Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder

Ralf W Dittmann, Esther Cardo, Peter Nagy, Colleen S Anderson, Ben Adeyi, Beatriz Caballero, Paul Hodgkins, Richard Civil, David R Coghill, Ralf W Dittmann, Esther Cardo, Peter Nagy, Colleen S Anderson, Ben Adeyi, Beatriz Caballero, Paul Hodgkins, Richard Civil, David R Coghill

Abstract

Objectives: A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously.

Methods: In this 9-week, double-blind, active-controlled study, patients aged 6-17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients <70 kg: 0.5-1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients ≥70 kg: 40, 80 or 100 mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (≥25, ≥30 or ≥50 %) or a Clinical Global Impressions (CGI)-Improvement (CGI-I) score of 1 or 2 throughout weeks 4-9. CGI-Severity (CGI-S) scores were also assessed, as an indicator of remission.

Results: A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p < 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also significantly (p < 0.05) higher among LDX-treated patients (ADHD-RS-IV ≥25, 66.1 %; ADHD-RS-IV ≥30, 61.4 %; ADHD-RS-IV ≥50, 41.7 %; CGI-I, 52.0 %) than among ATX-treated individuals (ADHD-RS-IV ≥25, 51.1 %; ADHD-RS-IV ≥30, 47.4 %; ADHD-RS-IV ≥50, 23.7 %; CGI-I, 39.3 %). Finally, by week 9, 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI-S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI-S category.

Conclusions: Both LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI-S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies.

Figures

Fig. 1
Fig. 1
Proportion of patients classified as responders using definitions based on a (a) ≥25 %, (b) ≥30 % or (c) ≥50 % reduction in ADHD-RS-IV total score [14] from baseline (last observation carried forward). *p < 0.05, **p < 0.01, ***p < 0.001 LDX versus ATX (Cochran–Mantel–Haenszel test stratified by country). Error bars show 95 % confidence intervals. Percentages are based on the number of patients in each treatment group at the indicated study visit. ADHD-RS-IV Attention Deficit Hyperactivity Disorder Rating Scale IV, ATX atomoxetine, LDX lisdexamfetamine dimesylate
Fig. 2
Fig. 2
Patients classified as sustained responders (weeks 4–9) using definitions based on (a) ADHD-RS-IV total scores or (b) CGI–I scores. *p < 0.05, **p < 0.01 LDX versus ATX (Cochran–Mantel–Haenszel test stratified by country). Sustained response was defined as the indicated percentage reduction in ADHD-RS-IV total score from baseline or an improved CGI–I score (1 or 2) at all study visits in weeks 4–9. Error bars show 95 % confidence intervals. Data are based on non-responder imputation. ADHD-RS-IV Attention Deficit Hyperactivity Disorder Rating Scale IV, ATX atomoxetine, CGI–I Clinical Global Impressions–Improvement, LDX lisdexamfetamine dimesylate

References

    1. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164(6):942–948. doi: 10.1176/appi.ajp.164.6.942.
    1. Fayyad J, De Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, et al. Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry J Ment Sci. 2007;190:402–409. doi: 10.1192/bjp.bp.106.034389.
    1. Simon V, Czobor P, Balint S, Meszaros A, Bitter I. Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry J Ment Sci. 2009;194(3):204–211. doi: 10.1192/bjp.bp.107.048827.
    1. American Psychiatric Association. Attention-deficit and disruptive behavior disorders. In: Diagnostic and statistical manual of mental disorders. 4th ed, text revision. Washington: American Psychiatric Press Inc., 2000, p. 85–93.
    1. National Institute for Health and Clinical Excellence. Diagnosis and management of ADHD in children, young people and adults. National clinical practice guideline number 72. London: National Institute for Health and Clinical Excellence, 2009.
    1. Danckaerts M, Sonuga-Barke EJ, Banaschewski T, Buitelaar J, Dopfner M, Hollis C, et al. The quality of life of children with attention deficit/hyperactivity disorder: a systematic review. Eur Child Adolesc Psychiatry. 2010;19(2):83–105. doi: 10.1007/s00787-009-0046-3.
    1. Adler LA, Goodman DW, Kollins SH, Weisler RH, Krishnan S, Zhang Y, et al. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69(9):1364–1373. doi: 10.4088/JCP.v69n0903.
    1. Biederman J, Boellner SW, Childress A, Lopez FA, Krishnan S, Zhang Y. Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry. 2007;62(9):970–976. doi: 10.1016/j.biopsych.2007.04.015.
    1. Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther. 2007;29(3):450–463. doi: 10.1016/S0149-2918(07)80083-X.
    1. Coghill D, Banaschewski T, Lecendreux M, Soutullo C, Johnson M, Zuddas A, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder. Eur Neuropsychopharmacol. 2013
    1. Findling RL, Childress AC, Cutler AJ, Gasior M, Hamdani M, Ferreira-Cornwell MC, et al. Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50(4):395–405. doi: 10.1016/j.jaac.2011.01.007.
    1. Wigal SB, Kollins SH, Childress AC, Squires L. A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder. Child Adolesc Psychiatry Ment Health. 2009;3(1):17. doi: 10.1186/1753-2000-3-17.
    1. Wigal T, Brams M, Gasior M, Gao J, Squires L, Giblin J. Randomized, double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design. Behav Brain Funct. 2010;6:34. doi: 10.1186/1744-9081-6-34.
    1. DuPaul GJ, Power T, Anastopoulos A, Reid R. The ADHD Rating Scale-IV, checklist, norms, and clinical interpretation. New York: Guildford; 1998.
    1. Bussing R, Fernandez M, Harwood M, Wei H, Garvan CW, Eyberg SM, et al. Parent and teacher SNAP-IV ratings of attention deficit hyperactivity disorder symptoms: psychometric properties and normative ratings from a school district sample. Assessment. 2008;15(3):317–328. doi: 10.1177/1073191107313888.
    1. Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, et al. Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry. 2001;40(2):168–179. doi: 10.1097/00004583-200102000-00011.
    1. Conners CK, Sitarenios G, Parker JD, Epstein JN. The revised Conners’ Parent Rating Scale (CPRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol. 1998;26(4):257–268. doi: 10.1023/A:1022602400621.
    1. Collett BR, Ohan JL, Myers KM. Ten-year review of rating scales. V: scales assessing attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2003;42(9):1015–1037. doi: 10.1097/01.CHI.0000070245.24125.B6.
    1. European Medicines Agency. Guideline on the clinical investigation of medicinal products for the treatment of attention deficit hyperactivity disorder (ADHD). London: European Medicines Agency; 2010.
    1. Dittmann RW, Cardo E, Nagy P, Anderson CS, Bloomfield R, Caballero B, et al. Efficacy and safety of lisdexamfetamine dimesylate and atomoxetine in the treatment of attention-deficit/hyperactivity disorder: a head-to-head, randomized, double-blind, phase IIIb study. CNS Drugs. 2013;27(12):1081–92. doi:10.1007/s40263-013-0104-8.
    1. Newcorn JH, Sutton VK, Weiss MD, Sumner CR. Clinical responses to atomoxetine in attention-deficit/hyperactivity disorder: the integrated data exploratory analysis (IDEA) study. J Am Acad Child Adolesc Psychiatry. 2009;48(5):511–518. doi: 10.1097/CHI.0b013e31819c55b2.
    1. Dickson RA, Maki E, Gibbins C, Gutkin SW, Turgay A, Weiss MD. Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies. Child Adolesc Psychiatry Ment Health. 2011;5:14. doi: 10.1186/1753-2000-5-14.
    1. Ginsberg L, Katic A, Adeyi B, Dirks B, Babcock T, Lasser R, et al. Long-term treatment outcomes with lisdexamfetamine dimesylate for adults with attention-deficit/hyperactivity disorder stratified by baseline severity. Curr Med Res Opin. 2011;27(6):1097–1107. doi: 10.1185/03007995.2011.567256.
    1. Hazell PL, Kohn MR, Dickson R, Walton RJ, Granger RE, Wyk GW. Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis. J Atten Disord. 2011;15(8):674–683. doi: 10.1177/1087054710379737.
    1. Jain R, Babcock T, Burtea T, Dirks B, Adeyi B, Scheckner B, et al. Efficacy of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder previously treated with methylphenidate: a post hoc analysis. Child Adolesc Psychiatry Ment Health. 2011;5(1):35. doi: 10.1186/1753-2000-5-35.
    1. Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore RJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry. 2008;165(6):721–730. doi: 10.1176/appi.ajp.2007.05091676.
    1. Soutullo C, Banaschewski T, Lecendreux M, Johnson M, Zuddas A, Anderson C, et al. A post hoc comparison of the effects of lisdexamfetamine dimesylate and osmotic-release oral system methylphenidate on symptoms of attention-deficit hyperactivity disorder in children and adolescents. CNS Drugs. 2013;27(9):743–751. doi: 10.1007/s40263-013-0086-6.
    1. Eli Lilly and Company. Straterra® (atomoxetine): prescribing information. 2014. . Accessed 17 Jun 2014.
    1. Guy D. ECDEU assessment manual for psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH, Psychopharmacology Research Branch Division of Extramural Research Programs, 1976.
    1. Goodman D, Faraone SV, Adler LA, Dirks B, Hamdani M, Weisler R. Interpreting ADHD Rating Scale scores: linking ADHD Rating Scale scores and CGI levels in two randomized controlled trials of lisdexamfetamine dimesylate in ADHD. Prim Psychiatry. 2010;17(3):44–52.
    1. Faraone SV. Using meta-analysis to compare the efficacy of medications for attention-deficit/hyperactivity disorder in youths. P T. 2009;34(12):678–694.
    1. Michelson D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002;159(11):1896–1901. doi: 10.1176/appi.ajp.159.11.1896.
    1. Wilens TE, Newcorn JH, Kratochvil CJ, Gao H, Thomason CK, Rogers AK, et al. Long-term atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder. J Pediatr. 2006;149(1):112–119. doi: 10.1016/j.jpeds.2006.01.052.
    1. Hanwella R, Senanayake M, de Silva V. Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis. BMC Psychiatry. 2011;11:176. doi: 10.1186/1471-244X-11-176.
    1. Hammerness P, McCarthy K, Mancuso E, Gendron C, Geller D. Atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: a review. Neuropsychiatr Dis Treat. 2009;5:215–226.

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