A randomized, double-blind, placebo-controlled phase 2 study of α4β2 agonist ABT-894 in adults with ADHD

Abstract

Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4β2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of α4β2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.

Figure 1

Study design and subject assignment.

Figure 2

Subject disposition (CONSORT flow chart).

Figure 3

Mean difference from placebo on primary efficacy end point: Inattentive score or the Hyperactive/Impulsive score of the Conners' Adult Rating Scale–Investigator Rated Scale (CAARS:Inv) Total score at day 28 by dose group (completers data set). ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane) at 4 mg twice daily (BID) significantly improved symptoms of attention-deficit/hyperactivity disorder (ADHD). Treatment with 40 mg BID atomoxetine resulted in a similar improvement in symptoms. No significant improvements were detected with lower doses of ABT-894.

Figure 4

Crossover results analyzed as two parallel-group periods (Cohort B). Model-based mean change from period-specific baseline during treatment with 4 mg twice daily (BID) ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane) or atomoxetine at each study visit (intent-to-treat (ITT) data set) in Period 1 (left panel; *P<0.05 vs placebo) and Period 2 (right panel). The patients who received placebo graphed in the left panel are shown receiving active treatment in the right panel (treated with either 4 mg BID ABT-894 or atomoxetine). In Period 1, both active treatments demonstrated significant improvement compared with placebo. In Period 2, the magnitudes of treatment response to ABT-894 4 mg BID and atomoxetine were similar. No placebo group is shown in Period 2 because of potential carryover effects from receiving active treatment in Period 1.