LOS ANGELES—A single infusion of natalizumab given within nine hours after stroke onset does not reduce focal infarct volume growth, but is associated with improved clinical outcomes over 90 days, compared with placebo, according to phase II trial results described at the International Stroke Conference 2016.
In experimental stroke models, brain ischemia triggers an inflammatory reaction that worsens outcomes. Natalizumab, a humanized monoclonal antibody that binds to alpha-4 beta-1 integrin and is approved for use in multiple sclerosis and Crohn’s disease, prevents leukocytes from migrating across the blood–brain barrier. In some experimental models of acute ischemic stroke, natalizumab reduces infarct volume and improves outcomes, said Jacob Elkins, MD, MAS, Senior Director of Clinical Development at Biogen in Cambridge, Massachusetts. Furthermore, natalizumab’s pharmacokinetic and pharmacodynamic profiles are well defined. “It works very quickly and, after a single infusion, it continues to block this inflammatory reaction for about 30 days,” he said.
The ACTION Trial
To test the efficacy and safety of a single dose of natalizumab in patients with acute ischemic stroke, the ACTION investigators conducted a 90-day, multicenter, double-blind study across 30 stroke centers in the United States and Europe. A total of 159 subjects were randomized to receive 300 mg of IV natalizumab or placebo within nine hours of when they were last known to be normal.
Patients were between ages 18 and 85, had an NIH Stroke Scale (NIHSS) score of 6 or more at screening, and had at least one acute infarct with a diameter larger than 2 cm on baseline brain diffusion-weighted imaging. Investigators excluded patients with any intracranial hemorrhage on head CT scan, nonpetechial intracranial hemorrhage on screening MRI, or stroke isolated to the brainstem. Patients who were immunocompromised, who had hypotension requiring the use of IV vasopressor support, or who had systolic blood pressure less than 90 mm Hg at the time of randomization also were excluded.
The primary end point was change in infarct volume from baseline to day five. Secondary end points were the NIHSS, modified Rankin Scale, and Barthel Index, and exploratory end points included the Montreal Cognitive Assessment and Stroke Impact Scale-16.
Eighty-two subjects received placebo, and 77 subjects received natalizumab. Participants’ average age was 71.1, and 45% were female. The mean NIHSS score was 13.1, and 76% of participants received t-PA. Average infarct size (largest diameter) was 5.4 cm, and median infarct volume was 23.7 mL. The groups were well balanced in terms of clinical and infarct characteristics.
Natalizumab did not affect infarct volume growth on MRI, nor did it affect focal neurologic examination findings on the NIHSS. Treatment was, however, associated with global clinical gains in functional independence, cognition, and patient-reported stroke impact.
Ten percent of controls versus 20.6% of patients who received natalizumab had a modified Rankin Scale score of 0 or 1 at 30 days. “This effect was somewhat attenuated at day 90, but at day 90 we also saw at least strong trends suggesting benefit with natalizumab on other related end points,” said Dr. Elkins. More patients in the natalizumab group than in the placebo group had a Montreal Cognitive Assessment score of 26 or greater (30.6% vs 20.4%), a Stroke Impact Scale-16 score greater than the median (69.6% vs 57.4%), and a Barthel Index score of 95 or greater (56.4% vs 41.0%).
When the investigators adjusted for potential confounders and compensated for missing data in various ways, “these trends were persistent and robust across all of those analyses,” he said. “The one outcome, though, that we did not see benefit on was the NIHSS, which we thought was interesting because this was perhaps the scale that most closely is related to the infarct volume.” A subgroup analysis found that treatment within six hours versus nine hours did not affect outcomes, suggesting an extended therapeutic window. There was stronger evidence of benefit in patients with smaller infarcts, he said.
The findings “are suggestive of a more diffuse process of postischemic inflammation, rather than one focused at the infarct location,” Dr. Elkins said. In addition, no safety concerns were identified.
“We are cautious about interpretation of these findings, including the potential for some false positive results, but based on the magnitude of the observed benefits and lack of safety signals, further studies are warranted,” said Dr. Elkins. The investigators plan to conduct another phase II trial to try to confirm the signals seen in this proof-of-concept trial, Dr. Elkins said.