Phosphodiesterase-5 Inhibitor PF-03049423 Effect on Stroke Recovery: A Double-Blind, Placebo-Controlled Randomized Clinical Trial.

BACKGROUND: The therapeutic potential of phosphodiesterase-5 inhibitor PF-03049423 was evaluated in a phase 2, multicenter, randomized, double-blind, placebo-controlled study of subjects with acute ischemic stroke ( CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov, unique identifier: NCT01208233; http://www.clinicaltrialsregister.eu, EudraCT number: 2010-021414-32). MATERIALS AND METHODS: Subjects (N = 70) received PF-03049423 6 mg (or placebo, N = 67) once daily, orally, commencing between 24 and 78 hours of stroke onset, and continuing for 90 days. Postbaseline efficacy assessments were performed on Days 7, 14, 30, 60, and 90. Modified Rankin Scale (mRS), Barthel Index, National Institutes of Health Stroke Scale, 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 were administered to evaluate poststroke recovery. The primary endpoint was the mRS responder rate (score 0-2 at Day 90). The study included a planned interim analysis of efficacy data. RESULTS: The primary efficacy analysis using logistic regression showed no statistically significant difference between PF-03049423 6 mg and placebo (responder rate of 42.6% and 46.2%, respectively). Although PF-03049423 showed a satisfactory safety and tolerability profile, no signal of efficacy emerged from any of the outcome measures. CONCLUSIONS: PF-03049423 showed no therapeutic potential for acute ischemic stroke.

WAVES: A Novel Test to Evaluate Visuospatial Construction Ability in a School-aged Population.

Objective: The paucity of valid diagnostic tools is one of the challenges preventing the effective implementation of child cognitive health testing in Sub-Saharan developing countries. WAVES addresses the need for new psychometric tests to evaluate visuospatial construction ability in a school-aged population. WAVES involves the standardized administration of a copy design task that is sequentially repeated by four distinct reproduction modalities: copy design with open eyes (CDO), immediate reproduction from memory with open eyes (IRMO), immediate reproduction from memory with closed eyes (IRMC), and delayed reproduction from memory with closed eyes (DRMC). Design: WAVES reliability and validity were assessed in a field trial using Classical Test Theory or Item Response Theory (IRT) methods. A total of 445 children, aged 5 to 17 years old, were recruited at multiple Zambian clinical sites and schools. Results: WAVES provides a visuographomotor construction processing (VGCP) index and three subscale inaccuracy of reproduction scores: perseveration, decreased spacing, and changing direction difficulty (CDD). WAVES scores depended on age and showed an age-related increase of reproduction accuracy. Altered visuospatial construction, as indicated by higher scores, was associated with poor health status (i.e., chronic neurologic or medical disease or prolonged exposure to psychosocial stress and deprivation). Reliability estimates, expressed as an intraclass correlation coefficient (ICC; 95% confidence interval [CI]), at test-retest (n=86) were: VGCP Index: 0.94 (0.91, 0.96); perseveration: 0.76 (0.62, 0.84); decreased spacing: 0.86 (0.79, 0.91); and CDD: 0.93 (0.89, 0.95). Conclusion: WAVES has potential for clinical utility in evaluating the effect of different health conditions on visuospatial construction ability. Study results warrant further research to validate its use in healthcare and clinical research settings.

Development of a Symbol Cancellation Test to Evaluate Attention in a School-aged Zambian Population.

Objective: The assessment of child cognitive health in Sub-Saharan developing countries poses significant challenges, including the paucity of valid diagnostic tools. We report the development and the initial validation of the Zambia Symbol Cancellation Test (ZSCT), a psychometric test to evaluate selective attention in a pediatric, school-aged population. Design: ZSCT reliability and validity were assessed in a field trial. A total of 409 children, aged 5 to 17 years, were recruited at multiple Zambian clinical sites and schools. The ZSCT provides a visuomotor processing index (VMPI), a measure of effortful processing to deliver accurate task response. Results: The VMPI reliability estimate at test-retest was found to be adequate for a clinical use (intraclass correlation coefficient [ICC]: 0.79, ICC-95% confidence interval [CI]: 0.69-0.86). Age showed a large effect on VMPI (n=323, r=-0.62, p=0.000). Impaired visuo-perceptual-motor processing, as measured by VMPI, was associated with poor health status (i.e., chronic neurologic or medical disease or prolonged exposure to psychosocial stress and deprivation). A two-way ANOVA found significant and small health status and age group effects [F (7, 408): 33.24, p=0.0000, η2=0.367]; the main effect of health status [F (1, 408): 37.79, p=0.000, η2=0.09], age group [F (3, 408): 35.06, p=0.000, η2=0.21], and their interaction was not significant (p=0.364). Conclusion: Study findings indicate that the ZSCT has satisfactory reliability, validity, and clinical utility to evaluate cognitive development and the effect of health conditions on attention. Study results warrant further research to validate its use in healthcare and clinical research settings.

WORDS: A New Verbal Memory Test to Evaluate Cognitive Health in a Zambian School-aged Population.

Objective: The paucity of psychometric instruments is one of the challenges preventing the effective implementation of child cognitive health testing in Sub-Saharan countries. WORDS is a new memory assessment tool originally validated in a Zambian school-aged population. Design: WORDS involves the standardized administration of a multitrial, verbal, free recall task with acquisition and immediate recall of a structured list of 16 words, followed by a second acquisition and delayed recall after a five-minute interference. A field trial was carried out to evaluate test feasibility of use, reliability, and validity. A total of 448 children, aged 5 to 17 years, were recruited at multiple Zambian clinical sites and schools. Results: WORDS provides a summary score of recall productivity derived from the sum of items correctly retrieved at immediate and delayed recalls. Recall productivity showed a moderate/good reliability at test-retest with alternate forms (N=53, 95% confidence interval of the intraclass correlation [CI-IC]: 0.73, 0.54-0.85). Recall productivity was found to increase with age. Altered memory functioning, as indicated by lower recall productivity, was associated with poor health status resulting from chronic neurologic or medical disease or prolonged exposure to psychosocial stress and deprivation [recall productivity, range: 0-32, healthy mean (standard deviation [SD]): 15.36 (4.7) vs. poor health, mean (SD): 12.62 (4.8); F (1,446)=27.79, p=0.000, d=0.58]. Conclusion: WORDS addresses the need for new psychometric tools to evaluate memory in a school-aged Zambian population. WORDS has the potential for clinical utility to evaluate cognitive development, as well as the effect of different health conditions on memory. Study results warrant research to further validate its use in Sub-Saharan clinical and epidemiological research settings.

Development of a Cognitive Ability Assessment Tool for a Pediatric School-aged Population.

OBJECTIVE: The assessment of a child's cognitive health in developing countries poses significant challenges, including the paucity of valid diagnostic tools. We report the development and initial psychometric evaluation of a new eight-item cognitive ability assessment tool (CAAT-8) for use in an African Sub-Saharan school-aged population. DESIGN: CAAT-8 reliability and validity were assessed in a field trial. Participants (446 children aged 5-17 years) were recruited at multiple clinical sites and schools. Methods and techniques based on Item Response Theory and Structural Equation Modeling were applied for item analysis and selection, reliability, and validity assessments. RESULTS: CAAT-8 includes eight cognitive tasks and provides a reliable measure of the factor of Knowledge Processing. Knowledge Processing consistently increased over age (simple regression model, R2=0.44). A poorer health status (e.g., due to a neurological or medical condition or chronic exposure to psychosocial stress and deprivation) was associated with lower Knowledge Processing. CONCLUSION: CAAT-8 is a viable methodology for cognitive health assessment in a pediatric school-aged population. The results from this study warrant further research to validate its use in healthcare and clinical research settings.

Assessment of Cognitive and Neurologic Recovery in Ischemic Stroke Drug Trials: Results from a Randomized, Double-blind, Placebo-controlled Study.

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-hoc analyses 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.

Differential characteristics of the aging process and the vascular cognitive impairment in the organization of memory retrieval.

Early identification of cognitive impairment in patients with chronic cerebral vascular disorders can allow for evaluating the time course of the disease up to the phase of conversion to dementia. The specific indicators of pathological cognitive decline should be identifiable vs. the concurrent age-associated changes in memory which accompany the aging process. We propose a method which evaluates memory dysfunctions in vascular cognitive impairment (VCI) as distinct from age-associated memory changes. This method is based on a serial learning task of concrete frequent words and it consists in controlling the effects of age and cerebral pathology on various characteristics of immediate recall, including serial effect and productivity. Ninety participants underwent a between group examination: younger adults vs. older adults vs. VCI patients who were outpatients with a positive history for chronic cerebral vascular disorder, positive neuroimaging examination, a Hachinski ischemic score ≥ 5 and a mild to moderate cognitive impairment. VCI patients show a reduced efficiency of retrieval and recall organization while, age-associated cognitive changes consist of a modification of the serial position effects. In particular, VCI patients, as distinct from same-age normal cases, can perform an only partial utilization of the inherent structure of the memory task with a very limited efficiency of relearning which is not sufficiently supported by the facilitating factors due to task repetition.