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• W2079431117 abstract "Kennedy Lees and colleagues (June 3, p 1949)1Lees KR Asplund K Carolei A et al.Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial.Lancet. 2000; 355: 1949-1954Summary Full Text Full Text PDF PubMed Scopus (291) Google Scholar present yet another phase III clinical trial (Glycine Antagonist [gavestinel] in Neuroprotection [GAIN] International) of a neuroprotective drug (gavestinel, GV150526) that fails to show any benefit at all in stroke patients, despite a 50% reduction in infarct volume in preclinical studies.2Di Fabio R Cugola A Donati D et al.Identification and pharmacological characterisation of GB150526, a novel glycine antagonist as a potent neuroprotective agent.Drugs Future. 1998; 23: 62-69Google Scholar The recurrent failure of apparently promising new drugs to improve functional outcome after stroke has been the subject of increasing speculation. A list of failings in the design of the clinical trials (which were articled in GAIN) has been suggested as the main reason.3DeGraba TJ Pettigrew LC Why do neuroprotective drugs work in animals but not in humans?.Neural Clinics. 2000; 19: 475-493Summary Full Text Full Text PDF Scopus (102) Google Scholar The appropriateness of animal models has also been questioned, but the recently introduced guidelines for preclinical assessment of neuroprotectants (STAIR)4Stroke Therapy Academic Industry Roundtable (STAIR)Recommendations for standards regarding preclinical neuroprotective and restorative drug development.Stroke. 1999; 30: 2752-2758Crossref PubMed Scopus (1072) Google Scholar will hopefully lead to better minimum standards for drug testing (too recent for gavestinel). However, we feel that more fundamental sources of bias in the preclinical assessment of neuroprotectants, so far overlooked (even in STAIR4Stroke Therapy Academic Industry Roundtable (STAIR)Recommendations for standards regarding preclinical neuroprotective and restorative drug development.Stroke. 1999; 30: 2752-2758Crossref PubMed Scopus (1072) Google Scholar), could explain the large discrepancies between trials in animals and trials in human beings. In clinical trials, as exemplified by GAIN, it is standard practice to go to great lengths to avoid bias: randomised treatment allocation; balanced randomisation on key baseline variables; masked treatment allocation; masked assessment of outcome (preferably by an independent outcome assessor); and use of intention-to-treat analyses. Also, in the assessment of any treatment, we should never rely on the results of just one trial, but carry out a methodologically rigorous systematic review and meta-analysis of all the available randomised evidence and guard against publication bias (ie, unpublished negative experiments). Have any of these points been given such careful attention in preclinical studies? Is it possible to ensure adequate masking of treatment allocation or outcome assessment within the laboratory environment where the same staff may be involved in the administration of test drug, day-to-day care of the (often very small) number of animals, and the assessment of outcome? Given the considerable pressure on laboratories to develop stroke treatments, the potential for bias in outcome assessment with any prior knowledge of treatment allocation is substantial. For example, the size of the observed reductions in infarct volume with gavestinel seem almost biologically implausible. It is imperative that preclinical study methodology be made more rigorous. It is unethical to subject thousands more patients to the risk (and intrusion into their privacy) of participating in more trials based on the results of misleading preclinical testing. At least in the case of gavestinel and several other neuroprotectants one could say “at least they did no harm”. Or did they? The commercially sponsored neuroprotection trials have occupied the research time of hundreds of the most active and organised stroke centres in the world for several years,5Dorman PJ Counsell C Sandercock PAG Reports of randomised trials in acute stroke, 1955 to 1995. What proportions were commercially sponsored?.Stroke. 1999; 30: 1995-1998Crossref PubMed Scopus (31) Google Scholar further delaying the implementation of an effective stroke treatment. The question the neuroprotection trialists should be asking themselves is not “has the neuroprotection hypothesis been disproved?” but “what basic methodological flaw or flaws allow preclinical studies to provide such inadequate and probably overoptimistic data?”" @default.
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• W2079431117 title "Neuroprotection disappointment yet aGAIN" @default.
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• W2079431117 doi "https://doi.org/10.1016/s0140-6736(05)73980-5" @default.
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