S., et al. (2012) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.05.042 · Cited by 19 · see citing works
Inhibition of alpha4 integrin to protect the brain against ischemic injury.
Relton, J. K. (2001) · PubMed · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Immune responses to stroke: mechanisms, modulation, and therapeutic potential.
Iadecola, C., Buckwalter, M. S., & Anrather, J. (2020) · Journal of Clinical Investigation · doi:10.1172/jci135530 · Cited by 853 · see citing works
The anatomy and immunology of vasculature in the central nervous system
Mastorakos, P., & McGavern, D. (2019) · Science Immunology · doi:10.1126/sciimmunol.aav0492 · Cited by 333 · see citing works
Translational Stroke Research: Vision and Opportunities
Bosetti, F., Koenig, J. I., Ayata, C., Back, S. A., Becker, K., Broderick, J. P., Carmichael, S. T., Cho, S., Cipolla, M. J., Corbett, D., et al. (2017) · Stroke · doi:10.1161/strokeaha.117.017112 · Cited by 171 · see citing works
Self-citationAging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?
Mayne, K., White, J. A., McMurran, C. E., Rivera, F. J., & de la Fuente, A. G. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.572090 · Cited by 167 · see citing works
Enzmann, G., Kargaran, S., & Engelhardt, B. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418794184 · Cited by 119 · see citing works
Temporally distinct myeloid cell responses mediate damage and repair after cerebrovascular injury
Mastorakos, P., Mihelson, N., Luby, M., Burks, S. R., Johnson, K., Hsia, A. W., Witko, J., Frank, J. A., Latour, L., & McGavern, D. B. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00773-6 · Cited by 113 · see citing works
- Authors
- Elkins, J., Veltkamp, R., Montaner, J., Johnston, S. C., Singhal, A. B., Becker, K., Lansberg, M. G., Tang, W., Chang, I., Muralidharan, K., Gheuens, S., Mehta, L., & Elkind, M. S. V.
- Affiliations
- Biogen (United States) (US)
- Imperial College London (GB)
- Vall d'Hebron Institut de Recerca (ES)
- The University of Texas at Austin (US)
- Massachusetts General Hospital (US)
- University of Washington (US)
- Stanford Medicine (US)
- Columbia University (US)
- Corresponding author
- Elkins, Jacob
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 16
- Issue
- 3
- Pages
- 217-226
- ISSN
- 1474-4422 (ISSN-L)
- OpenAlex
- W2587953391
- Cited by
- 224
- References
- 36
- Citations by year
- 2026: 21 · 2025: 18 · 2024: 16 · 2023: 20 · 2022: 28 · 2021: 31 · 2020: 29 · 2019: 26 · 2018: 22 · 2017: 11 · 2016: 1 · 2015: 1
- FWCI
- 18.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sanofi
- Biogen
- Regeneron Pharmaceuticals
- Topics
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Keywords
- natalizumab, acute ischemic stroke, CD49d, leukocyte-endothelial adhesion, neuroprotection, functional outcome, therapeutic time window, infarct size, NIHSS, modified Rankin Scale, Barthel Index, safety and tolerability, anti-CD20 monoclonal antibody, anti-CD3 antibody
- MeSH terms
- Natalizumab, Adolescent, Adult, Aged, Aged, 80 and over, Brain Ischemia, Double-Blind Method, Female, Humans, Immunologic Factors, International Cooperation, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Stroke, PubMed, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
