The α7 Nicotinic Agonist ABT-126 in the Treatment of Cognitive Impairment Associated with Schizophrenia in Nonsmokers: Results from a Randomized Controlled Phase 2b Study

Abstract

A double-blind, placebo-controlled, parallel-group, 24-week, multicenter trial was conducted to evaluate the efficacy and safety of 3 doses of ABT-126, an α7 nicotinic receptor agonist, for the treatment of cognitive impairment in nonsmoking subjects with schizophrenia. Clinically stable subjects were randomized in 2 stages: placebo, ABT-126 25 mg, 50 mg or 75 mg once daily (stage 1) and placebo or ABT-126 50 mg (stage 2). The primary analysis was the change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score for ABT-126 50 mg vs placebo using a mixed-model for repeated-measures. A key secondary measure was the University of California Performance-based Assessment-Extended Range (UPSA-2ER). A total of 432 subjects were randomized and 80% (344/431) completed the study. No statistically significant differences were observed in either the change from baseline for the MCCB neurocognitive composite score (+2.66 [±0.54] for ABT-126 50 mg vs +2.46 [±0.56] for placebo at week 12; P>0.05) or the UPSA-2ER. A trend for improvement was seen at week 24 on the 16-item Negative Symptom Assessment Scale total score for ABT-126 50 mg (change from baseline -4.27±[0.58] vs -3.00±[0.60] for placebo; P=0.059). Other secondary analyses were generally consistent with the primary end point results. Adverse event rates were similar for ABT-126 and placebo. ABT-126 did not demonstrate a consistent effect on cognition in nonsmoking subjects with schizophrenia; however, a trend toward an effect was observed on negative symptoms. ClincalTrials.gov registration: NCT01655680.

Figures

Figure 1

Subject disposition.

Figure 2

LS Mean change from baseline in MCCB neurocognitive composite total score. Error bars represent the standard error of the LS means. An increase in score indicates improvement. There were no statistically significant 1-sided p-values from the repeated measures model. The model included treatment, site, visit, baseline score, interactions of treatment and visit, and interaction of baseline score and visit; covariance structure was unstructured. LS, least squares; MCCB, MATRICS Consensus Cognitive Battery.

Figure 3

LS mean change from baseline in UPSA-2ER and NSA-16 total scores. The repeated measures model included treatment, site, visit, baseline score, interactions of treatment and visit, and interaction of baseline score and visit; covariance structure was unstructured. There were no statistically significant treatment effects from the repeated measures model analysis in the UPSA-2ER or NSA-16. The LS mean change from baseline on the UPSA-2ER total score in the primary set (a) and dose-ranging set (b). An increase in score indicates improvement and error bars represent the standard error of the LS means. The UPSA-2ER total score depicted in this graph does not include the medication management subscale score because the ex-US version does not use the medication management test. The range of the UPSA-2ER total score without the medication management subscale is 0 to 100. The LS mean change from baseline on the NSA-16 total score in the primary set (c) and dose-ranging set (d). A decrease in score indicates improvement and error bars represent the standard error of the LS means. LS, least squares; NSA-16, 16-item Negative Symptom Assessment Scale; UPSA-2ER, University of California San Diego Performance-based Skills Assessment-2 Extended Range.