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Effects of Guanfacine Extended Release on Oppositional Symptoms in Children Aged 6–12 Years with Attention-Deficit Hyperactivity Disorder and Oppositional Symptoms

A Randomized, Double-Blind, Placebo-Controlled Trial

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Abstract

Objective: To evaluate the efficacy and safety of guanfacine extended release (XR, Intuniv™; Shire Development Inc., Wayne, PA, USA) in the treatment of oppositional symptoms in children aged 6–12 years with a diagnosis of attention-deficit hyperactivity disorder (ADHD) and the presence of oppositional symptoms.

Subjects and Methods: In this randomized, double-blind, placebo-controlled, multicentre, flexible-dose, dose-optimization study, children aged 6–12 years were randomized to receive guanfacine XR (1–4mg/day) or placebo for 9 weeks. Screening and washout periods were followed by a 5-week dose-optimization period, a 3-week dose-maintenance period and a 1-week tapering period. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners’ Parent Rating Scale-Revised: Long Form (CPRS-R:L) score. Change in ADHD Rating Scale IV (ADHD-RS-IV) total score was a secondary efficacy measure. Safety assessments included adverse events (AEs), vital signs, ECG readings and laboratory studies.

Results: A total of 217 children were enrolled: 138 were randomized to receive guanfacine XR and 79 to receive placebo. Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were 10.9 in the guanfacine XR group compared with 6.8 in the placebo group (p<0.001; effect size = 0.59). A significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint was also seen in the guanfacine-treated group compared with the placebo group (23.8 vs 11.5, respectively; p<0.001; effect size = 0.92). A post hoc correlation analysis between percentage reduction from baseline to endpoint in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores indicated that the decreases in oppositional symptoms and ADHD symptoms were highly correlated (r = 0.74).

The most commonly reported, treatment-emergent AEs (TEAEs) in the guanfacine XR group were somnolence (50.7%), headache (22.1%), sedation (13.2%), upper abdominal pain (11.8%) and fatigue (11.0%) and most were mild or moderate in severity. TEAEs of sedation, somnolence or hypersomnia were experienced by 62.5% of subjects in the guanfacine XR group. These events were most common during the dose-titration period but most (63.5%) resolved prior to the taper period. TEAEs of fatigue, lethargy and asthenia were reported in 11.0%, 3.7% and 0.0% of subjects in the guanfacine XR group, respectively. Most subjects receiving guanfacine XR demonstrated modest changes in blood pressure, pulse rate and ECG readings that were not considered clinically significant.

Conclusions: In this population of children aged 6–12 years with ADHD and the presence of oppositional symptoms, significant reductions in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores were observed with guanfacine XR treatment compared with placebo. Treatment with guanfacine XR at optimized doses was associated with mostly mild or moderate TEAEs. The findings of this study support the efficacy of guanfacine XR in the treatment of children with ADHD and the presence of oppositional symptoms.

Clinical Trial Registration Number: NCT00367835.

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Acknowledgements

This clinical research was funded by Shire Development Inc. Authors directed writing assistance from Jennifer Steeber, PhD, an employee of Health Learning Systems. Editorial assistance in the form of proofreading, copy editing and fact checking was also provided by Health Learning Systems. Health Learning Systems was funded by Shire Development Inc. for authorship support in writing and editing this manuscript. Although the sponsor was involved in the design, collection, analysis, interpretation and fact checking of information, the ultimate interpretation was made by the independent authors, as was the content of this manuscript and the decision to submit it for publication in CNS Drugs.

Dr Daniel F. Connor receives honoraria and grant research support from Shire Pharmaceuticals, Inc. and is a speaker, consultant and is on the advisory board for Shire Pharmaceuticals, Inc. He also receives support from NIMH and the State of Connecticut, USA.

Dr Robert L. Findling receives or has received research support, acted as a consultant and/or served on a speaker’s bureau for Abbott, Addrenex, AstraZeneca, Biovail, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Johnson & Johnson, KemPharm Lilly, Lundbeck, Neuropharm, Novartis, Organon, Otsuka, Pfizer, sanofi-aventis, Sepracor, Shire Pharmaceuticals, Inc., Solvay, Supernus Pharmaceuticals, Validus and Wyeth.

Dr Scott H. Kollins has received research support and/or consultant fees from Shire Laboratories Inc., Addrenex Pharmaceuticals Inc., CoMentis Inc., the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute of Environmental Health Sciences, the National Institute of Neurological Disorders and Strokes, and the Environmental Protection Agency.

Dr Floyd Sallee receives funding through consultancies from AstraZeneca, Otsuka, P2D Inc., Sepracor and Shire Pharmaceuticals, Inc. and honoraria from Shire Pharmaceuticals, Inc. He has stock ownership and is a member of the board of directors for P2D Inc. Dr Sallee has given expert testimony on behalf of Johnson & Johnson and Sun Pharma. He has a patent pending on behalf of the University of Cincinnati and is a founder of Satiety Solutions, LLC.

Dr Frank A. López is a consultant for Celltech, Cephalon, Eli Lilly, New River, Novartis and Shire Pharmaceuticals, Inc. He has received honoraria from Novartis and Shire Pharmaceuticals, Inc. He has received grants from Bristol-Myers Squibb, Celltech, Cephalon, New River, Novartis, Pfizer and Shire Pharmaceuticals Inc.

Andrew Lyne is a full-time employee of Shire Pharmaceutical Development Ltd, Basingstoke, UK.

Dr Gerald Tremblay is a full-time employee of Shire Development Inc., Wayne, PA, USA.

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Authors and Affiliations

  1. Department of Psychiatry, Division of Child and Adolescent Psychiatry, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, Connecticut, 06030-1410, USA

    Daniel F. Connor (Lockean Distinguished Professor of Psychiatry and Division Chief of Child and Adolescent Psychiatry, MC 1410)

  2. University Hospitals Case Medical Center, Cleveland, Ohio, USA

    Robert L. Findling

  3. Duke University Medical Center, Durham, North Carolina, USA

    Scott H. Kollins

  4. Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA

    Floyd Sallee

  5. Children’s Developmental Center, Winter Park, Florida, USA

    Frank A. López

  6. Shire Pharmaceutical Development Ltd, Chineham, UK

    Andrew Lyne

  7. Shire Development Inc., Wayne, Pennsylvania, USA

    Gerald Tremblay

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  1. Daniel F. Connor
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Correspondence to Daniel F. Connor.

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Connor, D.F., Findling, R.L., Kollins, S.H. et al. Effects of Guanfacine Extended Release on Oppositional Symptoms in Children Aged 6–12 Years with Attention-Deficit Hyperactivity Disorder and Oppositional Symptoms. CNS Drugs 24, 755–768 (2010). https://doi.org/10.2165/11537790-000000000-00000

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