title: Assessment of Cognitive and Neurologic Recovery in Ischemic Stroke Drug Trials: Results from a Randomized, Double-blind, Placebo-controlled Study.
abstract: Objective.Ischemic stroke is a serious medical condition with limited therapeutic options. The evaluation of the therapeutic potential of novel pharmacological interventions is carried-out in Phase II trials. The study design, primarily intended to evaluate efficacy and safety, is a balance between utilizing as few patients as possible to minimize safety risk and enrolling sufficient patients to detect unambiguous efficacy signals. We sought to determine whether post-stroke recovery outcomes based on behavioral measures of cognitive and motor impairment yielded additional information beyond that of clinician-based methods.Design.This was a multicenter, multinational, randomized, parallel group, controlled versus placebo, efficacy, and safety study of PF-03049423 for treatment of acute ischemic stroke.Settings and participants.Our study subjects were acute ischemic stroke inpatients.Measurements.Outcome measures were derived from rating scales (Modified Rankin Scale, Barthel Index, and National Institutes of Health Stroke Scale) and behavioral tests (Box and Blocks Test, Hand Grip Strength Test, 10-Meter Walk Test, Repeatable Battery Assessment of Neuropsychological Status Naming and Coding Subtests, Line Cancellation Test, and Recognition Memory Test). Assessments were performed at Days 7, 14, 30, 60, and 90.Post-hocanalyses of correlations among the outcome measures at each measurement time point on a cohort of 137 subjects were conducted.Results.Results support the validity of measures from Box and Blocks Test, Hand Grip Strength Test, 10-Meter Walk Test, and Repeatable Battery Assessment of Neuropsychological Status Coding Subtests to monitor post-stroke recovery in clinical trial settings. Notably, the Recognition Memory Test did not show a correlation with the Modified Rankin Scale, and, in fact, did not show improvement over time.Conclusion.The behavioral measures of cognitive and motor functions included in this study may extend the evaluation of the therapeutic potential of new treatments for stroke recovery. The lack of correlation between Recognition Memory Test and the traditional efficacy endpoints, at least in part due to absence of any improvement in recognition memory, suggests that there may be cognitive elements not detected by the Modified Rankin Scale. This is clinically relevant and memory improvement has potential as an endpoint in future trials aiming to improve certain aspects of cognition.
authors.affiliation: Dr. Di Cesare is with Leoben Research Limited in Glasgow, UK; Dr. Mancuso is with Research Statistics at Pfizer in Groton, Connecticut, USA; Dr. Silver is with Rhode Island Hospital and Alpert Medical School of Brown University in Providence, Rhode Island, USA; and Dr. Loudon is with the Neuroscience and Pain Research Unit at Pfizer in Cambridge, UK.
authors.forename: Franco
authors.initials: F
authors.lastname: Di Cesare
authors.affiliation: Dr. Di Cesare is with Leoben Research Limited in Glasgow, UK; Dr. Mancuso is with Research Statistics at Pfizer in Groton, Connecticut, USA; Dr. Silver is with Rhode Island Hospital and Alpert Medical School of Brown University in Providence, Rhode Island, USA; and Dr. Loudon is with the Neuroscience and Pain Research Unit at Pfizer in Cambridge, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mancuso
authors.affiliation: Dr. Di Cesare is with Leoben Research Limited in Glasgow, UK; Dr. Mancuso is with Research Statistics at Pfizer in Groton, Connecticut, USA; Dr. Silver is with Rhode Island Hospital and Alpert Medical School of Brown University in Providence, Rhode Island, USA; and Dr. Loudon is with the Neuroscience and Pain Research Unit at Pfizer in Cambridge, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Silver
authors.affiliation: Dr. Di Cesare is with Leoben Research Limited in Glasgow, UK; Dr. Mancuso is with Research Statistics at Pfizer in Groton, Connecticut, USA; Dr. Silver is with Rhode Island Hospital and Alpert Medical School of Brown University in Providence, Rhode Island, USA; and Dr. Loudon is with the Neuroscience and Pain Research Unit at Pfizer in Cambridge, UK.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Loudon
keywords: Ischemic stroke; PDE5 Inhibitor; clinical trial; cognitive assessment; memory; neurorestoration; stroke recovery