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Phase III GXR study shows improvement in core symptoms of ADHD

Results published in demonstrate the efficacy of the Attention-Deficit/Hyperactivity Disorder () medication, guanfacine hydrochloride extended release (). The Phase III study (SPD503-316) shows a significant reduction in ADHD core symptoms and global functioning in children and adolescents living with the disorder when treated with .1

The placebo controlled Phase III study assessed the efficacy and safety of once-daily dose-optimised GXR in the treatment of children and adolescents aged 6-17 years with moderate-to-severe symptoms of ADHD. Subjects were randomised to receive GXR 1-4 mg/day (children)/ 4-7 mg/day (adolescents), placebo or atomoxetine (ATX) 10-100 mg/day as a reference arm to validate the study design.1 As ATX was included as a reference arm, no comparisons can be made between ATX and GXR.

GXR is a long-acting, once-daily, non-stimulant medicine which contains the active substance guanfacine hydrochloride – a selective alpha2A-adrenergic receptor agonist.2 It is currently approved for use in the US (as INTUNIV®) as a monotherapy and adjunctively with a stimulant medication for ADHD in children/adolescents aged 6-17.3 In Canada (as INTUNIV XR™) it is approved for the same indications in children/adolescents aged 6-12.4 In March 2014, Shire submitted the Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for the monotherapy treatment of ADHD in children/adolescents aged 6-17 years.

In this study, GXR (3.6 mg mean dose) was shown to significantly improve ADHD core symptoms compared with placebo [change in ADHD-RS-IV total score was -23.9 vs -15, respectively; p<0.001-. Similarly, ATX (42.1 mg mean dose) significantly improved ADHD-RS-IV total score compared with placebo [-18.8 vs -15; p=0.017], further validating the study design.1 ATX was included as a reference arm and therefore no comparison can be made between itself and GXR.

A key secondary endpoint was the change from baseline to endpoint on the Global Clinical Impression-Improvement (CGI-I) scale. The proportion of subjects achieving a CGI-I scale score of “much improved” or “very much improved” was 67.9% and 56.3% in the GXR and ATX groups, respectively, compared with 44.1% in the placebo group [p<0.001 and p=0.024 in the GXR and ATX groups, respectively].*1

The proportion of subjects experiencing treatment-emergent adverse events (TEAEs) were 77.2%, 67.9% and 65.8% in the GXR, ATX and placebo groups, respectively.* The majority of reported TEAEs were of mild or moderate intensity, and the most commonly reported TEAEs in the GXR group were headache, fatigue and somnolence.1

“We are pleased to report that GXR has shown improved outcomes compared with placebo for children and adolescents living with ADHD. These data increase the body of evidence on the safety and efficacy of GXR,” said Tamara Kiechle, Shire Global Medical Lead Neuroscience. “Each individual’s experience of ADHD is different, and Shire believes the individual needs of those living with ADHD must be considered, allowing for tailored therapy and appropriate management.”

About the SPD503-316 study1

  • A Phase III, double-blind, randomised, multicentre, parallel-group, placebo- and active-reference, dose-optimisation study
  • Male and female children/adolescents (6-17 years old [n=272]) with a diagnosis of ADHD of at least moderate severity, as defined by a baseline ADHD-RS-IV with a total score of 32 or higher and a minimum Clinical Global Impression-Severity (CGI-S) score of 4, were enrolled into the study
  • Subjects who took between 80% and 120% of their total medication were considered to be compliant with the study protocol
  • Children participated in the study for 10 weeks and adolescents for 13 weeks
  • Conducted in 58 centres across 11 European countries (Austria, France, Germany, Ireland, Italy, Poland, Romania, Spain, Sweden, the UK and Ukraine), the USA and Canada between January 2011 and May 2013
  • For more information on the SPD503-316 study, please refer to the online manuscript or ClinicalTrials.gov (http://1.usa.gov/1DUr1Zz)

Further SPD503-316 secondary endpoints1

  • Once-daily GXR significantly improved functioning compared with placebo
  • The placebo-adjusted difference in least squares (LS) mean change from baseline in the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) learning and school domain for GXR was -0.22 [p=0.003] and for WFIRS-P family domain was -0.21 [p=0.006]. The corresponding values for ATX were -0.16 [p=0.026] and -0.09 [p=0.242] respectively*
  • The placebo-adjusted difference in LS mean change from baseline in WFIRS-P global score for GXR was -0.17 [ p<0.001] and for ATX was -0.10 [ p=0.048]*
  • Once-daily GXR significantly improved individual ADHD equally well compared with placebo
    • The placebo-adjusted difference in LS mean change from baseline in ADHD-RS-IV hyperactivity/impulsivity subscale score for GXR was -4.8 [p<0.001] and a similar change was seen for the inattention subscale score -4.1 [p<0.001]. The corresponding values for ATX were -2.0 [p=0.014] and -1.6 [ p=0.053]*
  • Compared with placebo, the difference in the percentage of patients with normal/borderline CGI-S for GXR was 12.3% [p=0.004] and 0.7% [p=0.69] for ATX*
  • Source

    1. Hervas A, et al. Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, controlled, phase III trial. Primary Manuscript. Eur Neuropsychopharm 2014; 24:1861-1872

    2. Uhlén S & Wikberg JES. Delineation of rat kidney ?-2A and ?-2B-adrenoceptors with [3H]RX821002 radiology and binding: Computer modelling reveals that guanfacine is an ?-2A-selective compound. Eur J Pharmacol 1991; 202:235-243.

    3. Intuniv US Prescribing Information 2013.

    4. Intuniv XR Product Monograph 2013.

    Source: Shire