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Cited by 88Attention Deficit Hyperactivity DisorderPharmaceutical studies and practicesPharmacology and Obesity Treatment

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

Open access
Dittmann, Ralf W., Cardo, Esther, Nagy, Peter, Anderson, Colleen S., Bloomfield, Ralph, Caballero, Beatriz, Higgins, Nicholas, Hodgkins, Paul +3 more·2013·CNS Drugs
DOI 10.1007/s40263-013-0104-8PMC PMC3835923
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Abstract

OBJECTIVES: The aim of this study was to compare the efficacy and safety of the prodrug psychostimulant lisdexamfetamine dimesylate (LDX) and the non-stimulant noradrenergic compound atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had previously responded inadequately to methylphenidate (MPH). METHODS: This 9-week, head-to-head, randomized, double-blind, active-controlled study (SPD489-317; ClinicalTrials.gov NCT01106430) enrolled patients (aged 6-17 years) with at least moderately symptomatic ADHD and an inadequate response to previous MPH therapy. Patients were randomized (1:1) to an optimized 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). The primary efficacy outcome was time (days) to first clinical response. Clinical response was defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved). Secondary efficacy outcomes included the proportion of responders at each study visit and the change from baseline in ADHD Rating Scale (ADHD-RS-IV) and CGI-Severity scores. Tolerability and safety were assessed by monitoring treatment-emergent adverse events (TEAEs), height and weight, vital signs and electrocardiogram parameters. Endpoint was defined as the last post-baseline, on-treatment visit with a valid assessment. RESULTS: Of 267 patients randomized (LDX, n = 133; ATX, n = 134), 200 (74.9%) completed the study. The median time to first clinical response [95% confidence interval (CI)] was significantly shorter for patients receiving LDX [12.0 days (8.0-16.0)] than for those receiving ATX [21.0 days (15.0-23.0)] (p = 0.001). By week 9, 81.7% (95% CI 75.0-88.5) of patients receiving LDX had responded to treatment compared with 63.6% (95% CI 55.4-71.8) of those receiving ATX (p = 0.001). Also by week 9, the difference between LDX and ATX in least-squares mean change from baseline (95% CI) was significant in favour of LDX for the ADHD-RS-IV total score [-6.5 (-9.3 to -3.6); p < 0.001; effect size 0.56], inattentiveness subscale score [-3.4 (-4.9 to -1.8); p < 0.001; effect size 0.53] and the hyperactivity/impulsivity subscale score [-3.2 (-4.6 to -1.7); p < 0.001; effect size 0.53]. TEAEs were reported by 71.9 and 70.9% of patients receiving LDX and ATX, respectively. At endpoint, both treatments were associated with mean (standard deviation) increases in systolic blood pressure [LDX, +0.7 mmHg (9.08); ATX, +0.6 mmHg (7.96)], diastolic blood pressure [LDX, +0.1 mmHg (8.33); ATX, +1.3 mmHg (8.24)] and pulse rate [LDX, +3.6 bpm (10.49); ATX, +3.7 bpm (10.75)], and decreases in weight [LDX, -1.30 kg (1.806); ATX, -0.15 kg (1.434)]. CONCLUSIONS: LDX was associated with a faster and more robust treatment response than ATX in children and adolescents with at least moderately symptomatic ADHD who had previously responded inadequately to MPH. Both treatments displayed safety profiles consistent with findings from previous clinical trials.

AI snapshot

Written from the paper’s full text.

TL;DR

In children and adolescents with ADHD and an inadequate prior response to methylphenidate, lisdexamfetamine dimesylate (LDX) produced a faster and greater treatment response than atomoxetine (ATX) over 9 weeks. Both drugs had broadly similar tolerability, with no serious treatment-emergent adverse events or deaths reported.

Key findings

  • Median time to first clinical response was significantly shorter with LDX [12.0 days (95 % CI 8.0–16.0)] than ATX [21.0 days (95 % CI 15.0–23.0)] (p = 0.001).
  • By week 9, 81.7 % (95 % CI 75.0–88.5) of LDX patients had responded versus 63.6 % (95 % CI 55.4–71.8) of ATX patients (p = 0.001).
  • LDX showed greater improvement in ADHD-RS-IV total score: difference in least-squares mean change from baseline −6.5 (95 % CI −9.3 to −3.6), p < 0.001, effect size 0.56; inattentiveness −3.4 (95 % CI −4.9 to −1.8), effect size 0.53; hyperactivity/impulsivity −3.2 (95 % CI −4.6 to −1.7), effect size 0.53.
  • TEAEs occurred in 71.9 % of LDX and 70.9 % of ATX patients; no deaths or serious TEAEs were reported. Mean weight change was −1.30 kg with LDX versus −0.15 kg with ATX, and ≥7 % weight reduction occurred in 26.8 % versus 4.5 %, respectively.

Methods

  • 9-week, head-to-head, randomized, double-blind, active-controlled, parallel-group phase IIIb study (SPD489-317; NCT01106430) in patients aged 6–17 years with at least moderately symptomatic ADHD and inadequate response to previous MPH therapy; 267 patients randomized 1:1 to optimized LDX or ATX across 51 sites in Canada, the USA, and seven European countries.
  • Primary efficacy outcome was time to first clinical response (CGI-I score of 1 or 2); secondary outcomes included responder proportion at each visit, CGI-S change, and ADHD-RS-IV total/subscale changes. Safety assessments included TEAEs, weight, vital signs, and ECG parameters.
  • Time to response was analyzed by Kaplan–Meier estimates and a Peto–Peto–Prentice–Wilcoxon test stratified by country; responder proportions used Cochran–Mantel–Haenszel tests, and ADHD-RS-IV changes used ANCOVA with LOCF.

Limitations

  • The paper states that it is unclear whether the specific population, defined by detailed inclusion/exclusion criteria related to prior MPH response, would have favored one treatment arm over the other.
  • The paper states that the 9-week duration and once-daily ATX dosing may not have elicited the maximum potential treatment benefit of ATX.
  • Evident from the text: visit 4 ECG data were available only for a subset because the ECG was added by protocol amendment (LDX, n = 76; ATX, n = 83), limiting ECG comparisons; also, one patient randomized to ATX received LDX due to a dispensing error, handled by intent-to-treat in the full analysis set but counted in the LDX group in the safety population.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s40263-013-0104-8

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    By visit 9, the mean (SD) ADHD-RS-IV total score was 16.3 (11.16) in the LDX group and 22.5 (13.21) in the ATX group.

    “by visit 9, the mean (SD) ADHD-RS-IV total score was 16.3 (11.16) in the LDX group and 22.5 (13.21) in the ATX group.”
    Quote in the paperSubstantial claim
  • Findingown data

    By visit 9, the difference between LDX and ATX in LS mean change from baseline in ADHD-RS-IV total score was −6.5 (95% CI −9.3 to −3.6), with an effect size of 0.56.

    “By visit 9, the difference between LDX and ATX in LS mean change (95 % CI) from baseline was −6.5 (−9.3 to −3.6), with an effect size of 0.56.”
    Quote in the paperSubstantial claim
  • Findingown data

    The mean (SD) change from baseline in ADHD-RS-IV total score by visit 9 was −26.3 (11.94) in the LDX group and −19.4 (12.82) in the ATX group.

    “The mean (SD) change from baseline in ADHD-RS-IV total score by visit 9 was −26.3 (11.94) in the LDX group and −19.4 (12.82) in the ATX group.”
    Quote in the paperSubstantial claim
  • Findingown data

    LDX treatment was associated with significantly greater reductions from baseline in ADHD-RS-IV total score than ATX treatment (p < 0.001 for each study visit).

    “However, LDX treatment was associated with significantly greater reductions from baseline than ATX treatment (p < 0.001 for each study visit) (Fig. 4).”
    Quote in the paperSubstantial claim
  • Findingown data

    By week 9, the difference between LDX and ATX in least-squares mean change from baseline in the ADHD-RS-IV total score was significant in favour of LDX: −6.5 (95% CI −9.3 to −3.6), p < 0.001, effect size 0.56.

    “Also by week 9, the difference between LDX and ATX in least-squares mean change from baseline (95 % CI) was significant in favour of LDX for the ADHD-RS-IV total score [−6.5 (−9.3 to −3.6); p < 0.001; effect size 0.56], inattentiveness subscale score [−3.4 (−4.9 to −1.8); p < 0.001; effect size 0.53] and the hyperactivity/impulsivity subscale score [−3.2 (−4.6 to −1.7); p < 0.001; effect size 0.53”
    Quote in the paperSubstantial claim
  • May combine two claims. 20
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 17

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    By visit 9, the difference (LDX minus ATX) in LS mean change from baseline for the hyperactivity/impulsivity subscale was −3.2 (95% CI −4.6 to −1.7), effect size 0.53, statistically significant in favour of LDX (p < 0.001).

    “and the hyperactivity/impulsivity subscale [−3.2 (−4.6 to −1.7); effect size 0.53].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At endpoint, both treatments were associated with mean increases in systolic blood pressure (LDX +0.7 mmHg, ATX +0.6 mmHg), diastolic blood pressure (LDX +0.1 mmHg, ATX +1.3 mmHg) and pulse rate (LDX +3.6 bpm, ATX +3.7 bpm), and decreases in weight (LDX −1.30 kg, ATX −0.15 kg).

    “At endpoint, both treatments were associated with mean (standard deviation) increases in systolic blood pressure [LDX, +0.7 mmHg (9.08); ATX, +0.6 mmHg (7.96)], diastolic blood pressure [LDX, +0.1 mmHg (8.33); ATX, +1.3 mmHg (8.24)] and pulse rate [LDX, +3.6 bpm (10.49); ATX, +3.7 bpm (10.75)], and decreases in weight [LDX, −1.30 kg (1.806); ATX, −0.15 kg (1.434)].”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    The mean optimal dose during the dose-maintenance phase was 52.5 mg/day (SD 16.10) for LDX and 40.2 mg/day (SD 20.05) for ATX.

    “The mean optimal dose (which was the dose that was dispensed at visit 4) for patients who received LDX during the dose-maintenance phase was 52.5 mg/day [standard deviation (SD): 16.10]; 28/128 (21.9 %) received 30 mg/day, 36/128 (28.1 %) received 50 mg/day and 41/128 (32.0 %) received 70 mg/day.”
    • Also stated in: § Dose Optimization · plain
      “The mean optimal dose for patients who received ATX was 40.2 mg/day (SD: 20.05); 15/134 (11.2 %) and 95/134 (70.9 %) received a daily dose of 0.5 mg/kg and 1.2 mg/kg, respectively (patients weighing <70 kg; n = 127), and 2/134 (1.5 %), 1/134 (0.7 %) and 4/134 (3.0 %) received 40, 80 and 100 mg/day, respectively (patients weighing ≥70 kg; n = 7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The most commonly reported reasons for study discontinuation were adverse events (6.0%) and withdrawal by patient (6.0%) for LDX, and lack of efficacy (9.7%) and adverse events (7.5%) for ATX.

    “The two most commonly reported reasons for study discontinuation for patients receiving LDX were adverse events (8/133 patients; 6.0 %) and withdrawal by patient (8/133; 6.0 %), and for patients receiving ATX they were lack of efficacy (13/134 patients; 9.7 %) and adverse events (10/134; 7.5 %).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Treatment-emergent adverse events were reported by 71.9% of patients receiving LDX and 70.9% of patients receiving ATX.

    “TEAEs were reported by 71.9 and 70.9 % of patients receiving LDX and ATX, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No deaths or serious TEAEs were reported.

    “no deaths or serious TEAEs were reported.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At endpoint, shifts to lower BMI categories were reported for 19/127 patients receiving LDX and 15/132 on ATX, whereas 4/127 patients on LDX and 7/132 on ATX had shifted to a higher BMI category.

    “At endpoint, shifts to lower BMI categories were reported for 19/127 patients receiving LDX and 15/132 on ATX, whereas 4/127 patients on LDX and 7/132 on ATX had shifted to a higher BMI category.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Five patients moved into the underweight category (LDX n=4; ATX n=1); all five were in the healthy weight (low) category at baseline and all completed the study.

    “Five patients moved into the underweight category (LDX, n = 4; ATX, n = 1); all five were in the healthy weight (low) category at baseline and all completed the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Multiple randomized, double-blind, placebo-controlled trials have shown LDX to be an effective treatment for children, adolescents and adults with ADHD, with a tolerability and safety profile consistent with the known effects of psychostimulant therapy.

    “Multiple randomized, double-blind, placebo-controlled trials have shown LDX to be an effective treatment for children, adolescents and adults with ADHD, with a tolerability and safety profile consistent with the known effects of psychostimulant therapy [9–15].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [9] 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):1364–73. source

      Not checked in the free run.

    • cites [10] 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):970–6. source

      Not checked in the free run.

    • cites [11] 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):450–63. source

      Not checked in the free run.

    • cites [12] 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;. doi: 10.1016/j.euroneuro.2012.11.012 .

      Not checked in the free run.

    • cites [13] 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. source

      Not checked in the free run.

    • cites [14] 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. source

      Not checked in the free run.

    • cites [15] 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. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All study drugs were over-encapsulated so that they appeared identical.

    “All study drugs were over-encapsulated so they appeared identical.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Randomization of patients was stratified by country.

    “Randomization of patients was stratified by country, and an automated interactive response system was used to generate the random (concealed) allocation sequence and assign participants to study treatments; patients, caregivers and investigators were blinded to the treatment allocation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    An automated interactive response system was used to generate the random (concealed) allocation sequence and assign participants to study treatments.

    “Randomization of patients was stratified by country, and an automated interactive response system was used to generate the random (concealed) allocation sequence and assign participants to study treatments; patients, caregivers and investigators were blinded to the treatment allocation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The study was conducted in accordance with current applicable regulations, the International Conference on Harmonization of Good Clinical Practice and local ethical and legal requirements.

    “The study was conducted in accordance with current applicable regulations, the International Conference on Harmonization of Good Clinical Practice [16] and local ethical and legal requirements.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] ICH harmonised tripartite guideline: guideline for good clinical practice E6(R1). Geneva: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study was approved by an independent ethics committee/institutional review board and regulatory agency in each centre.

    “This double-blind, randomized, active-controlled, parallel-group study was approved by an independent ethics committee/institutional review board and regulatory agency in each centre (as appropriate).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In Europe, MPH is generally considered to be the first-line medication for ADHD.

    “In Europe, short- and long-acting MPH formulations are widely available, and MPH is generally considered to be the first-line medication for ADHD [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] 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, UK; 2009. http://wwwniceorguk/nicemedia/live/12061/42060/42060pdf . Accessed 04 April 2013.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Patients, caregivers and investigators were blinded to the treatment allocation.

    “Randomization of patients was stratified by country, and an automated interactive response system was used to generate the random (concealed) allocation sequence and assign participants to study treatments; patients, caregivers and investigators were blinded to the treatment allocation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Allowing for a 20% discontinuation rate, approximately 262 patients (131 per treatment group) were required to detect a difference in time to first clinical response between the treatment groups with a power of 85%.

    “Allowing for a 20 % discontinuation rate, approximately 262 patients (131 in each treatment group) were required to detect a difference in time to first clinical response between the treatment groups with a power of 85 %.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The noradrenaline reuptake inhibitor atomoxetine is approved in North America and several European countries for ADHD.

    “Of non-stimulant ADHD medications, the noradrenaline reuptake inhibitor atomoxetine (ATX) is approved in North America and several European countries [5], and the α2-adrenergic agonists clonidine and guanfacine are licensed in the USA but not Europe [6, 7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] 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;5:215–26.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several studies have demonstrated that, although the overall response to MPH and amfetamine is similar, the response to each varies among individual patients, and non-response to one class of psychostimulant does not predict non-response to a second.

    “In addition, several studies have demonstrated that, although the overall response to MPH and amfetamine is similar, the response to each varies among individual patients, and non-response to one class of psychostimulant does not predict non-response to a second [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Hodgkins P, Shaw M, Coghill D, Hechtman L. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry. 2012;21(9):477–92. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In addition to a faster onset of efficacy, the proportions of patients who responded to treatment (CGI-I of 1 or 2) or improved by at least one CGI-S category, and the improvements in mean ADHD-RS-IV total and subscale scores, all indicated that there was a greater reduction of symptoms in patients receiving LDX than ATX by visit 9.

    “In addition to a faster onset of efficacy, the proportions of patients who responded to treatment (CGI-I of 1 or 2) or improved by at least one CGI-S category, and the improvements in mean ADHD-RS-IV total and subscale scores, all indicated that there was a greater reduction of symptoms in patients receiving LDX than ATX by visit 9.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A meta-analysis of 32 clinical trials and a total of 15 ADHD medications supports these observations, concluding that both short- and long-acting psychostimulants were significantly more effective than non-stimulants.

    “A meta-analysis of 32 clinical trials and a total of 15 ADHD medications supports these observations, concluding that both short- and long-acting psychostimulants were significantly more effective than non-stimulants [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Faraone SV. Using meta-analysis to compare the efficacy of medications for attention-deficit/hyperactivity disorder in youths. P T. 2009;34(12):678–94.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The dose-optimized design of this study is likely to have had some influence on the time to first clinical response in both treatment arms.

    “The dose-optimized design of this study is likely to have had some influence on the time to first clinical response in both treatment arms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    As the dose-titration schedules for both treatments followed current clinical guidelines, the times to treatment response observed in this study are relevant to clinical practice.

    “Importantly, however, as the dose-titration schedules for both treatments followed current clinical guidelines, the times to treatment response observed in this study are relevant to clinical practice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Based on ADHD-RS-IV total scores, effect sizes relative to placebo were 0.75 in pre-treated patients and 0.97 in patients who had not received previous psychostimulant treatment (interaction with treatment, p = 0.607).

    “Based on ADHD-RS-IV total scores, effect sizes relative to placebo were 0.75 in pre-treated patients and 0.97 in patients who had not received previous psychostimulant treatment (interaction with treatment, p = 0.607) [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Wehmeier PM, Dittmann RW, Banaschewski T, Schacht A. Does stimulant pretreatment modify atomoxetine effects on core symptoms of ADHD in children assessed by quantitative measurement technology? J Atten Disord. 2012. doi: 108705471244518410.1177/1087054712445184 .

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The observed shorter time to first clinical response (CGI-I of 1 or 2) for LDX relative to ATX was not unexpected as psychostimulants are generally recognized to produce immediate treatment effects.

    “The observed shorter time to first clinical response (CGI-I of 1 or 2) for LDX relative to ATX was not unexpected as psychostimulants are generally recognized to produce immediate treatment effects [3, 4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] American Academy of Pediatrics. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Process of care supplemental appendix. Pediatrics. 2011a;128:SI1-21. http://pediatrics.aappublications.org/content/suppl/2011/10/11/peds.2011-2654.DC1/zpe611117822p.pdf . Accessed 04 April 2013. source

      Not checked in the free run.

    • cites [4] 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, UK; 2009. http://wwwniceorguk/nicemedia/live/12061/42060/42060pdf . Accessed 04 April 2013.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    Overall, these data support the importance of alternative treatment options for patients who have not improved satisfactorily on their current ADHD medication.

    “Overall, these data support the importance of alternative treatment options for patients who have not improved satisfactorily on their current ADHD medication.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There is a clinical need for alternative treatment options for children and adolescents with ADHD who have an inadequate response to MPH therapy.

  • May combine two claims.

    Premisecitation

    Estimates of the time required for ATX to reach its maximum effect generally range from 4 to 6 weeks, although one study suggests that it may take as long as 12 weeks.

    “In contrast, estimates of the time required for ATX to reach its maximum effect generally range from 4 to 6 weeks [3, 4], although, one study suggests that it may take as long as 12 weeks [36].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] American Academy of Pediatrics. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Process of care supplemental appendix. Pediatrics. 2011a;128:SI1-21. http://pediatrics.aappublications.org/content/suppl/2011/10/11/peds.2011-2654.DC1/zpe611117822p.pdf . Accessed 04 April 2013. source

      Not checked in the free run.

    • cites [4] 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, UK; 2009. http://wwwniceorguk/nicemedia/live/12061/42060/42060pdf . Accessed 04 April 2013.

      Not checked in the free run.

    • cites [36] 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):112–9. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The efficacy of LDX was significantly faster to onset and greater than that of ATX.

    “However, the efficacy of LDX was significantly faster to onset and greater than that of ATX.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    It is unclear why there are discrepancies between studies with respect to the impact of previous psychostimulant treatment on ATX response, but potential differences in the baseline severity of symptoms between previously treated and treatment-naïve patients may confound outcomes.

    “It is unclear why there are discrepancies between studies with respect to the impact of previous psychostimulant treatment on ATX response, but potential differences in the baseline severity of symptoms between previously treated and treatment-naïve patients may confound outcomes [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Wehmeier PM, Dittmann RW, Banaschewski T, Schacht A. Does stimulant pretreatment modify atomoxetine effects on core symptoms of ADHD in children assessed by quantitative measurement technology? J Atten Disord. 2012. doi: 108705471244518410.1177/1087054712445184 .

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The strengths of this study include its head-to-head, randomized, double-blind, parallel-group, dose-optimized design, and the large number of patients enrolled from multiple countries.

    “The strengths of this study include its head-to-head, randomized, double-blind, parallel-group, dose-optimized design, and the large number of patients enrolled from multiple countries.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    These findings will aid clinicians when developing treatment plans for patients who have achieved unsatisfactory improvements on MPH therapy.

    “These findings will aid clinicians when developing treatment plans for patients who have achieved unsatisfactory improvements on MPH therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    A clinically relevant difference in efficacy was observed between LDX and ATX, with LDX associated with a significantly faster, and more robust, treatment response in children and adolescents with ADHD of at least moderate severity and a previous inadequate response to MPH therapy.

    “A clinically relevant difference in efficacy was observed between LDX and ATX, with LDX associated with a significantly faster, and more robust, treatment response in children and adolescents with ADHD of at least moderate severity and a previous inadequate response to MPH therapy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    ATX, dosed once daily in the present study, may require twice-daily dosing to achieve its maximum beneficial effect.

    “It should be noted, however, that ATX, dosed once daily in the present study, may require twice-daily dosing to achieve its maximum beneficial effect [38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] 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. source

      Not checked in the free run.

33 of 33

  • The paper relies on this without support.

    A direct head-to-head comparison of the efficacy and safety of LDX and ATX in children and adolescents with ADHD who had responded inadequately to previous MPH therapy was needed (i.e., such a comparison had not been adequately performed).

    “This study was designed to provide a direct comparison of the efficacy and safety of LDX and ATX in children and adolescents with ADHD who had experienced an inadequate response to previous MPH therapy.”

  • The paper relies on this without support.

    There is a clinical need for alternative treatment options for children and adolescents with ADHD who have an inadequate response to MPH therapy.

    “Overall, these data support the importance of alternative treatment options for patients who have not improved satisfactorily on their current ADHD medication.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Lower frequencies of insomnia and higher frequencies of somnolence with atomoxetine than with long-acting stimulants have been reported as TEAEs in randomized, double-blind, parallel-group efficacy studies.

    “Lower frequencies of insomnia and higher frequencies of somnolence with atomoxetine than with long-acting stimulants have been reported as TEAEs in randomized, double-blind, parallel-group efficacy studies (Dittmann et al. 2013; Newcorn et al. 2008).”

    From Associations of sleep disturbance with ADHD: implications for treatment (2015) · cites this paper as Dittmann et al. 2013

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ATX analysis group exceeds the number randomized to ATX

    Minor

    The full analysis set is defined as patients who were randomized and received at least one dose, with patients analyzed according to their randomized treatment. It therefore cannot contain 135 ATX patients when only 134 were randomized to ATX.

1 of 1

Cites

Flagged first, then by citations

3 of the 44 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Goodman DW, 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. Primary Psychiatry. 2010;17(3):9.

Cited by

Sorted by citations

Related

Authors
Dittmann, R. W., Cardo, E., Nagy, P., Anderson, C. S., Bloomfield, R., Caballero, B., Higgins, N., Hodgkins, P., Lyne, A., Civil, R., & Coghill, D.
Affiliations
  • Hospital Son Llatzer (ES)
  • Shire (United Kingdom) (GB)
  • Shire (Switzerland) (CH)
  • University of Dundee (GB)
ORCID
Coghill, David
Venue
CNS Drugs
Publisher
Springer Science and Business Media LLC
Published
2013-08-20
Volume
27
Issue
12
Pages
1081-1092
ISSN
  • 1172-7047 (ISSN-L)
  • 1179-1934
DOI
10.1007/s40263-013-0104-8
PMC
PMC3835923
OpenAlex
W2067898213
Cited by
88
References
44
Citations by year
2026: 2 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 11 · 2021: 1 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 10 · 2016: 9 · 2015: 10 · 2014: 16 · 2013: 1
FWCI
8.53
Type
journal article
Language
en
Open access
Licence
Locations
  • CNS Drugs (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
  • Docusalut (Conselleria de Salut i Consum del Govern de les Illes Balears) (submittedVersion, cc-by-nc)
  • Hispana (submittedVersion, cc-by-nc)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
Funders
  • Eli Lilly and Company
  • Pfizer
  • Bundesinstitut für Arzneimittel und Medizinprodukte
  • University of Oxford
  • European Commission (EU-FP7)
  • Deutsche Forschungsgemeinschaft
  • Bundesministerium für Bildung und Forschung
  • Vifor Pharma
  • National Institute of Mental Health
  • Cilag
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords
lisdexamfetamine dimesylate, atomoxetine, attention deficit hyperactivity disorder, children and adolescents, treatment-emergent adverse events, tolerability, ADHD Rating Scale-IV
MeSH terms
Atomoxetine Hydrochloride, Lisdexamfetamine Dimesylate, Adolescent, Attention Deficit Disorder with Hyperactivity, Blood Pressure, Child, Dextroamphetamine, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Propylamines, Treatment Outcome, Adrenergic Uptake Inhibitors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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