Stroke remains a leading cause of disability worldwide, leaving many survivors with long-lasting and debilitating neurological impairments. Despite advances in acute stroke care, few efficacious medical treatment options are available for reducing these chronic post-stroke effects. This unmet need has spurred interest in new therapeutic approaches, including the use of perispinal etanercept treatment for stroke.

Etanercept is a medication that inhibits the binding of tumor necrosis factor (TNF) to its receptor. TNF is an immune signaling molecule that plays a pivotal role in modulating synaptic mechanisms in the brain. Following a stroke, chronic microglial activation and elevated levels of TNF occur in the brain, creating a disturbance of homeostasis that can perpetuate itself through an autocrine feed-forward loop. This persistent neuroinflammation is believed to contribute to a spectrum of neurological dysfunction seen in chronic stroke survivors, including pain. Perispinal etanercept treatment for stroke, as a TNF-alpha inhibitor approach, is proposed to attenuate neuroinflammation by neutralizing excess TNF and reducing microglial activation.

Etanercept is a large molecule, a dimeric fully human soluble TNF receptor Fc fusion protein. It works as a decoy receptor, binding to circulating TNF and reducing its biological effects. While FDA-approved for several inflammatory conditions, perispinal etanercept treatment for stroke represents an off-label application that has generated significant interest in the neurological community. The medication is typically administered via subcutaneous injection for its approved indications.

Interest in perispinal etanercept treatment for stroke has grown within the stroke survivor community based on anecdotal reports, case series, and observational studies. These reports have described impressive and immediate improvements in various post-stroke impairments such as gait, memory, pain, swallowing, and muscle strength after perispinal subcutaneous administration. For example, observational studies noted highly significant improvements in grip strength and improvements in the time to walk 20 meters, with 90% of respondents reporting favorable changes in motor effects. These effects were reported to be maintained over several weeks, often after a single administration, although anecdotal reports and a pilot study suggested additional improvements with repeated administration of perispinal etanercept treatment for stroke.

Existing clinical evidence for perispinal etanercept treatment for stroke is limited primarily to uncontrolled, single-center reports and one small, single-center randomized trial in patients with chronic post-stroke pain. This trial, referred to as the Gold Coast RCT, stopped early after enrolling 26 patients and showed a reduction in pain levels measured by a visual analog scale. This study is described as supporting the efficacy of perispinal etanercept for central post-stroke pain (CPSP).

Given the limited high-quality evidence, regulatory authorities have not approved etanercept for the treatment of post-stroke disability. In 2016, the American Academy of Neurology issued a practice advisory concluding that research is needed on the effects of etanercept on post-stroke disability, specifically recommending masked, randomized controlled trials with masked, standardized outcome measures to minimize bias. Responding to lobbying from consumer groups in Australia, the Australian Government created an open call for an etanercept trial, which led to the funding of the Perispinal Etanercept to Improve Stroke Outcomes (PESTO) trial.

The PESTO trial is designed as a phase 2b, multicenter, international, randomized placebo-controlled trial. Its primary aim is to determine whether perispinal etanercept treatment for stroke improves quality of life and is safe in patients with chronic, disabling effects of stroke. The trial is being conducted in Australia and Aotearoa New Zealand and represents a critical step in establishing the evidence base for this promising but still experimental approach to stroke recovery.

Key aspects of the PESTO trial design include:

• Patient Population: Adult stroke survivors aged up to 70 years, 1 to 15 years after their stroke (ischemic or hemorrhagic). Participants must have moderate-to-severe disability, defined by a modified Rankin Scale (mRS) of 3-5, or an mRS of 2 with a Short Form 36 Health Survey (SF-36) score below 80. The upper age limit of 70 was based on the funding body’s request for a trial in adults of working age.
• Inclusion Criteria: Confirmed stroke, age 18-70 (at stroke onset or enrollment), mRS 3-5 (or mRS 2 with SF-36 <80), stroke 1-15 years prior, SF-36 <95 (<80 if mRS 2), ability to complete SF-36 (or proxy), and consent.
• Exclusion Criteria: Contraindications to etanercept (hypersensitivity, infection, etc.), history of specific medical conditions (hepatitis B/C, TB, HIV, SLE, MS, heart failure, malignancy, etc.), current immunosuppressant use, history of certain liver or blood conditions, clinical dementia, low disability (mRS 0-1 or mRS 2 with SF-36 ≥80), recent botulinum toxin injection, pregnancy/breastfeeding, recent participation in other trials, terminal illness, or any condition posing hazard or affecting participation. Prior exposure to etanercept for stroke is also an exclusion criterion.
• Randomization: Participants are randomized 1:1 to receive either a single dose of etanercept (25 mg) or placebo (sterile saline). A subsequent randomization at day 28 allocates placebo recipients to a second placebo dose or a single etanercept dose, and initial etanercept recipients to a placebo dose or a second etanercept dose. This results in three equally sized arms (Placebo, Single Dose etanercept, Double Dose etanercept) for a secondary dose-response analysis at day 56. Randomization is stratified by SF-36 completion method, baseline mRS (2-3 vs 4-5), and time since stroke (1-5 vs 6-15 years). The trial uses concealed allocation and blinded measurement.
• Intervention: Etanercept 25 mg or placebo (sterile saline) is administered via perispinal subcutaneous injection between C6-C7 or C7-T1. After injection, participants are placed on an inversion table in the Trendelenburg position (20° incline, feet above head) for 4 minutes. Syringes are masked due to possible discoloration of etanercept.
• Primary Efficacy Outcome: Quality of life as measured using the Short Form 36 Health Inventory (SF-36) at day 28 after the first injection.
• Safety Outcomes: Include serious adverse events.
• Sample Size Target: A total of 168 participants (84 per arm initially), based on assumptions about SF-36 improvement rates in control (11%) and intervention (30%) arms, 80% power, and 5% alpha. The trial aimed to recruit 160 patients equally distributed between two arms to achieve 80% power for a 19% absolute risk difference, with an additional 8 participants to account for dropouts, for a total of 168.
• Funding and Oversight: The study is funded by the Medical Research Future Fund (Australian Government Department of Health). The Florey Institute of Neuroscience and Mental Health is the trial sponsor. The trial is overseen by a management committee advised by a steering committee, with independent monitoring by a contract research organization.

While PESTO is designed to provide level 1 evidence on the safety and efficacy of perispinal etanercept in chronic stroke patients, the design has been criticized by some experts. One critical perspective argues that RCTs failing to incorporate specific design elements are incapable of reaching reliable conclusions regarding perispinal etanercept efficacy.

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