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Randomized Controlled Trial
. 2025 Sep 23;105(6):e213981.
doi: 10.1212/WNL.0000000000213981. Epub 2025 Sep 4.

Safety and Efficacy of Perispinal Etanercept for Chronic Stroke: A Randomized Clinical Trial

Vincent N Thijs  1   2   3   4 , Geoffrey C Cloud  5   6 , Nigel Gilchrist  7 , Brooke Parsons  8 , Forum Tilvawala  3 , Jan Kee Ho  3 , Lara Ruthnam  3 , Vimal Stanislaus  5   6 , Nikola Sprigg  9   10 , Marion Walker  10 , Philip M Bath  9   10 , Leonid Churilov  4   8   11 , Julie Bernhardt  2   8
Affiliations
Randomized Controlled Trial

Safety and Efficacy of Perispinal Etanercept for Chronic Stroke: A Randomized Clinical Trial

Vincent N Thijs et al. Neurology. .

Abstract

Background and objectives: Stroke is a leading cause of long-term disability. Etanercept, a competitive tumor necrosis factor-α inhibitor, has been proposed as a potential treatment for post-stroke impairments when given through a perispinal subcutaneous injection. We aimed to evaluate the safety and efficacy of perispinal etanercept in patients with chronic stroke.

Methods: The Perispinal Etanercept for Stroke Outcomes Study was a randomized, double-blind, placebo-controlled, parallel group trial conducted in 3 ambulatory research clinics in Australia and New Zealand. Eligible patients were aged between 18 and 70 years, had a stroke between 1 and 15 years before enrollment, had a modified Rankin Scale score of 2-5, and demonstrated reduced quality of life as assessed by the 36-Item Short Form Survey (SF-36). Patients were randomized in a 1:1 ratio. The primary outcome was the difference in the proportion of participants at day 28 with an improvement of 5 points or more on the SF-36v2 compared with baseline after a single injection of etanercept 25 mg or equivalent placebo. The primary safety outcome was the difference in the proportion over 28 days of serious adverse events after a single injection of etanercept 25 mg or equivalent placebo. The primary outcome and safety were analyzed in the intention-to-treat population. Participants were followed up 56 days after the first injection of perispinal etanercept.

Results: Recruitment ceased early because of lack of continued funding. We screened 147 participants, of whom 126 were enrolled and randomized (63 etanercept: 63 placebo; 48 [38%] female, median (interquartile range) age 54.5 (45.0-60.0) years, median time since stroke 3 years). The primary outcome of improvement occurred in 33 of 63 participants (53%) in the etanercept arm and 36 of 63 participants (58%) in the placebo arm (adjusted odds ratio 0.82, 95% CI 0.40-1.67, standardized risk difference -5%, 95% CI -22% to 13%). The proportion of serious adverse events was similar in both treatment arms.

Discussion: Perispinal etanercept was safe, but we found no evidence of improvement in quality of life and other efficacy outcomes compared with placebo.

Trial registration information: The trial was registered at anzctr.org.au (ACTRN12620001011976) on October 7, 2020. Patients were enrolled between November 4, 2020, and September 1, 2023.

Classification of evidence: This study provides Class I evidence that in patients with imaging-confirmed ischemic or hemorrhagic stroke, perispinal etanercept (25 mg) injection does not improve the patients' quality of life 28 days after injection.

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Conflict of interest statement

V.N. Thijs reports speaker fees for Amgen, Allergan, Astra Zeneca, Atricure, BMS, Bayer, Boehringer Ingelheim, and Medtronic, unrelated to this publication; is on the editorial board for Annals of Neurology, Neurology®, International Journal of Stroke, and the European Stroke Journal; is on the steering committee of the Librexia trial, for which he receives modest compensation from Janssen; and chairs the DSMB of the Evaluating the Safety and Efficacy of Telemedicine Neurology Assessments on a Mobile Stroke Unit and the Emview Study. G.C. Cloud reports honoraria for speaking engagements and participation in advisory board consultation for Astra Zeneca. P.M. Bath is Stroke Association Professor of Stroke Medicine and an emeritus NIHR Senior Investigator; and has consulted for and received honoraria from CoMind, DiaMedica, Phagenesis, and Roche. J. Bernhardt is supported by the NHMRC Australia; has received honoraria for presentations to the American Congress of Rehabilitation Medicine, Moleac P/L, and the University Hospital of Bern; has received travel support from the World Stroke Organization, the Swiss Congress CHUV, the Global Stroke Alliance, and the Dutch Society of Neurorehabilitation; is an associate editor for the International Journal of Stroke and Section Editor, Stroke Recovery and Rehabilitation for Stroke; is the executive chair of the International Stroke Recovery and Rehabilitation Alliance; is a member on the Scientific Advisory of academic institutions in Norway and India; is the chair of the data safety monitoring board for the iWHO, SCI-MT, and ESTRELL trials; and is on the steering committee of the PISCES, UPLIFT, and ENABLE trials. All other authors report no disclosures. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Study Timeline
SF-36 = 36-Item Short Form Survey.
Figure 2
Figure 2. Study Disposition
Figure 3
Figure 3. Prespecified Subgroup Analysis
See this image and copyright information in PMC

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