PRIMED2 Preclinical Evidence Scoring Tool to Assess Readiness for Translation of Neuroprotection Therapies

Mersedeh Bahr-Hosseini,S Thomas Carmichael,Jeffrey L Saver,David S Liebeskind,Marco Iacoboni,Marom Bikson,Jason D Hinman

doi:10.1007/s12975-021-00922-4

Abstract

Many neuroprotective and other therapies for treatment of acute ischemic stroke have failed in translation to human studies, indicating a need for more rigorous, multidimensional quality assessment of the totality of preclinical evidence supporting a therapy prior to conducting human trials. A consensus panel of stroke preclinical model and human clinical trial experts assessed candidate items for the translational readiness scale, compiled from prior instruments (STAIR, ARRIVE, CAMARADES, RoB 2) based on importance, reliability, and feasibility. Once constructed, the tool was applied by two independent raters to four current candidate acute stroke therapies, including two pharmacologic agents [nerinetide and trans-sodium crocetinate] and two device interventions [cathodal transcranial direct current stimulation and fastigial nucleus stimulation]. The Preclinical evidence of Readiness In stroke Models Evaluating Drugs and Devices (PRIMED2) assessment tool rates the totality of evidence available from all reported preclinical animal stroke model studies in 11 domains related to diversity of tested animals, time windows, feasibility of agent route of delivery, and robustness of effect magnitude. Within each content domain, clearly operationalized rules assign strength of evidence ratings of 0–2. When applied to the four assessed candidate agents, inter-rater reliability was high (kappa = 0.88), and each agent showed a unique profile of evidentiary strengths and weaknesses. The PRIMED2 assessment tool provides a multidimensional assessment of the cumulative preclinical evidence for a candidate acute stroke therapy on factors judged important for successful basic-to-clinical translation. Further evaluation and refinement of this tool is desirable to improve successful translation of therapies for acute stroke.

Highlights

Many neuroprotective and other therapies for treatment of acute ischemic stroke have failed in translation despite demonstrating apparent preclinical evidence of efficacy [1,2,3,4,5]
We developed a novel assessment tool: the Preclinical evidence of Readiness In stroke Models Evaluating Drugs and Devices ( PRIMED2) translational assessment rating system
To identify potential topic domains to be analyzed by the instrument, first, existing content items were compiled from three existing preclinical study assessments (STAIR criteria, Animal Research: Reporting In Vivo Experiments (ARRIVE), CAMARADES) and two existing assessments of human clinical trial quality—the Consolidated Standards of Reporting Trials (CONSORT) checklist and the Cochrane Collaboration Risk of Bias 2 (RoB 2) assessment tool

Summary

Introduction

Many neuroprotective and other therapies for treatment of acute ischemic stroke have failed in translation despite demonstrating apparent preclinical evidence of efficacy [1,2,3,4,5]. For preclinical studies, identified methodologic weaknesses in study quality include absence of randomization, lack of blinded assessment of outcome, failure to prespecify a primary endpoint, use of clinically unattainable treatment times, and publication bias [6,7,8,9]. To address these deficiencies, consensus groups have developed two categories of methods to assess the quality of preclinical acute stroke studies to increase the odds of translational success.

Methods

Results

Conclusion