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Randomized Clinical Study of a Histamine H3 Receptor Antagonist for the Treatment of Adults with Attention-Deficit Hyperactivity Disorder

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Abstract

Background: Psychostimulants, including methylphenidate and amphetamine preparations, are commonly prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. Histamine H3 receptors reside on non-histamine neurons and regulate other neurotransmitters (e.g. acetylcholine, noradrenaline [norepinephrine]) suggesting that H3 antagonists have the potential to improve attention and impulsivity. Research indicates that H3 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 H3 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) methyl-phenidate 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 H3 antagonist, did not display significant clinical effectiveness in the treatment of adults with ADHD.

Clinical Trial Registration Number: NCT00880217

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Acknowledgements

Janssen Research & Development, LLC, provided funding for the design and conduct of the clinical study (31001074ATT2001), including collection, management and analysis of the data.

Richard Weisler was the principal investigator for the study and received no compensation for time spent in the preparation of this manuscript. Dr Weisler has been a consultant to, on the speaker’s bureaus of, and received research support from Johnson & Johnson or an operating company (McNeil Pharmaceutical, Janssen). He owns Johnson & Johnson stock in mutual funds or in managed accounts with no direct control.

Richard Weisler, MD, in his career, has also been a consultant to, on the speaker’s bureaus of, and/or received research support from the following: Abbott, speaker’s bureau, consultant, received research support; Agency for Toxic Substances and Disease Registry, consultant; Astra Zeneca, speaker’s bureau, consultant, received research support; Biovail, speaker’s bureau, consultant, received research support; Bristol-Myers Squibb, speaker’s bureau, consultant, received research support, stockholder has held or holds stock; Burroughs Wellcome, speaker’s bureau, received research support; Cenerx, received research support; Centers of Disease Control and Prevention, consultant; Cephalon, speaker’s bureau, consultant, received research support; Ciba Geigy, speaker’s bureau, received research support; CoMentis, received research support; Corcept, consultant, Cortex, stockholder has held or holds stock; Dainippon Sumitomo Pharma America, received research support; Eisai, received research support; Eli Lilly, speaker’s bureau, consultant, received research support; Forest, speaker’s bureau, consultant, received research support; GlaxoSmithKline, speaker’s bureau, consultant, received research support; Lundbeck, received research support; Medicinova, received research support; Medscape Advisory Board, consultant; Merck, received research support, stockholder has held or holds stock; National Institute of Mental Health, consultant, received research support; Neurochem, received research support; New River Pharmaceuticals, received research support; Novartis, speaker’s bureau, received research support; Organon, speaker’s bureau, consultant, received research support; Otsuka America Pharma, consultant; Pfizer, speaker’s bureau, consultant, received research support, stockholder has held or holds stock; Pharmacia, consultant, received research support; Repligen, received research support; Saegis, received research support; Sandoz, received research support; Sanofi, speaker’s bureau, consultant, received research support; Sanofi-Synthelabo, speaker’s bureau, consultant, received research support; Schwabe/Ingenix, received research support; Sepracor, received research support; Shire, speaker’s bureau, consultant, received research support; Solvay, speaker’s bureau, consultant; Sunovion, speaker’s bureau, consultant, received research support; Synaptic, received research support; Takeda, received research support; TAP, received research support; Transcept Pharma, consultant, received research support; TransTech, consultant; UCB Pharma, received research support; Validus, speaker’s bureau, consultant; Vela, received research support; and Wyeth, speaker’s bureau, consultant, received research support.

Gahan Pandina, Ella Daly, Kimberly Cooper and Cristiana Gassmann-Mayer are employees of Janssen Research & Development, LLC, and own stock in Johnson & Johnson.

All authors met International Committee of Medical Journal Editors (ICMJE) criteria and all those who fulfilled those criteria are listed as authors. Bradford Challis, an employee of Janssen Research & Development, LLC, contributed to writing of the initial draft with author guidance, copy editing and incorporating author comments. The study is registered at ClinicalTrials.gov: NCT00880217.

The following investigators in the US participated in the study (listed in alphabetical order): Richard Anderson (Saint Charles, MO), Valerie Arnold (Memphis, TN), Brian Bortnick (Atlanta, GA), Matthew Brams (Houston, TX), Daniel Chueh (Santa Ana, CA), Eduardo Cifuentes (Charleston, SC), Andrew Cutler (Brandenton, FL), Bernadette D’Souza (Dayton, OH), Beal Essink (Portland, OR), Donald Garcia Jr (Austin, TX), John Giblin (Little Rock, AR), Michael Greenbaum (Libertyville, IL), James Grimm (Eugene, OR), Linda S. Harper (Orlando, FL), Shivkumar Hatti (Media, PA), Willis Holloway (Oklahoma City, OK), Angela House (Eagle, ID), William Jonakin (Boise, ID), Mark Joyce (Jacksonville, FL), David Krakow (Mount Kisco, NY), Suena Massey (Washington, DC), Eliot Moon (Wildomar, CA), Jeffrey Newcorn (New York, NY), Margarita Nunez (St. Petersburg, FL), Nader Oskooilar (Los Alamitos, CA), Americo Padilla (South Miami, FL), Nilesh Patel (Wharton, TX), Richard Rubin (Burlington, VT), Keith Saylor (Herndon, VA), Frederick Schaerf (Fort Myers, FL), Scott Segal (North Miami, FL), Mary Shemo (Charlottesville, VA), Steve Skarky (Oklahoma City, OK), Vicky Spratlin (Atlanta, GA), Jerry Steiert (Seattle, WA), Leslie Taylor (Middleton, WI), Haydn Thomas (Prairie Village, KS), Kathleen Toups (Lafayette, CA), Mark Turner (Meridian, ID), Bradley Vince (Overland Park, KS), Richard Weisler (Raleigh, NC), Joel Young (Rochester Hills, MI).

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Authors and Affiliations

  1. Duke University Medical Center and University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Richard H. Weisler

  2. Private Practice, Raleigh, NC, USA

    Richard H. Weisler

  3. Janssen Research & Development, LLC, Raritan, NJ, USA

    Gahan J. Pandina, Ella J. Daly, Kimberly Cooper & Cristiana Gassmann-Mayer

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  1. Richard H. Weisler
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  2. Gahan J. Pandina
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  5. Cristiana Gassmann-Mayer
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Correspondence to Ella J. Daly.

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Weisler, R.H., Pandina, G.J., Daly, E.J. et al. Randomized Clinical Study of a Histamine H3 Receptor Antagonist for the Treatment of Adults with Attention-Deficit Hyperactivity Disorder. CNS Drugs 26, 421–434 (2012). https://doi.org/10.2165/11631990-000000000-00000

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