Brief Assessment Of Cognition In Schizophrenia Composite Score Research Articles

RESULTS OF PHASE 2B EAGLE TRIAL; A DOUBLE BLIND PLACEBO CONTROL STUDY EVALUATING THE EFFICACY AND SAFETY OF BL-1020, A GABA ENHANCED ANTIPSYCHOTIC FOR THE TREATMENT OF SCHIZOPHRENIA

Background: BL-1020 is a new chemical entity that combines dopamine antagonism with GABAergic activity. PK studies demonstrate that BL-1020 enters the brain, increases dopamine release in the prefrontal cortex and hippocampus and has the ability to reverse cognitive impairment induced by PCP in animal's behavioral models. Pre-clinical and clinical studies show that BL-1020 effectively reduces psychotic behavior with significantly fewer side effects. Methods: The EAGLE (Effective Antipsychosis via GABA Level Enhancement) study was conducted under a U.S. FDA, IND application at 40 sites in U.S., Europe and India. In this 6-week study, 363 patients were randomized equally to treatment with low (10 mg/day) or high dose (20-30 mg/day) of BL-1020, risperidone (2-8 mg/day) or placebo. The study was designed to demonstrate statistically significant superiority of the BL-1020 high dose to placebo on the primary efficacy measure; the total score of the PANSS. Key secondary efficacy measures included the CGI-S, CGI-C, RDQ and an exploratory end point: Effect on cognition as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). Risperidone at a dose of 2-8 mg was included as a positive control. Patients included were diagnosed with schizophrenia using the DSM-IV-TR experiencing an acute exacerbation of their psychosis, as evident from the following: PANSS total score ≥70; persistent positive symptoms; PANSS score ≥4 on conceptual disorganization, hallucinations, delusions, grandiosity, or suspiciousness; CGI-S rating of ≥4 (moderately ill); and duration of current episode less than one month. Results: The results in the ITT population using the LOCF for the primary efficacy measure, the total PANSS scores, indicated that treatment with BL-1020 high dose (LS mean -23.6; 95% CI-28.4;18.8), was statistically significant superior (p=0.002) to placebo; (LS mean -14.4; 95% CI: -19.1;-9.7). Risperidone treatment also was associated with significant improvement (LS means-26.2; 95% CI -31.0;-21.3) to placebo. BL-1020 low dose did not separate from placebo. There were no statistically significant differences between BL-1020 high dose and risperidone (p=0.390). The BL-1020 high dose was also statistically significantly superior for PANSS positive symptoms (p<0.001) and general psychopathology (P=0.003) and showed a trend for significance (P=0.067) for negative symptoms compared to placebo. These positive results on the PANSS, supported by the findings on the CGI-S and CGI-C. BL-1020 high dose showed significant increase in the number of ‘responders’ compared to placebo. The effect of BL-1020 on cognition provided evidence of a statistically significant and clinically relevant benefit. Analysis of the BACS composite score indicated significant superiority of the BL-1020 high dose group compared to placebo (p = 0.027) and risperidone (p=0.027) at the end of study, with an effect size of 0.5 compared to placebo. The maximum change from baseline in the ESRS score was comparable to that of risperidone. BL-1020 increase in prolactin was significantly lower than that of risperidone (p<0.001). There were no statistically significant or clinically relevant changes in the measurements of the ECG, laboratory or vital signs (BP, HR. Temp). There were no statistically significant or clinically relevant AEs of body weight gain, glucose increases, and changes in lipids. Discussion: These results are consistent with BL-1020 preclinical profile of an effective, safe and well tolerated, antipsychotic with GABA activity and a potential to improve cognition.

The Relationship of the Brief Assessment of Cognition in Schizophrenia (BACS) to Functional Capacity and Real-world Functional Outcome

The Brief Assessment of Cognition in Schizophrenia (BACS) assesses five different domains of cognitive function with six tests, and takes about 30–35 minutes to complete in patients with schizophrenia. Previous work has demonstrated the reliability of this measure, and its sensitivity to the deficits of schizophrenia. However, the relationship of this brief cognitive measure to functional outcome has not been determined. Further, future registration trials for potentially cognitive enhancing compounds may not only assess efficacy with cognitive performance measures, but with assessments of real-world functional outcome and functional capacity. The purpose of this study was to determine the relationship between the BACS and a potential co-primary measure for treatment studies of cognition in schizophrenia, and to determine if such a measure accounts for significant variance in functioning beyond that provided by cognitive function. The current study assessed 60 patients with schizophrenia over the course of six months. Cognitive functions were measured with the BACS. Functional capacity was measured with the UCSD Performance-based Skills Assessment (UPSA). Real-world functional outcome was measured with the Independent Living Skills Inventory (ILSI). BACS composite scores were significantly correlated with functional capacity as measured by the UPSA (r = .65, df = 55, p < .001), and real-world functional outcome as assessed by the ILSI (r = .37, df = 56, p = .005). In multiple regression analyses, UPSA scores did not account for additional variance in real-world functioning beyond that accounted for by the BACS. These data suggest that brief cognitive assessments such as the BACS are able to assess aspects of cognition that are related to important functional measures in clinical trials of cognitive enhancement. They also suggest that the measures being considered as potential co-primary indicators of cognitive function for registration trials are significantly correlated with cognition as assessed by brief cognitive assessments.

The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery

Studies of neurocognitive function in patients with schizophrenia use widely variable assessment techniques. Clinical trials assessing the cognitive enhancing effect of new medications have used neurocognitive assessment batteries that differed in content, length and administration procedures. The Brief Assessment of Cognition in Schizophrenia (BACS) is a newly developed instrument that assesses the aspects of cognition found to be most impaired and most strongly correlated with outcome in patients with schizophrenia. The BACS requires less than 35 min to complete in patients with schizophrenia, yields a high completion rate in these patients, and has high reliability. The BACS was found to be as sensitive to cognitive impairment in patients with schizophrenia as a standard battery of tests that required over 2 h to administer. Compared to healthy controls matched for age and parental education, patients with schizophrenia performed 1.49 standard deviations lower on a composite score calculated from the BACS and 1.61 standard deviations lower on a composite score calculated from the standard battery. The BACS composite scores were highly correlated with the standard battery composite scores in patients ( r=0.76) and healthy controls ( r=0.90). These psychometric properties make the BACS a promising tool for assessing cognition repeatedly in patients with schizophrenia, especially in clinical trials of cognitive enhancement.