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Lisdexamfetamine Dimesylate Demonstrates Significantly Faster Response, Greater Reductions Of Core ADHD Symptoms Than Atomoxetine In Study

Shire plc (LSE: SHP, NASDAQ: SHPG) presents scientific data comparing the efficacy and safety of the Attention Deficit/Hyperactivity Disorder (ADHD) treatments lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) at the 4th World Congress on ADHD, Milan, Italy. The study (SPD489-317) is the first head-to-head trial in children and adolescents with at least moderately symptomatic ADHD and an inadequate response to previous methylphenidate therapy.

LDX is a once-daily stimulant and is indicated as part of a comprehensive treatment programme for ADHD in children aged 6 years of age and over when response to previous methylphenidate treatment is considered clinically inadequate.3 ATX is a once-daily nonstimulant and is indicated for the treatment of ADHD in children 6 years and older and in adolescents as part of a comprehensive treatment programme.4

The primary efficacy outcome was the time (in days) to first clinical response, as defined using the Clinical Global Impressions-Improvement (CGI-I) clinical ratings score (global measure of clinical and functional improvement) of ‘much improved’ or ‘very much improved’.1 Median time to first clinical response was significantly faster for patients receiving LDX (12 days [95% confidence interval: 8.0, 16.0]) than for ATX (21 days [15.0, 23.0]) (p = 0.001).1

The secondary efficacy outcome highlighted that, at each weekly visit, a significantly greater proportion of patients had responded to treatment with LDX compared with ATX.2 Additionally, LDX was also associated with significantly greater reductions in core ADHD symptoms than ATX treatment (based on ADHD-RS-IV total score and inattentiveness and hyperactivity/impulsivity subscale scores). By the end of the study, the difference between LDX and ATX in least squares mean change from baseline was: ADHD-RS-IV total scores, -6.5 (95% confidence interval, -9.3, -3.6); inattentiveness subscale scores, -3.4 (-4.9, -1.8); hyperactivity/impulsivity subscale scores, -3.2 (-4.6, -1.7).2

“In general, every child or adolescent with ADHD is different and will vary in his or her response to available treatments. As the first head-to-head active controlled trial with LDX in this patient population, these data reinforce the role of LDX as a new treatment option to help children and adolescents who have had an inadequate response to methylphenidate therapy to manage their ADHD symptoms effectively,” said Ralf W. Dittmann, MSc, MD, PhD (Paediatric Psychopharmacology, CIMH Mannheim, Germany), principal study investigator.

The study showed that both LDX and ATX safety results were generally consistent with the known safety profiles from other previous clinical trials.1 A similar proportion of patients in both treatment groups reported treatment-emergent adverse events (TEAEs) (71.9% for LDX vs. 70.9% for ATX).1 The most common TEAEs for LDX were decreased appetite (25.8%), decreased weight (21.9%) and headache (13.3%).1 The most common TEAEs for ATX were headache (16.4%), nausea (15.7%) and somnolence (11.9%).1 Few patients in either study group experienced a TEAE leading to discontinuation of the study drug (6.3% for LDX vs. 7.5% for ATX).1 Adverse events observed with LDX reflected side effects commonly associated with stimulant medications.3

The patient population in the study comprised children and adolescents aged 6-17 years old with at least moderately symptomatic ADHD and who previously had an inadequate response to methylphenidate therapy.1 The criteria for assessing a clinically inadequate response to treatment were at the discretion of the treating physician. In this study they included, but were not limited to, one or more of the following:1

  • the presence of some residual ADHD symptoms
  • an inadequate duration of action
  • variable symptom control
  • if, based on the investigator judgement, the patient may benefit clinically from an alternative to methylphenidate.

About Study SPD489-317

  • SPD489-317 was a phase 3b, 9-week, double blind, randomised, active-controlled, parallel-group study comparing the efficacy and safety of LDX and ATX1

  • The study comprised a 4-week dose-optimisation phase, a 5-week dose-maintenance phase and a 1-week washout and follow-up period1
  • During optimisation, doses were adjusted until an acceptable response was achieved (defined as a ≥ 30% reduction from baseline in the ADHD-RS-IV total score and a CGI-I score of 1 or 2 with tolerable side effects)1
  • In total, 267 patients were randomised (1:1) to an optimised daily-dose of LDX (30, 50 or 70 mg) or ATX (patients < 70 kg, 0.5-1.2 mg/kg with total daily dose not to exceed 1.4 mg/kg; patients ≥ 70 kg, 40, 80 or 100 mg)1
  • Of 267 patients randomised, 200 completed the study (LDX, n=99; ATX = n101)
  • The safety population was defined as all patients who were randomised and received ≥ 1 dose of study drug (LDX, n=128; ATX, n=134)1

  • The primary efficacy outcome was the time (in days) to first clinical response, as defined using a CGI-I clinical ratings score (a 7-point global measure of clinical and functional improvement) of much improved (classified as a score of 1) or very much improved (classified as a score of 2)1

  • The secondary efficacy outcome was the proportion of patients who responded to treatment (those with a CGI-I score of either 1 or 2) at each study visit2
    - Changes from baseline in ADHD-RS-IV total (a well recognised clinical rating score designed to assess response to treatment in terms of the core symptoms of ADHD) and subscale scores were also secondary efficacy outcomes2

  • Tolerability and safety were assessed by monitoring TEAEs, weight, vital signs and electrocardiogram (ECG) parameters1

About LDX

LDX is a long-acting, once daily medication. It is indicated as part of a comprehensive treatment programme for ADHD in children 6 years of age and over when response to previous methylphenidate treatment is considered clinically inadequate.3 LDX is not indicated in all children with ADHD and the decision to use the drug must be based on a very thorough assessment of the severity and chronicity of the child’s symptoms in relation to the child’s age and potential for abuse, misuse or diversion.

LDX has been available in the UK since March 2013, in Denmark since April 2013 and Germany since June 2013 (brand name Elvanse®). It has also been available in the USA since 2007 and Canada since 2010 (brand name Vyvanse®), and in Brazil since 2011 (brand name Venvanse®). LDX has received marketing authorisation (but is not yet available) in Ireland (brand name Tyvense®) and Norway (brand name Elvanse®).

Safety Statement3

Please consult the Elvanse Summary of Product Characteristics (SPC) before prescribing, particularly in relation to abuse and dependence, pre-treatment evaluation and ongoing monitoring, cardiovascular adverse events, psychiatric adverse events, tics, long-term suppression of growth (height and weight), seizures, visual disturbance, prescribing and dispensing, and use with other sympathomimetic drugs.

Adverse reactions observed with LDX treatment mainly reflect side effects commonly associated with stimulant use. Very common adverse reactions include decreased appetite, insomnia, headache, decreased weight and upper abdominal pain.

Nonmedical Use3 Stimulants including LDX have a potential for abuse, misuse, dependence or diversion for non-therapeutic uses that physicians should consider when prescribing this product. Stimulants should be prescribed cautiously to patients with a history of substance abuse or dependence.

About ADHD

ADHD is a common psychiatric disorder in children and adolescents,5,6,7 and is recognised by the World Health Organization (WHO).8 While the exact origin of ADHD is not understood, it is thought to result from complex interactions between genetic and environmental factors.10,12-13 Environmental factors which may increase the risk of developing ADHD include low birth weight/prematurity and maternal smoking and/or alcohol use during pregnancy.13,14

Source

1. Dittman R, et al. A Head-to-Head, Double-Blind, Randomised, Phase 3b Trial Comparing the Efficacy and Safety of Lisdexamfetamine Dimesylate with Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Conference poster, presented at 4th World Congress on ADHD, 6-9 June 2013, Milan, Italy.

2. Dittman R, et al. A Head-to-Head, Double-Blind, Randomised, Phase 3b Trial Comparing the Efficacy of Lisdexamfetamine Dimesylate and Atomoxetine on Core Symptoms in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Conference poster, presented at 4th World Congress on ADHD, 6-9 June 2013, Milan, Italy.

3. Elvanse®, UK Summary of Product Characteristics (SPC), Shire Pharmaceuticals Limited 2013.

4. Strattera®, UK Summary of Product Characteristics (SPC), Eli Lilly and Company Limited 2012.

5. Pliszka S & the AACAP Work Group on Quality Issues. Practice Parameter for the Assessment and Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry 2007; 46(7):894-921.

6. Bloom B, et al. Summary Health Statistics for U.S. Children: National Health Interview Survey, 2010. Vital Health Stat 10. 2011; (250):1-80.

7. McCarthy S, et al. The Epidemiology of Pharmacologically Treated Attention Deficit Hyperactivity Disorder (ADHD) in Children, Adolescents and Adults in UK Primary Care. BMC Pediatr. 2012; 12:78.

8. International Classification of Diseases, 10th ed., (ICD-10). World Health Organization 2007: Chapter 5,F90. http://apps.who.int/classifications/icd10/browse/2010/en#/F90-F98. Last accessed May 2013.

9. Dickstein SG, et al. The Neural Correlates of Attention Deficit Hyperactivity Disorder: An ALE Meta-Analysis. J Child Psychol Psychiatry 2006; 47:1051-1062.

10. Valera EM, et al. Meta-Analysis of Structural Imaging Findings in Attention-Deficit/Hyperactivity Disorder. Biol Psychiatry 2007; 61:1369.

11. Volkow, et al. Evaluating Dopamine Reward Pathway in ADHD. JAMA 2009; 302(10):1084-1091.

12. Gizer IR, et al. Candidate Gene Studies of ADHD: A Meta-Analytic Review. Hum Genet 2009; 126:51-90.

13. Sagiv SK, et al. Pre- and Postnatal Risk Factors for ADHD in a Nonclinical Pediatric Population. J Atten Disord 2012; 17:47-57.

14. Heinonen K,Räikkönen K, Pesonen AK, et al. Behavioural symptoms of attention deficit/hyperactivity disorder in preterm and term children born small and appropriate for gestational age: a longitudinal study. BMC Pediatr 2010; 10: 91.

* Based on ADHD-RS-IV total score and inattentiveness and hyperactivity/impulsivity subscale scores

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