Useful data regarding the safety and efficacy of perispinal etanercept (PSE) for chronic stroke may be developed through properly designed randomized clinical trials (RCTs). Poorly designed clinical trials, however, may yield incomplete, misleading, or inaccurate data that do not reflect the clinical results observed in clinical practice. The design of clinical trials for innovative treatments, such as perispinal etanercept for chronic stroke, may be particularly difficult, particularly for physicians with limited experience utilizing perispinal etanercept for chronic stroke in the clinic. Fortunately now, in September 2025, the results of two randomized clinical trials studying the safety and efficacy of perispinal etanercept for chronic stroke have been performed. The results of the first double-blind, placebo-controlled randomized trial testing the safety and efficacy of perispinal etanercept for chronic stroke was completed in 2019 and published in January 2020. In this first trial remarkable and unprecedented reduction in intractable central post-stroke pain and significant improvement in shoulder mobility was documented in the participants who received perispinal etanercept, and both improvements were statistically significant in comparison with placebo. This first trial was conducted using the basic trial design conceived by Dr. Edward Tobinick, the inventor of the perispinal etanercept for chronic stroke treatment.
The published results of the second trial designed to provide data regarding the safety and efficacy of perispinal etanercept for chronic stroke were first made available on September 4, 2025. These results were from the Perispinal Etanercept to Improve Stroke Outcomes (PESTO) clinical trial. This trial did not use a design by Dr. Tobinick. The trial design of PESTO has been severely criticised. To understand why, one needs to start with an understanding of the scientific background. What follows is a review of basic background material, followed by a detailed discussion of the optimal design for clinical trials testing perispinal etanercept for chronic stroke.
TNF (tumor necrosis factor) is an immune signaling molecule that plays a pivotal role in the modulation of synaptic mechanisms in the brain[1-5]. Stroke results in chronic microglial activation and elevation of TNF in the brain, a disturbance of homeostasis that may self-perpetuate through an autocrine feed-forward loop[6-12]. Clinical and imaging evidence suggests that microglial activation is widespread in the brain and persists long after the acute stroke[10-16]. The 18-kDA translocator protein (TSPO), previously named the peripheral benzodiazepine receptor (PBR), is a mitochondrial protein that is markedly increased at sites of brain injury and is considered a marker of microglial activation[17,18]. Radioligands targeting TSPO have been used with positron emission tomography (TSPO PET) to image microglial activation in the brain after stroke, in humans and in basic science models[10,11,15,17,18].
Perispinal etanercept is an innovative biological treatment designed to improve recovery from stroke by neutralizing excess TNF and reducing microglial activation[13]. Perispinal etanercept has been used to improve neurological recovery after stroke since 2010[13,14,19]. Real-world evidence, derived from favorable clinical experience involving thousands of patients with chronic stroke treated with perispinal etanercept over the course of 14 years; basic science evidence; expert opinion; imaging studies and a double-blind, placebo-controlled RCT published in 2020 all support the use of perispinal etanercept to reduce chronic post-stroke neurological dysfunction and improve recovery from stroke[8,12-16,19-28]. However, formidable barriers to widespread acceptance exist, particularly for novel treatments that challenge existing dogma[27,29-35]. It is well known that an incorrect design of an early phase RCT could result in the failure of an effective treatment to reach those who could benefit[36-40]. Such a false negative result would be considered a Type II error, i.e. the failure to detect the true efficacy of an effective drug.
A primary consideration in the design of chronic stroke RCTs is the fact that the population of individuals with chronic post-stroke neurological dysfunction is inherently heterogeneous[39]. Neurological outcome and the magnitude of response to treatment in chronic stroke is influenced not only by the size and location of the lesion, but also by the type and subtype of stroke – ischemic (thrombotic, embolic, lacunar) or hemorrhagic (intraparenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, hemorrhagic transformation, etc.), as well as by external factors, such as the duration and severity of hypoxia, hypotension or hypoperfusion. This heterogeneity can present a particular challenge for small or even medium-size RCTs in which heterogeneity of the RCT study population could reduce the trial’s ability to detect a beneficial treatment effect. Generic outcome measures meant to quantitate response to treatment for heterogeneous, non-stroke populations, such as the SF-36 quality-of-life measure, may have significant issues regarding validity when used as primary outcome measures for stroke trials[41]. Fortunately there are available strategies, including the use of a prospectively enriched study population, which can improve the validity and the reliability of the efficacy conclusions of chronic stroke RCTs[39,42]. Trial enrichment is defined as “[t]he prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one in fact is present) is more likely than it would be in an unselected population[42].”
To add historical perspective, both infliximab and etanercept failed in early indications, such as sepsis, when they were first studied, more than 20 years ago[43,44]. Both drugs were repurposed and successfully used for the new indications for which they are now FDA-approved, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. From these early failures it appears that, at least for some of these disorders, such as sepsis, the time point within the natural history of the disease when the TNF antagonist is administered may be critical. For sepsis, the inflammatory cascade initiated by gram-negative bacteremia may be so rapid that by the time the patient is in septic shock it is too late to intervene with a TNF antagonist. For chronic stroke, clinical experience indicates that time to intervention is not critical, since patients respond favorably weeks, months, years or even decades after stroke or brain injury[13,14,19,22,45]. Part of the difference is that in the brain TNF plays a pivotal role in the modulation of synaptic function[1-5,25,46,47]. TNF’s key role in the regulation of brain function is distinct from its role as the master regulator and initiator of peripheral inflammatory cascades, which if unchecked, may eventuate in a cytokine storm[5,9,24,25,27,47-62]. This distinction is certainly part of the explanation why the required timing of TNF inhibition for these different categories of diseases is not identical.
The perispinal etanercept chronic stroke RCT guidelines detailed herein are formulated based upon clinical experience using perispinal etanercept for more than 5,000 chronic stroke patients. Although this review will focus on perispinal etanercept RCT design, the basic concepts may assist those designing clinical trials for other neurological indications.
The scientific background supporting the clinical use of perispinal etanercept for brain disorders has been reviewed in detail in previous publications[13,14,21-25,27,45-47,51,55,59,63-72]. The following is a current synopsis of selected aspects of the scientific background.
TNF is an immune signaling molecule and a neuromodulator that plays essential roles in immune and inflammatory responses throughout the body[55,73]. In the periphery, TNF is the master regulator of the inflammatory response[24]. In the brain, TNF is a neuromodulator that regulates synaptic and brain network function, including synaptic transmission, synaptic strength, synaptic scaling and synaptic plasticity[1-3,5,21]. Elevated brain levels of TNF are thought to be centrally involved in the pathogenesis of the chronic brain dysfunction that accompanies stroke, traumatic brain injury, Alzheimer’s disease and other brain disorders by mediating synaptic dysfunction and perpetuating microglial activation[9,13-15,19,21,22,24,25,27,45-47,55,69,74-77].
Etanercept is a dimeric fully human soluble TNF receptor Fc fusion protein manufactured using recombinant DNA biotechnology. It is a large molecule composed of 934 amino acids with a molecular weight (mw) of 150 kilodaltons (kDa). It consists of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNF receptor linked to the Fc portion of human IgG1. Etanercept reversibly binds to circulating TNF, acting as a decoy receptor, reducing the biologic effects of TNF, including TNF’s deleterious effects when present at levels in excess of its normal physiologic range. Etanercept’s first Food and Drug Administration (FDA) approval was in November 1998 for treatment of rheumatoid arthritis. Etanercept was subsequently approved for chronic use by once or twice weekly subcutaneous injections for multiple additional indications, including ankylosing spondylitis, psoriasis, psoriatic arthritis and juvenile arthritis for children as young as age 2. It has also been used off-label for multiple inflammatory conditions, including several neurological disorders. Since its introduction more than two decades ago it has maintained a favorable safety profile[78,79].
A growing body of evidence suggests that post-stroke microglial activation may persist in the stroke penumbra and in regions remote from the region of acute necrosis after both ischemic and hemorrhagic stroke[8,12,16,80,81]. This evidence includes the results of a 2021 positron emission tomographic imaging study (TSPO PET) of individuals with chronic middle cerebral artery (MCA) stroke that was conducted using a radioligand to the 18 kDa translocator protein (TSPO)[12]. TSPO is a mitochrondrial protein upregulated in activated glia and considered a marker of neuroinflammation[12]. The study found evidence of glial activation in multiple non-infarcted brain regions, both ipsilateral and contralateral, outside the MCA infarct zone, consistent with previous TSPO PET clinical imaging studies[10-12].
Autocrine activation of microglia by TNF creates a positive feed-forward loop that may perpetuate neuroinflammation and have neurotoxic consequences[7,9,13,82,83]. Etanercept reduces neuroinflammation in two ways:
In addition, neutralization of TNF by etanercept would be expected to reduce the concentration of other non-TNF inflammatory cytokines that could activate microglia because TNF sits on top of the inflammatory cascade as the master regulator of the inflammatory response[9,52-55,99-101]. The inflammatory cytokines IL-1, IL-6, etc. are downstream in the inflammatory cascade from TNF[9,52-55,99-101].
Etanercept has been found to reduce microglial activation in at least 17 animal models, including those studying stroke, as previously reviewed[14,57,60,72,84-96]. Interruption of the autocrine microglia-TNF feed-forward loop may explain the sustained and sometimes progressive neurological improvement that has been observed in chronic stroke patients after a single dose of perispinal etanercept [13,14,19]. The nearly instantaneous attenuation of the biological activity of TNF in the presence of etanercept, and TNF’s known pivotal role in the modulation of synaptic mechanisms, provide mechanisms to explain the rapid neurological improvements seen in stroke and other neuroinflammatory conditions following perispinal etanercept [1-5,14,19,21,22,45,72,75-77].
The veins, venous sinuses and venous plexuses of the brain and the spine together comprise the cerebrospinal venous system (CSVS), a unique, large capacity, interconnected, venous system that carries venous blood back and forth between its cerebral and spinal components[102-105]. The first of the two main divisions of this system, the intracranial veins, includes the cortical veins, the dural sinuses, the cavernous sinuses, and the ophthalmic veins. The second main division, the vertebral venous system, includes the vertebral venous plexuses, which course longitudinally up and down the entire length of the spine. The intracranial veins richly anastomose with the internal vertebral venous plexus (IVVP) in the suboccipital region. The external vertebral venous plexus (EVVP), the only division of the CSVS that contains valves, drains the anatomic region posterior to the spine and directs blood flow internally into the IVVP[106]. Venous blood flow within the IVVP can be bidirectional, due to the IVVP’s lack of venous valves[102-105]. Drugs or contrast delivered into areas that drain into the EVVP may flow cranially into the cerebral venous system via the IVVP[103-105]. The CSVS plays an important role in the regulation of intracranial pressure by facilitating venous flow into and out of the brain with changes in posture. The CSVS provides a direct vascular route enabling the rapid delivery of etanercept to the brain after perispinal injection[13,14,19-22,45-47,51,69,72,75,76,102,105,107].
The scientific rationale underlying the perispinal delivery method is supported by basic science experiments[20,26]; clinical investigations[21,105,108]; clinical trials[28,51]; and cadaver studies dating back more than 200 years, with further anatomic evidence developed in the 1940’s and in the last decade[102-105,109-112]; as well as 25 years of clinical experience[13,14,19,22,28,45,51,63-66,72,75,76,105]. The proper performance and implementation of this technique requires expertise and hands-on training with an expert[47,113].
a. Rapid delivery of radiolabeled cetuximab into the brain and the cerebrospinal venous system extending into the opthalmic venous plexus after perispinal injection in Rat 1.
b. Tracer confined to the perispinal area after perispinal injection in another rat. Image from M. E. Roerink, et al., Central delivery of iodine-125-labeled cetuximab, etanercept and anakinra after perispinal injection in rats: possible implications for treating Alzheimer's disease. Alzheimers Res Ther, 2015. 7(1): p. 70, link:[143]. Image used in accordance with Creative Commons License CC by 4.0 Attribution 4.0 International[144].
The supporting data includes evidence developed in animal models following perispinal delivery of biologics, including in vivo brain imaging[20,26,107]. In 2007 an animal positron emission tomography (PET) study performed at Stanford University demonstrated rapid delivery of radiolabeled etanercept (mw 150 kDa) into the cerebral ventricles, the choroid plexus and the CSF within the brain minutes after perispinal injection[20]. In 2015 a second animal study used single-proton emission computed tomography (SPECT) to study the biodistribution of several radiolabeled large molecules after perispinal injection in 5 rats[107].
Figure 1a is a SPECT image showing the biodistribution of radiolabeled cetuximab (mw 146 kDa) in Rat 1 following perispinal injection overlying the cervical spine at the C6-C7 level followed by placement of the rat in the head-down position for 3 minutes[107]. Five minutes after the perispinal injection SPECT scanning was performed, which took 20 minutes. The SPECT image reveals rapid delivery of radiolabeled cetuximab into the brain and the cerebrospinal venous system (CSVS) extending into the opthalmic venous plexus after the perispinal injection.
The authors of the 2015 study speculated that the injection in Rat 1 was inadvertently intrathecal (i.e. into the CSF)[107]. Close examination of the imaging evidence, however, disproves their hypothesis. Extension of the tracer signal to the orbital venous plexus, as shown in Figure 1a, would not be expected after an intrathecal injection, because the CSF has no anatomic connection to the orbital venous plexus[114,115]. In fact, the most intense tracer signal is in the veins comprising the CSVS, not in the CSF. This is not the pattern one would see if the injection were intrathecal; in that case the most intense signal would be in the CSF. Instead, the SPECT image clearly shows that the most intense signal is intravenous and it extends through the spinal and intracranial components of the CSVS all the way to the opthalmic (orbital) venous plexus, which itself is a component of the CSVS. The biodistribution of the labeled drug into the opthalmic venous plexus is unmistakable here due to the distinctive appearance of this venous plexus at the back of the eye[114,115] (Figure 1a).
Rapid delivery into the brain in Rat 1 after perispinal injection was confirmed post-mortem, with 4.05% of the injected dose/gram found in the brain, twice the concentration found in the blood, and 67.5 times the concentration found in the perispinal region, confirming brain delivery after perispinal injection[107]. The rapid delivery to the ophthalmic venous plexus after perispinal injection and head-down tilt documented here is supporting evidence that carriage of etanercept through the CSVS after perispinal injection is the anatomical basis for the nearly immediate improvement in visual perception that is commonly observed in the clinic after perispinal etanercept[14,19,22,45].
The apparent failure to deliver the radiolabeled drug into the CSVS in the other four rats, as suggested by the image in Figure 1b, results in accumulation of the drug superficial to the spine. This is not unexpected, because perispinal delivery into the CSVS in rats is technically difficult to accomplish due to the small caliber of the veins comprising their external vertebral venous plexus. Larger animals, such as dogs, pigs, primates or humans are more suitable for perispinal delivery experiments. The development of expertise in perispinal delivery, in both rats and humans, requires expert training[47].
A spectrum of rapid and sustained neurological improvements in chronic stroke and chronic brain injury following treatment with perispinal etanercept has been previously described[13,14,19,22,45]. In the clinic the most common neurological effects include improvements in cognition, central post-stroke pain (CPSP), post-stroke shoulder pain, gait, balance, visual perception, swallowing, spasticity, dysarthria, language abilities, fatigue, strength, attention, range of motion and sensation[13,14,19,22,45]; see also the extensive online videos documenting the clinical response to perispinal etanercept in chronic stroke[116].
Intimate familiarity with a drug, its precise method of delivery and its clinical effects is indispensable when designing an RCT evaluating the drug’s efficacy[36,39,40,113,117-120]. Without such familiarity, the optimal selection of a research question, dosing regimen, outcome measure(s), and study population is not possible[36,38-40,113,117-121]. RCT design is made more difficult when the treatment method is innovative and its clinical effects novel[24,27,47]. The following recommendations, are, in general, applicable to the design of RCTs examining the efficacy of novel drug therapies for treatment of conditions whose populations are heterogeneous, but are specifically meant to assist in the design of future trials of perispinal etanercept for chronic stroke and related indications. To help in illustration of these concepts, the differences in the design of the two perispinal etanercept chronic stroke RCTs that have been completed to date are compared in this section. These RCTs are the perispinal etanercept RCT conducted on the Gold Coast of Australia that published in 2020[28] (the “Gold Coast RCT”) and the Perispinal Etanercept to improve Stroke Outcomes (“PESTO”) RCT, whose protocol published on April 27, 2024[122].
Appropriate formulation of the research question is the most important first step in clinical trial design[40]. Until the efficacy of an innovative treatment for a disease with a heterogeneous population has been firmly established, the most suitable research questions are those directed to examining efficacy in narrowly defined subpopulations thought most likely to benefit. This guiding RCT design principle conforms with explicit FDA guidance[42].
Perispinal etanercept results in a spectrum of neurological improvements across different domains (cognition, motor function, central pain, spasticity, etc.) that can vary according to the stroke type, location, etc. For this reason, significant clinical experience using perispinal etanercept and observing its neurological effects in different stroke subpopulations is necessary in order to formulate a research question and a matching trial design that will minimize Type II error. The fundamental differences between the successful Gold Coast RCT and the failed PESTO trial were apparent even before the trials began. The Gold Coast RCT set out to answer a question directed to a narrowly defined stroke subpopulation, those with intractable central post-stroke pain. In contrast, PESTO’s research question, concerning quality of life, was directed to a heterogeneous, essentially unselected population of stroke survivors with a wide range of disability. PESTO’s choice of research question precluded the use of prospective enrichment in selection of its study population.
Clinical trial enrichment represents a powerful strategy for selecting a subset of the general population in which the effect of the drug can be more efficiently demonstrated. This approach has the potential to result in smaller studies, increased study power, and/or shortened development times …. Of critical importance, our data suggest that use of any type of enrichment approach is more likely to lead to clinical trial and development program success compared to not using enrichment as part of clinical trial design and execution[123].
[S]maller trials in clearly defined and homogeneous stroke pathologies can yield answers that may be obscured by dilution in larger groups of patients who are not as well characterized[39].
Enrichment designs are used to increase the efficiency of drug development and improve the chance of detecting the efficacy of a new drug. It is widely recognized that, with heterogeneous clinical syndromes, optimization of participant selection is central to the likelihood of the RCT’s success[39,40,42]. Trial enrichment can greatly increase the chance of reaching a correct conclusion, without compromising the trial’s validity or the meaningfulness of the conclusions reached[42,123,124]. RCT population enrichment as an RCT design strategy is intended both to decrease the time and expense involved in drug development and “… support precision medicine, i.e. tailoring treatments to those patients who will benefit based on clinical, laboratory, genomic and proteomic factors[42].”
The Gold Coast RCT utilized prospective population enrichment to select a narrowly defined study population. This homogeneous, enriched population consisted of selected individuals with chronic and intractable central post-stroke pain (CPSP): “All participants initially demonstrated significant intractable and constant daily CPSP with pain scores at baseline entry between 50 and 80 inclusive on the 0-100 point vNPRS-FPS, with their pain refractory to analgesic medications (including oxycodone or pregabalin[28].” Such patients were known through clinical experience to constitute a narrow subset of stroke survivors in which the favorable neurological effects of perispinal etanercept could be efficiently demonstrated[13,14]. Using this design, the Gold Coast RCT was able to successfully demonstrate that perispinal etanercept had efficacy for treating CPSP.
In contrast, rather than incorporate enrichment strategies in selection of its trial population, PESTO was deliberately designed to study a heterogeneous population. This is readily apparent from examination of PESTO’s inclusion and exclusion criteria. The inclusion criteria were very broad and the exclusion criteria were narrow. For example, PESTO, by design, specifically allowed individuals with a degree of disability ranging from modified Rankin scale (mRS) class 2 to mRS class 5 to enter the trial. By definition, this could include trial participants with only slight disability who are able to look after their own affairs without assistance (mRS 2), all the way to individuals with severe disability who require constant nursing care and attention and are bedridden and incontinent (mRS 5). Patients with aphasia were not excluded from the trial, even if they required a proxy to complete their SF-36 questionnaire. This was not a narrowly defined, homogeneous study population; it was exactly the opposite. PESTO failed; its decision not to study an enriched study population was a critical design error.
Enrichment of clinical study populations is carried out in order to select trial participants in whom a drug effect, if present, is more likely to be demonstrable[124]. Predictive enrichment attempts to identify individuals with an increased likelihood of favorable response to the drug being trialed for a mechanistic reason, such as possession of a suitable receptor, or, in the case of chronic stroke, possession of a well-defined clinical characteristic that reflects underlying pathophysiology likely to respond to the drug[124]. This was exactly the case in the Gold Coast RCT, in which predictive enrichment was used to prospectively select its study population, all of whom had moderate-to-severe CPSP. Trial enrichment has the fundamentally important advantage of enabling the use of an outcome measure that is matched to the study population and in that way increase study power and decrease Type II error. None of this is possible when studying a heterogeneous population, as done in the PESTO trial, that was “designed to include a representative sample of the patients that undergo off-label treatment with etanercept[122],” a population of patients that is inherently unenriched.
[S]electing the best outcome measure requires consideration of issues far beyond the usual questions about reliability and validity. The ultimate value of a clinical trial or outcome study will be directly tied to how well the selected outcome measure matches the researcher’s understanding of what he or she expects to change, to what degree it is expected to change, over what period of time this change will happen, and how that change can best be identified[118].
Selecting an appropriate primary outcome measure is a critical step in designing scientifically sound, ethical clinical trials[36,38,40,117-119]. Selection needs to consider features of outcome measures that may affect their validity and utility for the study’s purpose[118,125]. Experience with the drug’s effects in the selected study population is necessary to determine beforehand if the outcome measure is likely to be sensitive to the degree of change expected from the drug and thus appropriate for use in any given RCT[36,117-119]. Without the requisite experience, the ability of an outcome instrument to reliably measure the neurological changes produced by a novel drug in a chronic stroke population cannot be certain. This is particularly true for subjective, generic outcome measures, such as SF-36, that are not stroke specific.
The limitations of SF-36 as an outcome measure for stroke trials are illustrated by a real-world example: Botulinum toxin. Botulinum toxin (Botox®) is known to be efficacious for treatment of post-stroke spasticity. On that basis, one might think that botulinum toxin would increase the quality of life in an individual living with chronic spasticity after stroke. It might well do so, but a clinical trial of botulinum toxin for stroke spasticity showed no change in quality of life, as measured by SF-36[126]. The take-away is not that botulinum toxin is ineffective as a treatment for spasticity. Rather, it would appear that SF-36 is not responsive to the neurological improvement (reduction in spasticity) produced by botulinum toxin injection.
Other limitations with respect to outcome selection in stroke RCTs require consideration. Patient-reported outcome measures (PROMs), as a class, have less validity and reliability than objective measures, because they are subjective[127,128]. Common sequelae of stroke, including cognitive impairment or difficulties with language comprehension or expression, are likely to confound subjective outcome measures[127]. Such stroke sequelae may make it difficult or impossible for the individual to access and grade on an ordinate scale internal experiences, such as pain, fatigue, or quality of life[127]. Individuals with severe aphasia or severe cognitive dysfunction are unable to reliably self-complete PROM questionnaires[127]. In such cases, proxy completion of written questionnaires, such as SF-36, would be necessary. However, proxy completion can reduce the validity of the data reported[129]. Discrepancies between patient and proxy reporting may be large enough to impact the outcome assessment in stroke clinical trials[129].
Both the Gold Coast RCT and PESTO used PROMs as their primary outcome measure. The Gold Coast RCT used the vertical Numerical Pain Rating Scale supplemented with a Faces Pain Scale (vNPRS-FPS), a measure that is stroke-specific, has been validated in a chronic stroke population, and was developed specifically for quantitating pain after stroke[130]. The vNPRS-FPS is well suited for a trial evaluating perispinal etanercept for CPSP. Validated pain scales, such as vNPRS, were known from previous clinical experience to be responsive to the reduction in stroke pain caused by perispinal etanercept[14]. By design vNPRS does not require proxy completion[13,14]. In contrast, PESTO used SF-36, a generic subjective measure that was not stroke-specific[41]; and that was not matched to any specific symptom in PESTO’s heterogeneous study population. PESTO, by design, and as specified in its inclusion criteria, also explicitly allowed proxies to complete the SF-36 questionnaire, its primary outcome measure, for the patient. SF-36 had not been used in any perispinal etanercept RCT, so PESTO’s designers could not be certain that the SF-36 measure would be responsive to perispinal etanercept’s neurological effects. In sum, selection of SF-36 as PESTO’s primary outcome measure was another critical design error.
[A] study with a sample that is too small will be unable to detect clinically important effects. Such a study may thus be scientifically useless, and hence unethical in its use of subjects and other resources[121].
One of the requirements for an RCT to be ethical is that it have a sample size large enough to adequately test the research question that is posed, particularly in the absence of explicit plans for definitive studies in the future[38,119]. The greater the heterogeneity of the study population, the more difficult it is to detect a treatment effect[39,40,42,131]. For an RCT to reliably determine whether a new therapy shows at least some promise of benefit, it must be properly powered[38,113]. Thorough familiarity with a novel treatment is necessary to perform power calculations adequate to determine the sample size needed to reliably detect a treatment effect. RCTs evaluating drug efficacy for brain disorders may require a sample size greater than 1,000 to reach valid scientific conclusions if the study population is heterogeneous[117]. Enrichment strategies can enable scientifically reliable results to be obtained with smaller trials, as a comparison between the Gold Coast RCT and PESTO illustrates[39,40,42,131]. The Gold Coast RCT was able to demonstrate efficacy using an enriched trial population consisting of 22 participants. PESTO was unable to demonstrate efficacy using a larger, unenriched, heterogeneous trial population consisting of 126 participants, which fell short of its pre-specified sample size target of 168. This shortfall would tend to increase Type II error.
Insufficient dosing of a new intervention can lead to premature conclusions about the ineffectiveness of a general intervention approach if a different (but untested) dose would have been effective.[120]
Selection of dosing for an RCT includes the determination of the amount of each dose, the number of doses to be studied, the dose interval, and the method of administration[40,117,120,132]. From a large pharmaceutical company perspective, “the greatest challenge in clinical research is finding the therapeutic dose[133].” Clinical experience and RCT evidence (based upon the Gold Coast RCT’s published results) suggest optimal dosing for a perispinal etanercept chronic stroke RCT is as follows:
The above schedule was the dosing used in the successful Gold Coast RCT. PESTO used different dosing:
PESTO employed only 50% of the etanercept dose used in the Gold Coast RCT prior to measurement of the primary efficacy outcome, and measured the outcome at an interval twice as long after the last dose (28 days vs. 14 days). PESTO employed a sub-optimal dosing regimen, another flaw in its design that increased its chance of a making a Type II error, i.e. failing to detect the true efficacy of perispinal etanercept.
Placebo responses are especially problematic in studies that rely on subjective patient-reported outcomes, and can have severe detrimental effects on assay sensitivity, contributing to the failure of trials of efficacious therapies[134].
The higher the placebo responder rate, the more difficult it is for the active drug to achieve superiority and the trial to succeed[134,135]. For example, a systematic review of clinical trials of drugs meant to prevent migraines showed a statistically significant difference in trial success rate (60%) between RCTs with ≤20% placebo responders and studies with >30% placebo responders[135].
When PESTO’s partial results were presented at the 2024 European Stroke Conference, the 58% placebo responder rate was an immediate red flag. This rate was more than 5½ times larger than the 11% rate expected, as stated in PESTO’s published protocol[122]. It is likely that several factors falsely inflated this rate:
To minimize the number of placebo responders, it is recommended that future perispinal etanercept RCTs utilize buffered saline control solutions to eliminate painful perispinal injections and incorporate prospective measures known to reduce the placebo responder rate, such as interventions to reduce staff and subject expectations and improve the ability of subjects to accurately report symptom severity[134].
Based upon more than a decade of clinical experience, as well as the results of the Gold Coast RCT, the design of an exemplary perispinal etanercept chronic stroke RCT would include the following elements:
The elements of future RCTs seeking to confirm perispinal etanercept’s efficacy for specific chronic stroke indications that are necessary to ensure valid results include:
PESTO failed to incorporate any of these elements, making it unable to generate valid conclusions regarding the efficacy of perispinal etanercept for improving recovery after stroke.
Intimate familiarity with perispinal etanercept, its novel method of drug delivery and the characteristics of ideal enriched study populations is necessary for those designing future perispinal etanercept stroke trials. Hands-on training with experts is necessary for trialists to enable them to accomplish effective perispinal delivery of etanercept to the brain through carriage in the CSVS. Careful attention to the design of future perispinal etanercept RCTs will help ensure that such trials reach valid conclusions regarding efficacy. SF-36 and other generic quality of life measures that have not been validated in perispinal etanercept trials are unsuitable for use as primary outcome measures in clinical trials to support determination of effectiveness of perispinal etanercept.
There were multiple critical flaws in the design of the placebo control arm of the PESTO trial, including the use of a painful placebo control injection and the use of a subjective, patient-reported primary outcome measure not well-suited for perispinal etanercept stroke trials, all of which would tend to falsely inflate the placebo response rate, particularly considering the elevated patient expectations that would be engendered by the widespread favorable media attention that perispinal etanercept had received. Moreover, there is no indication in the protocol that any measures were taken to mitigate the multiple design flaws in the PESTO trial, all of which would tend to falsely amplify the placebo response.
The preliminary report of some of PESTO results indicated that 53% of the trial participants successfully reached the trial’s pre-determined efficacy threshold after a single perispinal etanercept dose, a rate 76% higher than the 30% success rate predicted in the sample size calculation published in the PESTO protocol[122,142]. However, even this higher than expected efficacy result was unable to overcome the hurdle presented by PESTO’s excessive placebo response rate. The flaws in the design of the placebo control arm of the PESTO trial, in combination with the selection of SF-36 as the primary outcome measure, were critical errors that contributed to PESTO’s inability to generate valid efficacy conclusions.
If future trials are designed in accordance with the recommended guidelines, perispinal etanercept for a specific chronic stroke indication, such as severe central post-stroke pain, could receive regulatory approval and become widely available within 10 years. Such approval would open the door to further studies of perispinal etanercept in populations with other chronic stroke symptoms, such as severe post-stroke cognitive dysfunction, post-stroke shoulder pain, post-stroke spasticity, gait and balance disturbances, etc., as well as open the door to further study of perispinal etanercept for additional brain indications.
The ability of perispinal etanercept to reduce chronic neurological dysfunction after stroke naturally leads to another question: Does perispinal etanercept have potential as an acute stroke treatment? A definitive answer is not known at this time, because to reach the answer would require large, multi-center, RCTs performed in hospital settings. What has been known for more than two decades is that elevated levels of TNF occur in acute stroke and, at least in animal models, neutralization of TNF reduces focal ischemic brain injury. The evidence suggests that this approach merits immediate investigation.
Basic research increasingly supports the pivotal role of TNF in the regulation of synaptic mechanisms in the brain. In addition to its clinical utility, perispinal administration as a method to enhance delivery of large molecules to the brain has promise as a basic science and clinical research tool. Additional basic science studies of the biodistribution of radiolabeled large molecules given by perispinal injection should be initiated without delay. These biodistribution studies should be performed in large animals because of the difficulty of achieving reliable delivery of drugs into the CSVS after perispinal injection in rodents.
In humans, TSPO PET brain imaging has the potential to contribute valuable information regarding the pathophysiology of chronic stroke and its response to perispinal etanercept. Several studies have now documented that acute stroke results in chronic, widespread neuroinflammation in the brain. At present, the standard methods of brain imaging, computed tomography and magnetic resonance imaging, are unable to visualize or quantitate neuroinflammation. TSPO PET brain imaging does enable visualization of the pattern and extent of microglial activation after stroke. It is as yet unknown if TSPO PET will be sensitive enough to detect the effects of perispinal etanercept on microglial activation. It is an exciting prospect. If such changes were visualized they could be used as an objective measure of biological response and an outcome measure for perispinal etanercept clinical trials. Additionally, TSPO PET imaging might also have the ability to aid in participant selection in future perispinal etanercept chronic stroke trials, particularly if one could correlate patterns of microglial activation in patients with their response to perispinal etanercept treatment.
Favorable basic science and clinical data using etanercept has given a clue to the wide spectrum of brain disorders that could benefit from perispinal etanercept, including, but not limited to, ischemic and hemorrhagic stroke; Alzheimer’s disease and other neurodegenerative disorders; brain injury due to trauma, hypoxia, or cardiac arrest; and long COVID. All of these disorders share in common sustained microglial activation, a pathology that is perpetuated through a positive feed-forward physiological loop created by autocrine activation of microglia by TNF, and all, therefore, may potentially benefit from perispinal etanercept.
Many of the early discoveries regarding the role of cytokines in regulating synaptic and neuronal network function had yet to be made when perispinal etanercept first emerged as a potential treatment for neuroinflammatory disorders 25 years ago. Only now is the pivotal role of TNF in modulating these mechanisms, in health and disease, becoming more widely recognized in the brain research community. We look forward to the future, when a new generation of neuroscientists will arise, for whom the central role of cytokines in brain physiology will be basic knowledge, and the promise of perispinal delivery of large molecules to address brain disorders is fully realized.
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