Perispinal Etanercept Shows No Efficacy in Treating Chronic Stroke

Recently published findings from a phase 2a randomized clinical trial showed that perispinal etanercept, a competitive tumor necrosis factor-α inhibitor, was safe in patients with chronic stroke, but had no impact on efficacy outcomes relative to placebo.¹

Otherwise known as the Perispinal Etanercept for Stroke Outcomes Study, this double-blind, placebo-controlled, parallel-group trial enrolled 126 participants, aged 18-70 years, who had stroke between 1 and 15 years before enrollment, with a modified Rankin scale (mRS) score of 2-5. The trial, which ended recruitment early because of lack of continued funding, randomly assigned patients 1:1 to either perispinal etanercept or placebo, using 5-point improvement in 36-Item Short Form Survey (SF-36) as the primary end point.

Led by Vincent Thijs, MD, a neurologist and clinical researcher at the University of Melbourne, 53% of patients in the etanercept arm achieved the primary outcome of 5-point improvement vs 58% of those on placebo (adjusted odds ratio [aOR], 0.82 [95% CI, 0.40-1.67]; standardized risk difference, –5% [95% CI, –22% to 13%]). Conducted from 2020 to 2023, there were no between-group differences on any of the individual subscales of the SF-36, which included Total, Physical, and Mental Component summaries.

Entanercept, a TNF-α inhibitor, was hypothesized to dampen chronic post-stroke inflammation and thereby improve recovery of function even years after the initial result. While the lack of clinical benefit in the trial underscored the difficulty of translating immunomodulatory strategies into meaningful neurological outcomes, it also highlighted the need for more precise approaches to patient selection, timing of intervention, and understanding of post-stroke inflammatory pathways.

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On secondary outcomes, investigators reported a similar proportion of patients with at least a 5-point improvement on the SF-36v2 on day 56, regardless of whether they received etanercept twice (54%; 22 of 41), a single dose of etanercept (66%; 25 of 38), or placebo twice (58%; 21 of 36). There were no significant differences on a number of exploratory outcomes, including National Institute Stroke Scale Severity scores, Functional Independence Measure, mRS, General Anxiety Disorder-7, and Montreal Cognitive Assessment.

"Although the study did not demonstrate a statistically significant treatment effect, the findings are nonetheless important for informing clinical practice,” Thijs et al wrote.¹ "Given previous claims of substantial benefit with perispinal etanercept, our results suggest that such claims may not be supported by high-quality clinical trial data. While the lack of a significant treatment effect may reduce enthusiasm for this intervention, the study contributes valuable evidence to the field, reinforcing the need for robust, controlled evaluations of novel therapies."

On exploratory outcomes, the only significant between-group difference was found on Visual Analog Scale scores, with a –9.5-point difference (95% CI, –17.30 to –1.7) for the single dose vs placebo and –9.5 (95% CI, –18.47 to –0.53) for the double dose at day 56. Of note, regression at the 75^th percentile showed a difference for the single dose vs placebo (–10.43; 95% CI, –19.63 to –1.24).

In terms of safety, etanercept was considered safe across the study period. Within this group, there was 1 serious adverse event (SAE) recorded between recruitment and day 28, owing to a diagnosis of renal carcinoma with pancreatic and brain metastasis on day 15. In addition, between day 28 and day 56, there was 1 patient with malaise and possible aspiration on day 53 who was assigned etanercept initially but switched to placebo on day 28.

REFERENCE
1. Safety and Efficacy of Perispinal Etanercept for Chronic Stroke: A Randomized Clinical Trial. Neurology. 2025;105(6). doi:10.1212/WNL.0000000000213981