Randomized Clinical Study of a Histamine H-3 Receptor Antagonist for the Treatment of Adults with Attention-Deficit Hyperactivity Disorder

Background: Psychostimulants, including methylphenidate and amphetamine preparations, are commonly prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. Histamine H-3 receptors reside on non-histamine neurons and regulate other neurotransmitters (e.g. acetylcholine, noradrenaline [norepinephrine]) suggesting that H-3 antagonists have the potential to improve attention and impulsivity. Research indicates that H-3 receptor antagonists due to their novel mechanism of action may have a unique treatment effect offering an important alternative for the treatment of ADHD. Bavisant (JNJ-31001074) is a highly selective, orally active antagonist of the human H-3 receptor with a novel mechanism of action, involving wakefulness and cognition, with potential as a treatment for ADHD. Objective: The objective of this study was to evaluate the efficacy, safety and tolerability of three dosages of bavisant compared with placebo in adults with ADHD. Study design: This randomized, double-blind, placebo- and active-controlled, parallel-group, multicentre study evaluated three dosages of bavisant (1 mg/day, 3 mg/day or 10 mg/day) and two active controls in adults with ADHD. The study consisted of a screening phase of up to 14 days, a 42-day double-blind treatment phase and a 7-day post-treatment follow-up phase. Efficacy and safety assessments were performed. Setting: The study was conducted at 37 study centres in the US from April 2009 through January 2010. Participants: Men and women aged 18-55 years with an established diagnosis of ADHD as confirmed by clinician and self-report diagnostic measures were enrolled. Intervention: Participants were randomly assigned equally to one of six treatment groups: placebo, bavisant 1 mg/day, 3 mg/day or 10 mg/day, atomoxetine hydrochloride 80 mg/day or osmotic-release oral system (OROS) methylphenidate hydrochloride 54 mg/day. Main outcome measure: The primary efficacy endpoint was the change in the Attention Deficit Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total score from baseline (day 1) to the end of the treatment phase (day 42), and included all randomized participants who received one or more doses of study drug and had baseline and one or more post-baseline assessments (intent-to-treat [ITT] population). Safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests and ECG readings. Results: 430 participants were randomized, 424 received one or more doses of study medication and 335 (78%) of those randomized completed the study. Study participants had a mean age of 33.9 years and were predominantly White men. Mean treatment duration ranged from 31.4 to 38.8 days across groups. Mean change from baseline in the total ADHD-RS-IV score at day 42 (primary efficacy endpoint) was -8.8 in the placebo group versus -9.3, -11.2 and -12.2 in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively; the change in the 10 mg/day group was not statistically superior to placebo (p = 0.161), and hence statistical comparisons of the 1 mg/day and 3 mg/day groups with placebo based on a step-down closed testing procedure were not performed. Mean change from baseline in the total ADHD-RS-IV score at day 42 was superior to placebo in the atomoxetine (-15.3) and OROS methylphenidate (-15.7) groups (p < 0.005). Secondary efficacy assessments demonstrated a similar pattern with a non-significant trend towards improvement in the bavisant groups. The two lower dosages showed a good tolerability profile, but the higher dosage of bavisant was less well tolerated, as evidenced by the incidence of total TEAEs (61.8%, 82.4%, 89.0%), and discontinuations due to TEAEs (4.4%, 7.4%, 19.2%) in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively, compared with 58.9% and 2.7%, respectively on placebo. In the atomoxetine and OROS methylphenidate groups, the incidence of total TEAEs was 83.8% and 82.4% and discontinuations due to TEAEs was 10.8% and 8.8%, respectively. Conclusion: Bavisant, a highly selective, wakefulness-promoting H-3 antagonist, did not display significant clinical effectiveness in the treatment of adults with ADHD.