Efficacy and Safety of the α7-Nicotinic Acetylcholine Receptor Agonist ABT-126 in the Treatment of Cognitive Impairment Associated With Schizophrenia: Results From a Phase 2b Randomized Controlled Study in Smokers.

OBJECTIVE: To evaluate the efficacy and safety of the α7-nicotinic receptor agonist ABT-126 for treatment of cognitive impairment in stable subjects with schizophrenia who smoke. METHODS: A 12-week double-blind, placebo-controlled, parallel-group study was conducted from August 2012 to March 2014. Subjects with a diagnosis of schizophrenia based on DSM-IV-TR criteria (confirmed by the Mini-International Neuropsychiatric Interview version 6.0.0) were randomized 1:1:1 to ABT-126 25 mg, ABT-126 75 mg, or placebo once daily while maintained on their background antipsychotic medication. The primary endpoint was the change from baseline on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) neurocognitive composite score; the primary analysis compared ABT-126 with placebo at week 12 using a mixed-effects model for repeated measures. Secondary endpoints included the change from baseline on the University of California San Diego Performance-based Skills Assessment-2 Extended-Range, the 16-item Negative Symptom Assessment scale (NSA-16), and safety assessments. RESULTS: Of the 157 randomized subjects, 82% completed the study. The mean baseline MCCB neurocognitive composite score for the entire study sample was 28.8; scores were similar across groups. No statistical difference in the change from baseline score between any of the ABT-126 dose groups and placebo was observed on the MCCB neurocognitive composite score (ABT-126 25 mg, +0.28; ABT-126 75 mg, +0.41; placebo, +1.42). Differences in the NSA-16 total score were seen with ABT-126 75 mg versus placebo at week 6 (-2.79; P = .011) and week 12 (-1.94; P = .053). Adverse events with ABT-126 were similar to placebo, except for constipation (5.8% for ABT-126 vs 0% for placebo). CONCLUSIONS: ABT-126 did not demonstrate a procognitive effect in subjects with stable schizophrenia who smoke. A trend for improvement in negative symptoms was observed with the high dose. The safety profile of ABT-126 was similar to placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01678755​.

A Randomized Trial to Assess the Efficacy and Safety of ABT-126, a Selective α7 Nicotinic Acetylcholine Receptor Agonist, in the Treatment of Cognitive Impairment in Schizophrenia.

OBJECTIVE: The authors sought to evaluate the efficacy and safety of ABT-126, a selective α7 nicotinic receptor partial agonist, in stable patients with schizophrenia. METHOD: A 12-week, double-blind, placebo-controlled, parallel-group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests. RESULTS: A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence). CONCLUSIONS: ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention.

Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin.

This was a multicenter, double-blind (DB), placebo-controlled, randomized discontinuation trial to evaluate the efficacy of pregabalin monotherapy for durability of effect on fibromyalgia (FM) pain. The trial included a 6-week open-label (OL) pregabalin-treatment period followed by 26-week DB treatment with placebo or pregabalin. Adults with FM and 40-mm score on 100-mm pain visual analog scale (VAS) were eligible. During OL weeks 1-3, patients received escalating dosages of pregabalin to determine their optimal dosages. During OL weeks 4-6, patients received their optimal fixed dosages (300, 450, 600mg/d). To be randomized, patients must have had 50% decrease in pain VAS and a self-rating of "much" or "very much" improved on Patient Global Impression of Change (PGIC) at the end of OL. Double-blind treatment was with placebo or the patient's optimal fixed dosage of pregabalin. Primary outcome was time to loss of therapeutic response (LTR), defined as <30% reduction in pain (from OL baseline) or worsening of FM. A total of 1051 patients entered OL; 287 were randomized to placebo, 279 to pregabalin. Time to LTR was longer for pregabalin versus placebo (P<.0001). Kaplan-Meier estimates of time-to-event showed half the placebo group had LTR by Day 19; half the pregabalin group still had not lost response by trial end. At the end of DB, 174 (61%) placebo patients met LTR criteria versus 90 (32%) pregabalin patients. Pregabalin was well tolerated, though 178 (17%) discontinued during OL for treatment-related adverse events (AE), and more pregabalin than placebo patients discontinued for AEs during DB. In those who respond, pregabalin demonstrated durability of effect for relieving FM pain.