Stroke Clinical Trials Research Articles

Clinical trials in stroke in 2022: new answers and questions

In 2022, several clinical trials have answered important research questions about revascularisation, and about the indications for endovascular thrombectomy, but their answers have raised additional questions. For example, two multicentre, open-label, randomised trials (DIRECT-SAFE and SWIFT-DIRECT)1,2 compared endovascular thrombectomy alone with combined intravenous thrombolysis and endovascular thrombectomy to find out if intravenous alteplase could be withheld in patients with large vessel occlusion who present directly to a hospital at which endovascular thrombectomy can be done (referred to as mothership patients).

Enhancing generalizability of stroke clinical trial results: Illustrations from upper-limb motor recovery trials.

Broadening eligibility criteria has been a focus to increase the generalizability of trial findings. Using upper-limb motor trials conducted early post-stroke as the illustrative domain, we sought to (1) investigate whether the published aim and conclusion statements adequately reflect the generalizability of findings and (2) explore internal validity and feasibility as constraints to achieving generalizability. We systematically applied a conceptual model of a trial sampling process to published literature from systematic review and prospective cross-sectional data. The eligibility criteria reported and used to exclude patients were classified by consensus as related to safety, internal validity, feasibility, or a combination thereof. Categorical data were reported as counts/proportions, and continuous data were reported as median (interquartile range (IQR)). Thirty trials (n = 1638 participants) were included in the published literature and 1013 patients in the prospective data set. Thirty-seven percent of trials did not describe their target population in the aim and conclusion, and 80% did not report all trial screening data. Eligibility criteria related to internal validity were the most common type reported and applied to exclude patients across both data sets. In the prospective data set, 70% of patients were excluded for more than one reason. Key information to support the generalizability of trial findings was insufficiently reported in published upper-limb motor research conducted early post-stroke. Broadening eligibility criteria alone is unlikely to sufficiently improve trial inclusivity due to internal validity constraints. Trials could achieve inclusivity through targeting multiple sub-populations, that in combination, produce clinically relevant results that are applicable to a broader population.

Abstract 14903: Augmenting Prediction of Intracranial Aneurysm Rupture Status With Computed Velomics

Background Although race is a social construct without biological meaning, race significantly impacts health outcomes. Race is under-reported in clinical trials making it difficult to identify and address health inequities. In this study, we analyze studies pertaining to cerebrovascular accidents (CVA) with the primary purpose to assess the inclusion of racial data in CVA clinical trials. Our secondary purpose is to assess the representation of the various races in CVA clinical trials. Methods: This meta-analysis study consisted of CVA clinical trial data from ClinicalTrials.gov. Two researchers extracted data independently. Microsoft Excel was used for data collection and analysis. The search term “stroke” was used to search clinical trials from 1995-2021. The primary outcome is the prevalence of trials with racial data reported. The secondary outcome is the prevalence of each racial subgroup and gender subgroups among trials that report race data. Results: 7004 trials were identified using “stroke” as a search term. After excluding non-interventional trials, 468 trials remained. A sample of 115 trials were included in preliminary analyses. Out of the 115 trials, 50 studies (43.5%) did not report race. The 65 trials with racial data totaled 7368 participants. 38.7% were female and 61.3% were male. 46.2% of participants were White, 17.3% were Black and 33.8% a “combined other” category (Asian, American Indian, Native Hawaiian, other, and unknown/not reported). Of 12 trials with pharmacologic intervention, 41.7% did not report race. There were a total of 1485 participants from the seven trials with pharmacologic intervention, of which 47.2% were female and 52.7% male. Furthermore, 68.3% of participants were White, 7.5% were Black and 22.9% were the “combined other” category. Conclusions: Of the studies reviewed, 43.5% of stroke clinical trials and 41.7% of stroke studies with pharmacologic interventions did not report racial data. Moreover, women and non-White subjects were significantly underrepresented in the stroke clinical trials. The under-representation of women and non-White subjects in these clinical trials raises the concern regarding access to stroke clinical trials and the need to further study the reason behind these disparities.

Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke.

Epigenetic changes in stroke may revolutionize cell-based therapies aimed at reducing ischemic stroke risk and damage. Epigenetic changes are a novel therapeutic target due to their specificity and potential for reversal. Possible targets for epigenetic modification include DNA methylation and demethylation, post-translational histone modification, and the actions of non-coding RNAs such as microRNAs. Many of these epigenetic modifications have been reported to modulate atherosclerosis development and progression, ultimately contributing to stroke pathogenesis. Furthermore, epigenetics may play a major role in inflammatory responses following stroke. Stem cells for stroke have demonstrated safety in clinical trials for stroke and show therapeutic benefit in pre-clinical studies. The efficacy of these cell-based interventions may be amplified with adjunctive epigenetic modifications. This review advances the role of epigenetics in atherosclerosis and inflammation in the context of stroke, followed by a discussion on current stem cell studies modulating epigenetics to ameliorate stroke damage.

Endogenous reparative pluripotent Muse cells with a unique immune privilege system: Hint at a new strategy for controlling acute and chronic inflammation.

Multilineage-differentiating stress enduring (Muse) cells, non-tumorigenic endogenous pluripotent stem cells, reside in the bone marrow (BM), peripheral blood, and connective tissue as pluripotent surface marker SSEA-3(+) cells. They express other pluripotent markers, including Nanog, Oct3/4, and Sox2 at moderate levels, differentiate into triploblastic lineages, self-renew at a single cell level, and exhibit anti-inflammatory effects. Cultured mesenchymal stromal cells (MSCs) and fibroblasts contain several percent of SSEA-3(+)-Muse cells. Circulating Muse cells, either endogenous or administered exogenously, selectively accumulate at the damaged site by sensing sphingosine-1-phosphate (S1P), a key mediator of inflammation, produced by damaged cells and replace apoptotic and damaged cells by spontaneously differentiating into multiple cells types that comprise the tissue and repair the tissue. Thus, intravenous injection is the main route for Muse cell treatment, and surgical operation is not necessary. Furthermore, gene introduction or cytokine induction are not required for generating pluripotent or differentiated states prior to treatment. Notably, allogenic and xenogenic Muse cells escape host immune rejection after intravenous injection and survive in the tissue as functioning cells over 6 and ∼2months, respectively, without immunosuppressant treatment. Since Muse cells survive in the host tissue for extended periods of time, therefore their anti-inflammatory, anti-fibrotic, and trophic effects are long-lasting. These unique characteristics have led to the administration of Muse cells via intravenous drip in clinical trials for stroke, acute myocardial infarction, epidermolysis bullosa, spinal cord injury, neonatal hypoxic ischemic encephalopathy, amyotrophic lateral sclerosis, and COVID-19 acute respiratory distress syndrome without HLA-matching or immunosuppressive treatment.

Pharmacological Inhibition of Class III Alcohol Dehydrogenase 5: Turning Remote Ischemic Conditioning Effective in a Diabetic Stroke Model.

The restoration of cerebral blood flow (CBF) to achieve brain tissue oxygenation (PbtO2) is the primary treatment for ischemic stroke, a significant cause of adult mortality and disability worldwide. Nitric oxide (NO) and its bioactive s-nitrosylated (SNO) reservoirs, such as s-nitrosoglutathione (GSNO), induce hypoxic vasodilation to enhance CBF during ischemia. The endogenous pool of SNOs/GSNO is enhanced via the activation of endothelial NO synthase (eNOS/NOS3) and by the suppression of class III alcohol dehydrogenase 5 (ADH5), also known as GSNO reductase (GSNOR). Remote ischemic conditioning (RIC), which augments NOS3 activity and SNO, is an emerging therapy in acute stroke. However, RIC has so far shown neutral effects in stroke clinical trials. As the majority of stroke patients are presented with endothelial dysfunctions and comorbidities, we tested the hypothesis that NOS3 dysfunction and diabetes will abolish the protective effects of RIC therapy in stroke, and the prior inhibition of GSNOR will turn RIC protective. Our data demonstrate that RIC during thrombotic stroke failed to enhance the CBF and the benefits of thrombolysis in NOS3 mutant (NOS3+/−) mice, a genetic model of NOS3 dysfunction. Interestingly, thrombotic stroke in diabetic mice enhanced the activity of GSNOR as early as 3 h post-stroke without decreasing the plasma nitrite (NO2−). In thrombotic stroke, neither a pharmacological inhibitor of GSNOR (GRI) nor RIC therapy alone was protective in diabetic mice. However, prior treatment with GRI followed by RIC enhanced the CBF and improved recovery. In a reperfused stroke model, the GRI–RIC combination therapy in diabetic mice augmented PbtO2, a translatory signature of successful microvascular reflow. In addition, RIC therapy unexpectedly increased the inflammatory markers at 6 h post-stroke in diabetic stroke that were downregulated in combination with GRI while improving the outcomes. Thus, we conclude that preexisting NOS3 dysfunctions due to comorbidities may neutralize the benefits of RIC in stroke, which can be turned protective in combination with GRI. Our findings may support the future clinical trial of RIC in comorbid stroke. Further studies are warranted to test and develop SNO reservoirs as the blood-associated biomarker to monitor the response and efficacy of RIC therapy in stroke.

Translating Animal Models of Ischemic Stroke to the Human Condition.

Ischemic stroke is a leading cause of death and disability. However, very few neuroprotective agents have shown promise for treatment of ischemic stroke in clinical trials, despite showing efficacy in many successful preclinical studies. This may be attributed, at least in part, to the incongruency between experimental animal stroke models used in preclinical studies and the manifestation of ischemic stroke in humans. Most often the human population selected for clinical trials are more diverse than the experimental model used in a preclinical study. For successful translation, it is critical to develop clinical trial designs that match the experimental animal model used in the preclinical study. This review aims to provide a comprehensive summary of commonly used animal models with clear correlates between rodent models used to study ischemic stroke and the clinical stroke pathologies with which they most closely align. By improving the correlation between preclinical studies and clinical trials, new neuroprotective agents and stroke therapies may be more accurately and efficiently identified.

Join us on an amazing journey towards next-generation treatments for CNS disorders: Launch of Neuroprotection, a new high-quality journal in translational neuroscience.

Join us on an amazing journey towards next-generation treatments for CNS disorders: Launch of Neuroprotection, a new high-quality journal in translational neuroscience.

Modified Rankin scale assessment by telephone using a simple questionnaire

Purpose: The modified Rankin Scale (mRS) is widely used as a measure of post-stroke physical disability in clinical stroke trials; however, it is affected by inter-rater discrepancies. A Japanese version of the simplified mRS questionnaire (J-RASQ) has the potential to overcome the inter-rater discrepancies and might be feasible for clinical surveys. We aimed to determine the reliability of J-RASQ in a telephone survey administered by non-medical staff. Methods: We recruited 103 patients (age = 73 ± 11 years; 57% males) with a history of ischemic stroke who visited the outpatient clinic of the department of neurology at our hospital between March and May, 2021. After obtaining informed consent for participation in the study, a stroke neurologist assessed the mRS score during the visit using the Japanese version of mRS. On the same day, a clerk telephoned the patient or his/her family members to administer the J-RASQ. The percentage of agreement between mRS and J-RASQ scores was evaluated using the kappa coefficient and weighted kappa coefficient. Results: The median time for the telephone survey was 85 s (interquartile range = 70–135 s). The mRS and J-RASQ scores had an agreement of 63.1%, with a kappa statistic of 0.51 (95% confidence interval [CI] = 0.39–0.63). The weighted kappa statistic, which takes into account the extent of disagreement, was 0.81 (95% CI = 0.75–0.88). Conclusion: J-RASQ is easy to administer and reliable for assessment in telephone-based surveys performed by non-medical staff

Analysis of Prescriptions for Dual Antiplatelet Therapy After Acute Ischemic Stroke

After the publication of the CHANCE (Clopidogrel in High Risk Patients With Acute Nondisabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke) clinical trials, the American Heart Association/American Stroke Association (AHA/ASA) issued a new class 1, level of evidence A, recommendation for dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) for secondary prevention in patients with minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤3). The extent to which variations in DAPT prescribing patterns remain and the extent to which practice patterns in the US are consistent with evidence-based guidelines are unknown. To evaluate the discharge DAPT prescribing patterns after publication of the new AHA/ASA guidelines and assess the extent of hospital-level variation in the use of DAPT for secondary prevention in patients with minor stroke (NIHSS score ≤3), as indicated by guidelines, and in patients with nonminor stroke (NIHSS score >3), for whom the risks and benefits of DAPT have not been fully established. This multicenter retrospective cohort study involved 132 817 patients from 1890 hospitals participating in the AHA/ASA Get With The Guidelines-Stroke program. Patients who were hospitalized for acute ischemic stroke and prescribed antiplatelet therapy at discharge between October 1, 2019, and June 30, 2020, were included. Minor ischemic stroke (NIHSS score ≤3) vs nonminor ischemic stroke (NIHSS score >3). The primary outcome was DAPT prescription at discharge. The extent to which variations in DAPT use were explained at the hospital level was assessed by calculating the median odds ratio (OR), which was derived using multivariable logistic regression analysis and compared the likelihood that 2 patients with identical clinical features admitted to 2 randomly selected hospitals (1 with higher propensity and 1 with lower propensity for DAPT use) would receive DAPT at discharge. Associations between hospital-level DAPT use among patients with minor vs nonminor stroke were evaluated using Pearson ρ correlation coefficients. Among 132 817 patients (median [IQR] age, 68 [59-78] years; 68 768 men [51.8%]), 4282 (3.2%) were Asian, 11 254 (8.5%) were Hispanic, 27 221 (20.5%) were non-Hispanic Black, 84 468 (63.6%) were non-Hispanic White, and 5592 (4.2%) were of other races and/or ethnicities (including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, and unable to determine). Overall, 86 551 patients (65.2%) presented with minor ischemic stroke, and 46 266 patients (34.8%) presented with nonminor ischemic stroke. After the 2019 AHA/ASA guideline updates, 40 661 patients (47.0%) with minor stroke (NIHSS median [IQR] score, 1 [0-2]) and 19 703 patients (42.6%) with nonminor stroke (NIHSS median [IQR] score, 6 [5-9]) received DAPT at discharge. Despite guideline recommendations, 45 890 patients (53.0%) with minor stroke did not receive DAPT. After accounting for patient characteristics, substantial hospital-level variations were found in the use of DAPT in those with minor stroke (median [IQR] hospital-level DAPT prescription rate, 44.8% [33.7%-57.7%]; range, 0%-91.7%; median OR, 2.03 [95% CI, 1.97-2.09]) when comparing 2 patients with identical risk factors discharged from 2 randomly selected hospitals, 1 with higher propensity and 1 with lower propensity for DAPT use. The use of DAPT in patients with nonminor stroke also varied significantly (median [IQR] hospital-level DAPT prescription rate, 41.4% [30.0%-53.8%]; range, 0%-100%; median OR, 1.90 [95% CI, 1.83-1.97]). Overall, hospitals that were more likely to prescribe DAPT for minor strokes were also more likely to prescribe DAPT for nonminor strokes (Pearson ρ = 0.72; P < .001). This cohort study found that despite updated AHA/ASA guidelines, more than 50% of patients with minor acute ischemic stroke did not receive DAPT at discharge. In contrast, more than 40% of patients with nonminor stroke received DAPT despite lack of evidence in this setting. These findings suggest that enhancing adherence to evidence-based DAPT practice guidelines may be a target for quality improvement in the treatment of patients with ischemic stroke.

Digital Health-Enabled Clinical Trials in Stroke: Ready for Prime Time?

As stroke continues to represent a major global health care problem, advancing our knowledge of new effective and safe stroke interventions represents a public health priority. The identification of these therapies requires the conduct of high-quality and well-powered randomized clinical trials. Despite its potential to inform clinical practice, traditional randomized clinical trial models have their drawbacks, including elevated costs, long completion times, failure to recruit the target sample sizes, lack of diversity, and complex operational procedures. Therefore, improving the participants' experience and trials' overall efficiency constitutes an important unmet need. Innovative models such as virtual and decentralized patient-centric trials have been proposed as a valuable strategy in this pursuit. In this narrative review, we discuss the limitations of traditional randomized clinical trial models and present the concept, advantages, and challenges of decentralized digitally enabled approaches to the conduct of stroke clinical trials.

Understanding factors contributing to participant satisfaction in stroke walking recovery clinical trials

BackgroundIndividuals with stroke face a distinct set of challenges, barriers and facilitators that need to be understood to streamline efficacy of stroke clinical trials and improve participant retention. Few long-term stroke rehabilitation trials have evaluated participant perception of their laboratory experience. MethodsWe collected data regarding trial satisfaction from 33 individuals with stroke who participated in 12 sessions of treadmill training which included pre, post and follow-up non-invasive brain stimulation and clinical assessments. We evaluated factors such as overall trial satisfaction, burden of testing, perceived benefits, perceived barriers, and perceived support using a participant satisfaction questionnaire (PSQ) that assessed participants’ overall trial experience. Results97% of our participants found participating in the study to be rewarding and would recommend it to other persons with stroke. Transcranial magnetic stimulation (TMS) testing was found to be the major perceived burden of participation while travelling to the lab was found to be the major perceived barrier to participation. Significant correlations were found between various items of the PSQ and clinical assessments. ConclusionsThis study helped us get a preliminary perspective into the benefits and barriers faced by persons with stroke enrolled in a 4-week long clinical trial. We observed that participant satisfaction was driven by various factors including functional status, personal relevance to the research, perceptive physical and mental health improvements, interaction with research personnel, and ease of testing protocols.

Evolution of ischemic stroke drug clinical trials in mainland China from 2005 to 2021.

BackgroundTo assess the temporal changes in the characteristics of ischemic stroke drug clinical trials conducted in mainland China in 2005–2021.MethodsA statistical analysis of registered clinical trials on ischemic stroke was performed using the platform of the Center for Drug Evaluation of China National Medical Products Administration, the Chinese Clinical Trial Registry, and ClinicalTrials.gov websites.ResultsFrom January 1, 2005 to August 1, 2021, a total of 384 registered drug clinical trials on ischemic stroke were identified in mainland China. Over time, the number of trials gradually increased each year, with a significant growth in 2014, from 16 in 2013 to 42 in 2014. Phase IV trials (31.8%) accounted for the majority, followed by phase II (16.4%), phase I (10.9%), and phase III (8.6%). In terms of sponsorship, the proportion of investigator‐initiated trials (IITs) (60.7%) was higher than industry‐sponsored trials (ISTs) (39.3%). Additionally, trials involving traditional Chinese medicines (TCMs) (36.2%) accounted for the largest proportion, followed by trials involving antithrombotic therapy (19.5%) and cerebral protection agents (16.7%). Furthermore, over the past 17 years, the number of leading drug clinical trial units for ischemic stroke in mainland China has continuously increased. The leading principal units from Beijing, Shanghai, Guangdong, Jiangsu, and Liaoning accounted for the majority of the trials (67.4%).ConclusionIn the past 17 years, great progress has been made in the research and development (R&D) of drugs and clinical trials for ischemic stroke in mainland China. The most extensive progress was observed in TCMs, antithrombotic therapy, and cerebral protection agents. More clinical trials are needed to confirm whether the newly developed drugs can improve the clinical efficacy of ischemic stroke. Simultaneously, more pharmaceutical R&D efforts of innovative drugs are warranted.

Therapeutic Trends of Cerebrovascular Disease during the COVID-19 Pandemic and Future Perspectives.

As of May 2022, there have been more than 400 million cases (including re-infections) of the systemic acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), and nearly 5 million deaths worldwide. Not only has the coronavirus disease 2019 (COVID-19) pandemic been responsible for diagnosis and treatment delays of a wide variety of conditions, and overwhelmed the allocation of healthcare resources, it has impacted the epidemiology and management of cerebrovascular disease. In this narrative review, we summarize the changing paradigms and latest data regarding the complex relationship between COVID-19 and cerebrovascular disease. Paradoxically, although SARS-CoV-2 has been associated with many thrombotic complications—including ischemic stroke—there have been global declines in ischemic stroke and other cerebrovascular diseases. These epidemiologic shifts may be attributed to patient avoidance of healthcare institutions due to fear of contracting the novel human coronavirus, and also related to declines in other transmissible infectious illnesses which may trigger ischemic stroke. Despite the association between SARS-CoV-2 and thrombotic events, there are inconsistent data regarding targeted antithrombotics to prevent venous and arterial events. In addition, we provide recommendations for the conduct of stroke research and clinical trial planning during the ongoing COVID-19 pandemic, and for future healthcare crises.

Automated detection of arterial landmarks and vascular occlusions in patients with acute stroke receiving digital subtraction angiography using deep learning

BackgroundDigital subtraction angiography (DSA) is the gold-standard method of assessing arterial blood flow and blockages prior to endovascular thrombectomy.ObjectiveTo detect anatomical features and arterial occlusions with DSA using artificial intelligence...

Effect of Sex on Outcomes of Mechanical Thrombectomy in Basilar Artery Occlusion: A Multicentre Cohort Study

Introduction: Identifying differences in outcome of basilar artery occlusion (BAO) between males and females may be useful in aiding clinical management. Recent studies have demonstrated widespread underrepresentation of women in acute stroke clinical trials. This international multicentre study aimed to determine sex differences in outcome after mechanical thrombectomy (MT) for patients with acute BAO. Methods: We performed a retrospective analysis of consecutive patients with BAO who had undergone MT in seven stroke centres across five countries (Singapore, Taiwan, United Kingdom, Sweden, and Germany), between 2015 and 2020. Primary outcome was a favourable functional outcome measured by a modified Ranking Scale (mRS) of 0–3 at 90 days. Secondary outcomes were mRS 0–3 upon discharge, mortality, symptomatic intracranial haemorrhage (sICH) and subarachnoid haemorrhage (SAH). Results: Among the 322 patients who underwent MT, 206 (64.0%) patients were male and 116 (36.0%) were female. Females were older than males (mean ± SD 70.9 ± 14.3 years vs. 65.6 ± 133.6 years; p = 0.001) and had higher rates of atrial fibrillation (38.9% vs. 24.2%; p = 0.012). Time from groin puncture to reperfusion was shorter in females than males (mean ± SD 57.2 ± 37.2 min vs. 71.1 ± 50.9 min; p = 0.021). Despite these differences, primary and secondary outcome measures were similar in females and males, with comparable rates of favourable 90-day mRS scores (mean ± SD 46 ± 39.7 vs. 71 ± 34.5; OR = 1.20; 95% confidence interval [CI] = 0.59–2.43; p = 0.611), favourable discharge mRS scores (mean ± SD 39 ± 31.6 vs. 43 ± 25.9; OR = 1.38; 95% CI = 0.69–2.78; p = 0.368) and in-hospital mortality (mean ± SD 30 ± 25.9 vs. 47 ± 22.8; OR = 1.15; 95% CI = 0.55–2.43; p = 0.710. Rates of complications such as sICH (mean ± SD 5 ± 4.3 vs. 9 ± 4.4; OR = 0.46; 95% CI = 0.08–2.66; p = 0.385) and SAH (mean ± SD 4 ± 3.4 vs. 5 ± 2.4; OR = 0.29; 95% CI = 0.03–3.09; p = 0.303) comparably low in both groups. Conclusion: Females achieved comparable functional outcomes compared with males after undergoing MT for BAO acute ischemic stroke.

The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues-such as incomplete mechanistic knowledge and faulty clinical trial design-a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.

Recycled Translation: Repurposing Drugs for Stroke.

Stroke, which continues to be a leading cause of death and long-term disability worldwide, has often been described as a clinical graveyard. While multiple small molecule therapeutics have undergone clinical trials in stroke, currently only one Food and Drug Administration (FDA)-approved medication exists for the treatment of stroke, the biological, recombinant tissue plasminogen activator (rt-PA). Repurposing of therapeutics which have previously gained FDA approval for alternative indications serves as a prospective option for stroke therapeutic translation. In contrast to de novo drug development, repurposing strategies have patient-centered and economic advantages. These include increased safety, increased chance of approval, decreased time to approval, and decreased capital investment. Presently, 37 active stroke clinical trials utilize repurposed therapeutics with various initial indications and dosing paradigms. The currently studied repurposed therapeutics fall into six mechanistic categories: (1) anticoagulation; (2) vasculature integrity, response, or red blood cell (RBC) alterations; (3) immune system regulation; (4) neurotransmission; and (5) neuroprotection. Directed hypothesis-driven computational investigation utilizing drug databases, in silico drug-protein interaction modeling, genomic data, and consensus methodology can determine if the current mechanistic repurposing categories have the highest chance of translational success or if other mechanistic avenues should be explored. With this increased focus on repurposed therapeutic strategies over de novo strategies, evolution and optimization of regulatory protections are needed to incentivize innovators and investigators.

Getting the Most out of Consent: Patient-Centered Consent for an Acute Stroke Trial.

Informed consent for clinical trials in acute stroke is characterized by challenges related to urgency, cognitive impairment, and geographical separation. Context-appropriate approaches are needed for this setting. We conducted a mixed-methods project involving focus groups and interviews as well as collaboration with a patient advisory panel and a central institutional review board (CIRB) to design and implement a patient-driven consent process for a multicenter trial incorporating adaptive randomization. Remote consent was recognized as challenging but acceptable. Adaptive randomization was viewed positively, but significant potential for misunderstanding was appreciated. Collaboration between the patient advisory panel and the CIRB resulted in a shortened, more patient-centered consent form that was approved at all sites with few modifications. An information sheet was developed as a resource for patients and surrogates after enrollment. Collaboration between investigators, patient partners, and a CIRB can facilitate innovation and implementation of patient-centered, context-appropriate consent strategies.

Mesenchymal Stem Cells: Therapeutic Mechanisms for Stroke.

Due to aging of the world’s population, stroke has become increasingly prevalent, leading to a rise in socioeconomic burden. In the recent past, stroke research and treatment have become key scientific issues that need urgent solutions, with a sharp focus on stem cell transplantation, which is known to treat neurodegenerative diseases related to traumatic brain injuries, such as stroke. Indeed, stem cell therapy has brought hope to many stroke patients, both in animal and clinical trials. Mesenchymal stem cells (MSCs) are most commonly utilized in biological medical research, due to their pluripotency and universality. MSCs are often obtained from adipose tissue and bone marrow, and transplanted via intravenous injection. Therefore, this review will discuss the therapeutic mechanisms of MSCs and extracellular vehicles (EVs) secreted by MSCs for stroke, such as in attenuating inflammation through immunomodulation, releasing trophic factors to promote therapeutic effects, inducing angiogenesis, promoting neurogenesis, reducing the infarct volume, and replacing damaged cells.