Safety and Efficacy of Perispinal Etanercept for Chronic Stroke

 You'll want to read all of the previous posts on Etanercept for other uses and risks and the previous unproven uses. Unless you really think your doctor has a good handle on this.

etanercept (41 posts to February 2011)

Safety and Efficacy of Perispinal Etanercept for Chronic Stroke

Vincent N. Thijs https://orcid.org/0000-0002-6614-8417, Geoffrey C. Cloud https://orcid.org/0000-0002-8365-6907, Nigel Gilchrist, Brooke Parsons, Forum Tilvawala https://orcid.org/0009-0007-1209-3880, Jan Kee Ho, Lara Ruthnam https://orcid.org/0009-0009-4526-3895, … Show All … , and Julie Bernhardt https://orcid.org/0000-0002-2787-8484Authors Info & Affiliations

September 23, 2025 issue

105 (6)

https://doi.org/10.1212/WNL.0000000000213981

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.

Introduction

 Despite advances in management, a considerable proportion of stroke survivors are left with disabling neurologic impairments. Medical treatment options are limited.Tumor necrosis factor-α (TNF-α) has been implicated in the pathophysiology of stroke recovery.^2-4 TNF-α is a proinflammatory cytokine that plays a critical role in the neuroinflammatory response after stroke. Elevated levels of TNF-α have been associated with blood-brain barrier disruption, neuronal injury, and impaired neuroplasticity, suggesting that modulation of TNF-α activity may support functional recovery.^2,3 Preclinical studies have demonstrated that inhibiting TNF-α signaling can reduce secondary brain injury and improve outcomes in experimental models.3 Emerging hypotheses further propose that persistent microglial activation, sustained through an autocrine positive feedback loop involving TNF-α, may underlie chronic neurologic dysfunction after stroke.5 However, although biologically plausible, this model remains speculative and requires further experimental validation.

Etanercept competitively inhibits TNF-α but is unable to cross the blood-brain barrier because of its high molecular weight.6 Nevertheless, etanercept has been proposed to improve post-stroke impairments when administered subcutaneously in the interspinous cervical spine, followed by head-down positioning.7-9 This method purportedly bypasses the blood-brain barrier. In a preclinical study, CNS penetration with perispinal administration of radiolabeled etanercept was shown in a single rat.10 However, a subsequent study challenged this assertion, finding no evidence for the passage of radiolabeled etanercept into the CNS after perispinal injection in rats.11 Instead, the drug was observed to accumulate locally in the perispinal region. Nevertheless, human observational studies have documented substantial improvements in various post-stroke impairments. A retrospective review of 617 patients with chronic stroke—treated an average of 3.5 years after stroke with some treated even decades later—reported significant improvements in motor function, spasticity, sensory perception, cognition, and pain relief after perispinal etanercept treatment.7 Effects persisted at least for weeks after a single administration, with some patients reporting additional effects with repeated administration.7 An additional report in 3 patients showed improvements within minutes in multiple domains after a single administration, with further improvement after a second administration.12 A pilot, double-blind placebo controlled randomized trial of 26 patients with chronic post-stroke pain tested 2 doses of perispinal etanercept. This study was stopped after an interim analysis showed a significant, rapid improvement in pain levels and improvement in mobility of the shoulder. There was no improvement in fatigue and depression levels or sit-to-stand measures.8

Interviews with patients who received off-label etanercept in private clinics further indicated that treatment is offered to patients with moderate-to-severe disability and that receiving 2 injections is common practice.

To generate high-quality evidence, stroke survivors in Australia successfully lobbied the Australian government to fund a clinical trial to independently evaluate the current practice of etanercept to treat stroke.

The aim of the Perispinal Etanercept for Stroke Outcomes Study (PESTO) trial was to assess whether perispinal administration of etanercept (25 mg) was superior to placebo in improving health-related quality of life in patients with imaging-confirmed ischemic or hemorrhagic stroke with chronic disability and reduced quality of life 28 days after injection.

Methods

Study Design and Participants

The PESTO trial was a phase 2b, double-blind, placebo-controlled, randomized study conducted across 3 outpatient centers in Australia and New Zealand. The study adopted a parallel group design with concealed allocation, blinded assessment of outcomes, and analysis based on the intention-to-treat (ITT) principle. An independent Data Safety Monitoring Board (DSMB) oversaw the trial safety and reviewed study conduct. The investigator team included a stroke survivor, who provided essential guidance on selecting outcome measures, structuring study visits to minimize participant burden, and shaping the patient-facing materials from a lived-experience perspective. The study was conducted following the principles of Good Clinical Practice.

Standard Protocol Approvals, Registrations, and Patient Consents

Study protocols and amendments were approved by the ethics committee at each site. All participants or their legal representatives provided written informed consent. The first and most recent version of the signed protocol and the statistical analysis plan finalized before the study data lock are provided as supplemental material (eSAP1). The trial was registered at the Australian and New Zealand Clinical Trial Registry (ACTRN12620001011976), and the trial protocol was published.13 The following amendments to the inclusion criteria were made during the course of the trial to increase recruitment rates: Age at time of stroke was expanded and permitted inclusion of patients with stroke at age 16 or 17 but were at least 18 at time of inclusion (protocol version 2.1) and inclusion of patients with stroke up to age 70 (previously 65, protocol version 2.0). Time since stroke was increased to 15 years (previously 5 years, protocol version 2.0). We also permitted inclusion of patients with modified Rankin Scale (mRS) score 2 with reduced quality of life, as measured using a 36-Item Short Form Survey (SF-36) score of <80 (previously only mRS scores 3–5 were included, protocol version 2.1).

Participant Criteria

The study included adults aged 18–70 years who had an imaging-confirmed ischemic or hemorrhagic stroke 1–15 years before enrollment. We enriched the trial population by including participants with moderate-to-severe disability, as indicated by a mRS score of 3–5 and an SF-36 score of 95 or less, or a mRS score of 2 with an SF-36 score less than 80.14 Exclusion criteria were contraindications to etanercept, certain infectious diseases, immunosuppressive agent use, severe heart conditions, malignancy history, or recent botulinum toxin injection as listed in the detailed criteria in the protocol.

Randomization and Allocation

Randomization was stratified by whether the prerandomization quality-of-life questionnaire was completed by the participant, or, if not possible, by a proxy; baseline mRS scores (dichotomized as mRS scores 2–3 vs mRS scores 4–5); and time since stroke (1–5 years vs >5 years after stroke onset). Stratification by baseline mRS scores was performed using combined categories (mRS scores 2–3 vs mRS scores 4–5), rather than individual mRS scores. Participants were first randomized in a 1:1 ratio to receive either a single dose of the etanercept (etanercept arm) or placebo (the control arm) using a centralized computer-generated random assignment procedure with permuted blocks of various sizes as part of the Research Electronic Data Capture electronic case record form. At the second step of the randomization procedure conducted at the same time point, the participants in the placebo arm were subsequently randomized into receiving either the second dose of placebo or a single dose of etanercept at day 28 after the first injection (based on a 2:1 allocation ratio), whereas participants in the etanercept arm were subsequently randomized into receiving either a single dose of placebo or the second dose of etanercept at day 28 (based on a 1:2 allocation ratio). This resulted in 3 equally sized, covariate-balanced arms (placebo n = 56, single dose of etanercept n = 56, and two doses of etanercept n = 56) for the secondary dose-response analysis of the efficacy outcome at day 56. The study flow is presented in Figure 1. A researcher not otherwise involved in the trial undertook the randomization and allocation to treatment arms, thereby ensuring allocation concealment. The treatment allocation was sent electronically to the unblinded study pharmacist who prepared the investigational product. Because etanercept may produce a yellow discoloration, the syringe was wrapped in a yellow transparent foil by the unblinded pharmacist and handed over to the blinded study investigator before the delivery. Participants, study investigators, study site personnel assessing outcomes, and the sponsor were masked to treatment group allocation.