A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia

Department of Public Health, Cornell University, Итак, New York, United States
Schizophrenia Bulletin (Impact Factor: 8.45). 02/2005; 31(1):5-19. DOI: 10.1093/schbul/sbi020
Source: PubMed


On April 23, 2004, a joint meeting of the FDA, NIMH, MATRICS investigators, and experts from academia and the pharmaceutical industry was convened to develop guidelines for the design of clinical trials of cognitive-enhancing drugs for neurocognitive impairments in patients with schizophrenia.
Experts were asked to address specific questions relating to clinical trial design of adjunctive/co-treatment and broad spectrum agents. At the workshop, experts reviewed relevant evidence before offering the discussion panel proposed guidelines for a given subset of questions. The discussion panel, which consisted of presenters and representatives from FDA, NIMH, academia, and industry, deliberated to reach consensus on suggested guidelines. When evidence was insufficient, suggested guidelines represent the opinion of a cross-section of the presenters and discussion panel.
Guidelines were developed for inclusion criteria, the use of co-primary outcome measures, and statistical approaches for study design. Consensus was achieved regarding diagnostic and concomitant medication inclusion criteria and on the use of cognitive screening measures. A key guideline was to limit the trial to patients in the residual phase of their illness, who have a predefined level of positive, negative, and affective symptoms. The most difficult issues were the feasibility of including a co-primary measure of functional improvement and the choice of comparator agent for a trial of a broad spectrum agent (with antipsychotic and cognitive-enhancing effects).
The suggested guidelines represent reasonable starting points for trial design of cognitive-enhancing drugs, with the understanding that new data, subsequent findings, or other methodological considerations may lead to future modifications.

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    • "As part of the MATRICS initiative, the Food and Drug Administration (FDA) suggested that the use of a single, objective cognitive performance-based measure should be adopted as part of a standardized approach to assessment for the approval of cognitive enhancing drugs. In addition, the FDA decided to require documentation of improvements on a functionally meaningful co-primary measure that has face validity for patients and clinicians (Buchanan et al., 2005). The UPSA was selected by the MATRICS committee as a recommended co-primary measure because of its high correlation with objective neurocognitive functioning. "
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    ABSTRACT: Background: Progress has been made in developing interview-based measures for the assessment of cognitive functioning, such as the Cognitive Assessment Interview (CAI), as co-primary measures that compliment objective neurocognitive assessments and daily functioning. However, a few questions remain, including whether the relationships with objective cognitive measures and daily functioning are high enough to justify the CAI as an co-primary measure and whether patient-only assessments are valid. Methods: Participants were first-episode schizophrenia patients (n=60) and demographically-similar healthy controls (n=35), chronic schizophrenia patients (n=38) and demographically similar healthy controls (n=19). Participants were assessed at baseline with an interview-based measure of cognitive functioning (CAI), a test of objective cognitive functioning, functional capacity, and role functioning at baseline, and in the first episode patients again 6months later (n=28). Results: CAI ratings were correlated with objective cognitive functioning, functional capacity, and functional outcomes in first-episode schizophrenia patients at similar magnitudes as in chronic patients. Comparisons of first-episode and chronic patients with healthy controls indicated that the CAI sensitively detected deficits in schizophrenia. The relationship of CAI Patient-Only ratings with objective cognitive functioning, functional capacity, and daily functioning were comparable to CAI Rater scores that included informant information. Conclusions: These results confirm in an independent sample the relationship of the CAI ratings with objectively measured cognition, functional capacity, and role functioning. Comparison of schizophrenia patients with healthy controls further validates the CAI as an co-primary measure of cognitive deficits. Also, CAI change scores were strongly related to objective cognitive change indicating sensitivity to change.
    Full-text · Article · Feb 2016 · Schizophrenia Research
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    • "To examine transfer to untrained tasks the MATRICS Consensus Cognitive Battery (MCCB; Nuechterlein et al., 2008) and Cogstate (Westerman et al., 2001) were administered before and after the ten cognitive training sessions. Two baseline measures were taken (B1 and B2) in line with clinical trial recommendations done to reduce variance due to task unfamiliarity (Buchanan et al., 2005). "
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    ABSTRACT: Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    Full-text · Article · Mar 2015 · European Neuropsychopharmacology
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    • "(2015), patients (Mausbach et al., 2008). UPSA has been recommended as a coprimary assessment of cognition in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project (Buchanan et al., 2005), in line with its potential sensitivity to change (Leifker et al., 2010). Currently, several clinical trials employ improvements in UPSA scores as one of the outcomes when evaluating a possible " cognitive-enhancing " drug or remediation. "
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    ABSTRACT: The UCSD Performance-based Skills Assessment (UPSA) is a measure of Functional Capacity and assesses skills involved in community tasks. It has good psychometrics properties, and is currently recommended as a co-primary assessment of cognition in the MATRICS Project. To our knowledge so far, there are no studies in western developing countries concerning Functional Capacity in Schizophrenia. The aims of this study were to translate, culturally adapt and validate the UPSA to assess Functional Capacity in community-dwelling patients with Schizophrenia living in Brazil. Eighty-two subjects (52 patients, 30 controls) were evaluated using: the Brazilian version of the UPSA (UPSA-1-BR), PANSS, Personal and Social Performance (PSP) and Global Assessment of Functioning (GAF). In the reliability test, UPSA-1-BR showed good Internal Consistency (Cronbach’s alpha of 0.88) and strong correlation between test and retest (4-month gap; r = 0.91; p < 0.01). Spearman’s rho values showed a moderate correlation between UPSA-1-BR and both PSP (0.50; p < 0.01) and GAF (0.46; p < 0.01) scores. UPSA-1-BR is capable of differentiating people with and without Schizophrenia. Patients scored lower than controls (58.9 versus 79.1), with an AUC of 0.79 (95%IC: 0.69–0.89). Sensitivity and specificity values of 0.71 and 0.70, respectively, were found in the cut-off point of 73.5, for separation of patients and controls, with predictive values of 80% (positive) and 58% (negative). UPSA-B-BR was also evaluated. UPSA-1-BR and its brief version presented adequate psychometric properties and proved to be valid and reliable instruments in the assessment of Functional Capacity in subjects with Schizophrenia.
    Full-text · Article · Jan 2015 · Schizophrenia Research: Cognition
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