Abstract
BackgroundEfficacy of neuroprotective treatments for ischemic stroke was not convincingly demonstrated in clinical phase III trials so far, whereas some preceding early phase studies found neuroprotection to be beneficial. We aimed to determine the frequency with which phase III studies are preceded by positive early phase studies, and to identify characteristics of early phase studies that are associated with correct prediction of phase III studies.MethodsWe identified phase III studies and corresponding early phase studies of neuroprotective treatments for stroke. Data on study characteristics of early phase trials were extracted and compared between studies that were classified according to their results as “false positive” and “true neutral” using logistic regression analysis.ResultsForty-six phase III studies and 59 corresponding early phase studies were identified. Only one phase III study was positive and this study was followed by a larger negative study. Twenty-two (37.3%) early phase studies were considered to be false positive and 37 (62.7%) to be true neutral. None of the early phase study characteristics were significantly associated with correct prediction of phase III studies.ConclusionsMore than one third of early phase studies on neuroprotective stroke treatments are false positive. Neither the results nor specific study design characteristics of early phase stroke studies reliably predict success in phase III trials. Further efforts are needed to improve early phase studies regarding its predictability and to identify those early studies that should be advanced to phase III trials.
Highlights
Efficacy of neuroprotective treatments for ischemic stroke was not convincingly demonstrated in clinical phase III trials so far, whereas some preceding early phase studies found neuroprotection to be beneficial
We aimed to determine the frequency with that phase III studies are preceded by positive early studies, and to identify study characteristics of early phase studies that are associated with correct prediction of subsequent phase III studies
Seven further studies were identified by searching review articles on clinical acute stroke studies
Summary
Efficacy of neuroprotective treatments for ischemic stroke was not convincingly demonstrated in clinical phase III trials so far, whereas some preceding early phase studies found neuroprotection to be beneficial. Neuroprotective treatments for stroke were considered to be promising for clinical development. This process usually progresses from phase I to phase II to phase III studies. The primary objectives of phase I studies are to assess the safety and tolerability of a treatment in a small group of healthy participants or patients. Phase II trials evaluate the efficacy of a drug and further investigate its safety in a larger group of patients. In phase III trials a therapeutic intervention is compared to standard treatment to confirm its efficacy. Phase III studies are usually required for approval by regulatory agencies and
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