Efficacy and safety of the novel α ₄β ₂ neuronal nicotinic receptor partial agonist ABT-089 in adults with attention-deficit/hyperactivity disorder: A randomized, double-blind, placebo-controlled crossover study

Rationale: α ₄β ₂ Neuronal nicotinic receptors (NNRs) are implicated in the pathophysiology of attention-deficit/ hyperactivity disorder (ADHD). Objectives: This study examined the efficacy and safety of the α ₄β ₂ NNR partial agonist ABT-089 versus placebo in adults with ADHD. Methods: In this multicenter, randomized, double-blind, placebo-controlled crossover study, subjects received placebo followed by ABT-089 (2 mg once daily [QD], 5 mg QD, 15 mg QD, 40 mg QD, or 40 mg twice daily [BID]), or vice versa, in a 2 × 2 crossover design. Each treatment period was 4 weeks, separated by a 2-week washout period. The primary efficacy endpoint was the Conners' Adult ADHD Rating Scale-Investigator Rated (CAARS:Inv) total score at the end of each treatment period. Secondary outcomes based on clinician- and self-rated efficacy scales were evaluated. Results: Of the 221 subjects enrolled, 171 met criteria for inclusion in the completers dataset for efficacy analyses. ABT-089 was superior to placebo on the CAARS:Inv total score at 40 mg QD and 40 mg BID (model-based least square mean difference from placebo: -4.33, P = 0.02; -3.02, P = 0.03, respectively). ABT-089 also demonstrated significant improvements on several secondary measures of efficacy. ABT-089 was generally safe and well tolerated. The most commonly reported adverse events (≥5%) for total ABT-089-treated subjects at rates higher than placebo were headache, upper respiratory tract infection, irritability, insomnia, and nasopharyngitis. Conclusions: In this phase 2 crossover study, the NNR partial agonist ABT-089, at doses of 40 mg QD and 40 mg BID, was efficacious and generally well tolerated in treatment of adults with ADHD.