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Cited by 112Attention Deficit Hyperactivity DisorderPharmacology and Obesity TreatmentPharmaceutical studies and practices

A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder

Open access
the 311 Study Group, Wigal, Sharon B, Kollins, Scott H, Childress, Ann C, Squires, Liza·2009·Child and Adolescent Psychiatry and Mental Health
DOI 10.1186/1753-2000-3-17PMC PMC2704174
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Abstract

BACKGROUND: Lisdexamfetamine dimesylate (LDX) is indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children 6 to 12 years of age and in adults. In a previous laboratory school study, LDX demonstrated efficacy 2 hours postdose with duration of efficacy through 12 hours. The current study further characterizes the time course of effect of LDX. METHODS: Children aged 6 to 12 years with ADHD were enrolled in a laboratory school study. The multicenter study consisted of open-label, dose-optimization of LDX (30, 50, 70 mg/d, 4 weeks) followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each). Efficacy measures included the SKAMP (deportment [primary] and attention [secondary]) and PERMP (attempted/correct) scales (secondary) measured at predose and at 1.5, 2.5, 5, 7.5, 10, 12, and 13 hours postdose. Safety measures included treatment-emergent adverse events (AEs), physical examination, vital signs, and ECGs. RESULTS: A total of 117 subjects were randomized and 111 completed the study. Compared with placebo, LDX demonstrated significantly greater efficacy at each postdose time point (1.5 hours to 13.0 hours), as measured by SKAMP deportment and attention scales and PERMP (P < .005). The most common treatment-emergent AEs during dose optimization were decreased appetite (47%), insomnia (27%), headache (17%), irritability (16%), upper abdominal pain (16%), and affect lability (10%), which were less frequent in the crossover phase (6%, 4%, 5%, 1%, 2%, and 0% respectively). CONCLUSION: In school-aged children (6 to 12 years) with ADHD, efficacy of LDX was maintained from the first time point (1.5 hours) up to the last time point assessed (13.0 hours). LDX was generally well tolerated, resulting in typical stimulant AEs. TRIAL REGISTRATION: Official Title: A Phase IIIb, Randomized, Double-Blind, Multi-Center, Placebo-Controlled, Dose-Optimization, Cross-Over, Analog Classroom Study to Assess the Time of Onset of Vyvanse (Lisdexamfetamine Dimesylate) in Pediatric Subjects Aged 6-12 With Attention-Deficit/Hyperactivity Disorder. ClinicalTrials.gov Identifier: NCT00500149 http://clinicaltrials.gov/ct2/show/NCT00500149.

AI snapshot

Written from the paper’s full text.

TL;DR

In school-aged children with ADHD, lisdexamfetamine dimesylate maintained efficacy versus placebo from 1.5 to 13.0 hours postdose in a laboratory school crossover study. It was generally well tolerated, with typical stimulant adverse events.

Key findings

  • Among 117 randomized subjects (111 completed), LDX was significantly better than placebo at every postdose time point from 1.5 to 13.0 hours on SKAMP deportment (primary), SKAMP attention, and PERMP attempted/correct (SKAMP-D P < .005; SKAMP-A P ≤ .001; PERMP P < .0001).
  • SKAMP-D LS mean difference for LDX vs placebo was -0.45 (95% CI -0.62, -0.28; P < .0001) at 1.5 hours and -0.26 (-0.43, -0.08; P < .005) at 13.0 hours; the mean over the treatment day was -0.74 (-0.85, -0.63; P < .0001).
  • During dose optimization, common treatment-emergent AEs were decreased appetite (47%), insomnia (27%), headache (17%), irritability (16%), upper abdominal pain (16%), and affect lability (10%); in the crossover phase these were 6%, 4%, 5%, 1%, 2%, and 0%, respectively.
  • During crossover, 82.3% were rated improved on LDX vs 19.5% on placebo by CGI-I; ADHD-RS-IV total LS mean change was -25.8 for LDX vs -8.7 for placebo.

Methods

  • Randomized, double-blind, multicenter, placebo-controlled, dose-optimization, 2-way crossover laboratory school study at 7 US sites; enrolled children aged 6–12 years with DSM-IV-TR ADHD combined or hyperactive-impulsive subtype, baseline ADHD-RS-IV ≥ 28, and IQ ≥ 80.
  • After open-label dose optimization to LDX 30, 50, or 70 mg/d over 4 weeks, subjects received 1 week LDX at optimized dose and 1 week placebo in randomized order; assessments occurred predose and at 1.5, 2.5, 5, 7.5, 10, 12, and 13 hours postdose.
  • Primary efficacy was SKAMP-D; secondary measures included SKAMP-A, SKAMP quality of work, SKAMP total, PERMP-A/C, ADHD-RS-IV, and CGI-I; analysis used a linear mixed model with sequence, period, and treatment as fixed effects and subject-within-sequence as random effect (ITT n = 113; safety n = 129).

Limitations

  • Stated: short treatment and assessment phases may underestimate TEAEs; severe comorbid psychiatric conditions were excluded; open-label dose optimization limits interpretation; no measurements beyond 13 hours postdose; high baseline severity, no inattentive-type ADHD group, and under-representation of minority populations limit generalizability.
  • Stated: pharmacokinetic data were not collected, so pharmacologic effects could not be correlated with blood levels.
  • Evident from the text: the sample was predominantly male (76.0%) and Caucasian (70.5%), and the crossover treatment periods were only 1 week each, so long-term safety and durability are not addressed.

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

Integrity signals

Registry

Crossref · 10.1186/1753-2000-3-17

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

1 of 38 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    The higher (worse) predose SKAMP deportment and attention ratings in the LDX group compared with placebo may be in part related to residual drug from the previous treatment day.

    “While there may be multiple factors that contributed to the higher ratings, the group differences may be, in part, related to residual drug from the previous treatment day as has been seen in another study with an amphetamine-based long-acting stimulant [32].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] McCracken JT, Biederman J, Greenhill LL, Swanson JM, McGough JJ, Spencer TJ, Posner K, Wigal S, Pataki C, Zhang Y, Tulloch S: Analog classroom assessment of a once-daily mixed amphetamine formulation, SLI381 (Adderall XR), in children with ADHD. J Am Acad Child Adolesc Psychiatry. 2003, 42: 673-683. 10.1097/01.CHI.0000046863.56865.FE. source

      The Discussion (page unavailable) reports higher behavior-problem ratings at the first assessment in the active-treatment groups, supporting the citation as an example of a similar predose pattern with an amphetamine-based stimulant. It cautiously suggests a possible morning rebound effect, but does not attribute the ratings to residual drug from the previous treatment day. The study examined SLI381 (Adderall XR), not LDX. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Findingown data

    LDX showed separation from placebo at all postdose time points for both the PERMP-A and PERMP-C score analyses (P < .0001 for all time points).

    “LDX showed separation from placebo at all postdose time points for both the PERMP-A [(Figure 3), actual and change from predose, top and bottom, respectively] and PERMP-C [(Figure 3), actual and change from predose, top and bottom, respectively] score analyses (as measured by LS mean [SE]; P < .0001 for all time points).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.
  • Findingown data

    For PERMP-A and PERMP-C, efficacy was shown at each postdose time point, at 1.5 hours and continuing up to and including 13.0 hours.

    “For PERMP-A and PERMP-C, efficacy was shown at each postdose time point, at 1.5 hours and continuing up to and including 13.0 hours (Figures 3).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.
  • Findingown data

    LS mean (SE) PERMP-A and PERMP-C scores for LDX groups [85.54 (4.88) and 81.86 (4.84), respectively] were significantly different from placebo groups [102.43 (4.88) and 99.17 (4.84), respectively; P < .005] at predose assessments.

    “LS mean (SE) PERMP-A and PERMP-C scores for LDX groups [85.54 (4.88) and 81.86 (4.84), respectively] were significantly different from placebo groups [102.43 (4.88) and 99.17 (4.84), respectively; P < .005] at predose assessments (Figures 3).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.
  • Findingown data

    There was significant separation of LDX from placebo at all postdose time points for the SKAMP-D score analysis (P < .005 for all time points).

    “There was significant separation of LDX from placebo at all postdose time points for the SKAMP-D score analysis (as measured by LS mean [SE]; P < .005 for all time points) (Table 2) and [(Figure 2) top].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.
  • May combine two claims. 35
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingown data

    The differences in LS means (95% CI) of LDX vs placebo at 1.5 hours and 13.0 hours were -0.45 (-0.62, -0.28; P < .0001) and -0.26 (-0.43, -0.08; P < .005), respectively.

    “The differences in LS means (95% CI) of LDX vs placebo at 1.5 hours and 13.0 hours were -0.45 (-0.62, -0.28; P < .0001) and -0.26 (-0.43, -0.08; P < .005), respectively.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.

  • May combine two claims.

    Findingown data

    Twelve of the 18 study discontinuations occurred during dose optimization while each subject was receiving 30 mg/d LDX (8 due to AEs, 1 due to protocol violation, and 3 due to withdrawal of consent). Six discontinuations occurred during the crossover phase: 2 while the subject was receiving LDX (protocol violation, withdrawal of consent), and 4 while the subjects were receiving placebo (loss to

    “Twelve of the 18 study discontinuations (Table 1) occurred during dose optimization while each subject was receiving 30 mg/d LDX (8 due to AEs, 1 due to protocol violation, and 3 due to withdrawal of consent). Six discontinuations occurred during the crossover phase: 2 while the subject was receiving LDX (protocol violation, withdrawal of consent), and 4 while the subjects were receiving placebo (”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At baseline, all subjects were diagnosed with the combined ADHD subtype and had a mean (SD) ADHD-RS-IV total score of 42.4 (7.1).

    “At baseline, all subjects were diagnosed with the combined ADHD subtype and had a mean (SD) ADHD-RS-IV total score of 42.4 (7.1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Post hoc analysis of SKAMP-D scores in the LDX group showed that significant improvement relative to predose was seen at all postdose time points except 12 and 13 hours. At 12 and 13 hours postdose, SKAMP-D scores in this group were numerically worse but not statistically different from predose levels. Conversely, SKAMP-D scores were significantly worse than predose at all postdose time points in

    “Post hoc analysis of SKAMP-D scores in the LDX group showed that significant improvement relative to predose was seen at all postdose time points except 12 and 13 hours. At 12 and 13 hours postdose, SKAMP-D scores in this group were numerically worse but not statistically different from predose levels. Conversely, SKAMP-D scores were significantly worse than predose at all postdose time points in”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.

  • May combine two claims.

    Findingown data

    The most common treatment-emergent AEs during dose optimization were decreased appetite (47%), insomnia (27%), headache (17%), irritability (16%), upper abdominal pain (16%), and affect lability (10%), which were less frequent in the crossover phase (6%, 4%, 5%, 1%, 2%, and 0% respectively).

    “The most common treatment-emergent AEs during dose optimization were decreased appetite (47%), insomnia (27%), headache (17%), irritability (16%), upper abdominal pain (16%), and affect lability (10%), which were less frequent in the crossover phase (6%, 4%, 5%, 1%, 2%, and 0% respectively).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LDX demonstrated significant improvement on the SKAMP-D compared with placebo, at 1.5 hours (the first postdose time point measured; primary endpoint) and continuing through all time points up to and including 13.0 hours postdose (the last time point measured; key secondary endpoint).

    “LDX demonstrated significant improvement on the SKAMP-D compared with placebo, at 1.5 hours (the first postdose time point measured; primary endpoint) and continuing through all time points up to and including 13.0 hours postdose (the last time point measured; key secondary endpoint).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.

  • May combine two claims.

    Findingcitation

    The adverse events reported in this study were similar in nature to those reported in studies of other stimulants and included decreased appetite, insomnia, headache, irritability, upper abdominal pain, and affect lability.

    “The AEs reported here were similar in nature to those reported in studies of other stimulants and included decreased appetite, insomnia, headache, irritability, upper abdominal pain, and affect lability [10,13,27-29].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [10] 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: 450-463. 10.1016/S0149-2918(07)80083-X. source
    • cites [13] 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: 970-976. 10.1016/j.biopsych.2007.04.015. source
    • cites [27] Wigal S, Swanson JM, Feifel D, Sangal RB, Elia J, Casat CD, Zeldis JB, Conners CK: A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d, l-threo-methylphenidate hydrochloride in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2004, 43: 1406-1414. 10.1097/01.chi.0000138351.98604.92. source
    • cites [28] Biederman J, Lopez FA, Boellner SW, Chandler MC: A randomized, double-blind, placebo-controlled, parallel-group study of SLI381 (Adderall XR) in children with attention-deficit/hyperactivity disorder. Pediatrics. 2002, 110: 258-266. 10.1542/peds.110.2.258. source
    • cites [29] Wolraich ML, Greenhill LL, Pelham W, Swanson J, Wilens T, Palumbo D, Atkins M, McBurnett K, Bukstein O, August G: Randomized, controlled trial of OROS methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics. 2001, 108: 883-892. 10.1542/peds.108.4.883. source

  • May combine two claims.

    Findingown data

    The differences in LS means (95% CI) of LDX vs placebo in PERMP-C at 1.5 hours and 13 hours were 19.10 (12.25, 25.94) and 28.14 (21.46, 34.83), respectively (both, P < .0001).

    “The differences in LS means (95% CI) of LDX vs placebo in PERMP-C at 1.5 hours and 13 hours were 19.10 (12.25, 25.94) and 28.14 (21.46, 34.83), respectively (both, P < .0001).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.

  • May combine two claims.

    Findingown data

    There were no new TEAEs with an incidence ≥ 10% during the double-blind crossover period, and no TEAEs during the crossover phase resulted in discontinuations.

    “There were no new TEAEs with an incidence ≥ 10% during the double-blind crossover period.”
    • Also stated in: § Safety assessment · plain
      “No TEAEs during the crossover phase resulted in discontinuations.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Mean differences in LS means for SKAMP-D, SKAMP-A, SKAMP quality of work, and SKAMP total scores by optimized dose group (30, 50, 70 mg/d) all favored LDX over placebo.

    “Overall mean difference (95% CI) for placebo vs LDX was analyzed by optimized dose groups for SKAMP-D, SKAMP-A, SKAMP quality of work, and SKAMP total scores (Table 3), and these scores across optimized dose groups during the open-label, nonrandomized phase of this study were found to be consistent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Small decreases in weight from baseline were observed and were consistent with the known effect of psychostimulants.

    “Small decreases in weight from baseline were observed and were consistent with the known effect of psychostimulants [21-23].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Adderall XR [package insert]. 2007, Wayne, PA: Shire US Inc

      Not checked in the free run.

    • cites [22] Concerta [package insert]. 2008, Titusville, NJ: McNeil Pediatrics

      Not checked in the free run.

    • cites [23] Focalin XR [package insert]. 2008, East Hanover, NJ: Novartis Pharmaceuticals Corporation

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    No deaths or serious adverse events were reported during this study.

    “No deaths or serious AEs were reported during this study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The differences in LS means (95% CI) of LDX vs placebo in PERMP-A at 1.5 hours and 13.0 hours were 16.97 (9.39, 24.56) and 28.28 (21.51, 35.04), respectively (both, P < .0001).

    “The differences in LS means (95% CI) of LDX vs placebo in PERMP-A at 1.5 hours and 13.0 hours were 16.97 (9.39, 24.56) and 28.28 (21.51, 35.04), respectively (both, P < .0001).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.
    • Rests on an assumption: The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.
    • Rests on an assumption: The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.

  • May combine two claims.

    Findingown data

    Most subjects reported mild or moderate TEAEs during the dose-optimization phase; 5 subjects (3.9%) reported severe TEAEs.

    “Most subjects reported mild or moderate TEAEs during this phase; 5 subjects (3.9%) reported severe TEAEs (blunted affect, insomnia, increased insomnia, and irritability each reported in 1 subject; accidental overdose and upper abdominal pain both reported in the same subject).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    ECG interval data exhibited no clinically meaningful trends, and no subject had a QT, QTcF, or QTcB interval ≥ 480 msec or a change from baseline > 60 msec.

    “Consistent with prior clinical studies of LDX, ECG interval data exhibited no clinically meaningful trends.”
    • Also stated in: § Safety assessment · plain
      “However, no subject had a QT, QTcF, or QTcB interval ≥ 480 msec or a change from baseline > 60 msec.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Modest increases in mean SBP, DBP, and pulse were observed during the crossover period, consistent with the known effects of psychostimulants.

    “Modest increases in mean SBP, DBP, and pulse were observed, consistent with the known effects of psychostimulants: typically increases of 2 to 4 mm Hg in blood pressure and 3 to 6 bpm in heart rate are reported [21-23].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Adderall XR [package insert]. 2007, Wayne, PA: Shire US Inc

      Not checked in the free run.

    • cites [22] Concerta [package insert]. 2008, Titusville, NJ: McNeil Pediatrics

      Not checked in the free run.

    • cites [23] Focalin XR [package insert]. 2008, East Hanover, NJ: Novartis Pharmaceuticals Corporation

      Not checked in the free run.

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

    Study design and conductown data

    This study was a randomized, double-blind, multicenter, placebo-controlled, dose-optimization, crossover, laboratory school study of LDX conducted at 7 study sites in the United States.

    “This randomized, double-blind, multicenter, placebo-controlled, dose-optimization, crossover, laboratory school study of LDX was conducted at 7 study sites in the United States.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The SKAMP scale is a validated rating scale that assesses manifestations of ADHD in a classroom setting through several subscales, including deportment (behavior) and attention.

    “The SKAMP scale is a validated rating scale that assesses manifestations of ADHD in a classroom setting through several subscales, including deportment (behavior) and attention [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Wigal SB, Gupta S, Guinta D, Swanson JM: Reliability and validity of the SKAMP rating scale in a laboratory school setting. Psychopharmacol Bull. 1998, 34: 47-53.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    As in the previous study, LDX was generally well tolerated, with an AE profile similar to that of other extended-release stimulant products.

    “As in the previous study, LDX was generally well tolerated, with an AE profile similar to that of other extended-release stimulant products [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] 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: 450-463. 10.1016/S0149-2918(07)80083-X. source

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

    Study design and conductnone given

    All study activities were performed in accordance with the principles of the International Conference on Harmonization Good Clinical Practice, 18th World Medical Assembly (Helsinki 1964), and amendments of the 29th (Tokyo 1975), the 35th (Venice 1983), the 41st (Hong Kong 1989), and the 48th (South Africa 1996) World Medical Assemblies.

    “All study activities were performed in accordance with the principles of the International Conference on Harmonization Good Clinical Practice, 18th World Medical Assembly (Helsinki 1964), and amendments of the 29th (Tokyo 1975), the 35th (Venice 1983), the 41st (Hong Kong 1989), and the 48th (South Africa 1996) World Medical Assemblies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The primary population for efficacy assessments was the intent-to-treat population (ITT), which consisted of all randomized subjects who received at least 1 dose of study medication with at least 1 postrandomization measurement of the primary efficacy variable available for analysis.

    “The primary population for efficacy assessments was the intent-to-treat population (ITT) population, which consisted of all randomized subjects who received at least 1 dose of study medication with at least 1 postrandomization measurement of the primary efficacy variable (mean SKAMP-D score over the course of a day) available for analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a previous laboratory school study, LDX demonstrated efficacy 2 hours postdose with duration of efficacy through 12 hours.

    “In a previous laboratory school study, LDX demonstrated efficacy 2 hours postdose with duration of efficacy through 12 hours.”
    • Also stated in: § Background · plain
      “A 6-week, randomized, double-blind, crossover study in a laboratory school setting [13] similar to the current study showed that LDX was significantly more effective in reducing ADHD symptoms compared with placebo (P < .0001), as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham deportment (SKAMP-D) subscale throughout the day [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 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: 970-976. 10.1016/j.biopsych.2007.04.015. source

  • Classified as probably not a substantial claim.

    Premisecitation

    A second 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in children with ADHD evaluated the efficacy and safety of LDX (30, 50, and 70 mg/d) over 4 weeks of treatment.

    “A second 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in children with ADHD evaluated the efficacy and safety of LDX (30, 50, and 70 mg/d) over 4 weeks of treatment [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] 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: 450-463. 10.1016/S0149-2918(07)80083-X. source

  • May combine two claims.

    Study design and conductown data

    A total of 129 subjects were enrolled and entered the open-label, dose-optimization phase; of these, 117 (90.7%) were randomized to the double-blind crossover phase, 113 (87.6%) were included in the ITT population, and 111 (86.0%) completed the study.

    “A total of 129 subjects were enrolled and entered the open-label, dose-optimization phase (Table 1). Of these, 117 (90.7%) were randomized to the double-blind crossover phase, 113 (87.6%) were included in the ITT population, and 111 (86.0%) completed the study.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Subjects were randomized to receive daily LDX treatment (at the optimized dose) for 1 week followed by daily placebo capsules (identical in appearance to LDX capsules) for 1 week, or vice versa.

    “Subjects were randomized to receive daily LDX treatment (at the optimized dose) for 1 week followed by daily placebo capsules (identical in appearance to LDX capsules) for 1 week, or vice versa.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Four of the 117 subjects in the randomized population were not included in the ITT population because they did not have at least 1 SKAMP-D score available after randomization.

    “Four of the 117 subjects in the randomized population were not included in the ITT population because they did not have at least 1 SKAMP-D score available after randomization.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Stimulants are the mainstay of pharmacotherapy for ADHD, and their safety and efficacy have been well documented.

    “Stimulants are the mainstay of pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Their safety and efficacy have been well documented [1-3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Pliszka SR, Crismon ML, Hughes CW, Conners CK, Emslie GJ, Jensen PS, McCracken JT, Swanson JM, Lopez M, the Texas Consensus Conference Panel on Pharmacotherapy of Childhood Attention-Deficit/Hyperactivity Disorder: The Texas Children's Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006, 45: 642-657. 10.1097/01.chi.0000215326.51175.eb. source
    • cites [2] Dulcan M, the Work Group on Quality Issues: Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1997, 36 (10 suppl): 85S-121S. source
    • cites [3] Stein MA, Baren M: Welcome progress in the diagnosis and treatment of ADHD in adolescence. Contemp Pediatr. 2003, 20: 83-110.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    LDX was generally well tolerated with adverse events (AEs) similar to those seen with other once-daily stimulants.

    “LDX was generally well tolerated with adverse events (AEs) similar to those seen with other once-daily stimulants [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] 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: 970-976. 10.1016/j.biopsych.2007.04.015. source

  • May combine two claims.

    Study design and conductreasoning

    Since the study had a crossover design and assessed duration of efficacy, the last observation carried forward (LOCF) method was not a valid approach for data that were incomplete because of discontinuation or unavailability; therefore, incomplete data due to these reasons were set as missing for purposes of statistical analysis.

    “Since the study had a crossover design and assessed duration of efficacy, the last observation carried forward (LOCF) method was not a valid approach for data that were incomplete because of discontinuation or unavailability. Therefore, incomplete data due to these reasons were set as missing for purposes of statistical analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    LDX was generally well tolerated, resulting in typical stimulant AEs.

    “LDX was generally well tolerated, resulting in typical stimulant AEs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Efficacy in LDX-treated subjects compared with placebo was significant beginning at 2 hours postdose and lasted up to 12 hours postdose, the last time point measured.

    “Efficacy in LDX-treated subjects compared with placebo was significant beginning at 2 hours postdose and lasted up to 12 hours postdose, the last time point measured.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 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: 970-976. 10.1016/j.biopsych.2007.04.015. source

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

    Study design and conductnone given

    SKAMP assessments were performed by observers who were provided with training to help ensure reliability.

    “SKAMP assessments were performed by observers who were provided with training to help ensure reliability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Of the 7 study sites, 1 site was also a site from the previous LDX analog classroom study; per the principal investigator of that site, there was no subject overlap and, therefore, no subjects with prior exposure to LDX from clinical trials were included in this study.

    “Of the 7 study sites, 1 site was also a site from the previous LDX analog classroom study. Per the principal investigator of that site, there was no subject overlap and, therefore, no subjects with prior exposure to LDX from clinical trials were included in this study [Previous exposure clarification. Personal Communication with AC. Childress on December 8, 2008].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [Previous exposure clarification. Personal Communication with AC. Childress on December 8, 2008]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductown data

    According to the prespecified statistical analysis plan, efficacy analyses were based on the ITT population of 113 subjects and safety analyses were based on the safety population of 129 subjects.

    “According to the prespecified statistical analysis plan, efficacy analyses were based on the ITT population of 113 subjects and safety analyses were based on the safety population of 129 subjects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Study limitations include that short treatment duration and assessment phases may underestimate TEAEs, exclusion of severe comorbid psychiatric conditions may under-represent psychiatric comorbidities, open-label dose-optimization limits interpretation, no measurements beyond 13 hours postdose were captured, and the population had uniformly high baseline severity, lacked inattentive type ADHD, and

    “Consistent with laboratory school study designs, the short treatment duration and assessment phases may provide an underestimate of the number and severity of TEAEs typically seen with lengthier treatment of ADHD.”
    • Also stated in: § Discussion · hedged
      “Typical of ADHD studies, subjects with severe comorbid psychiatric conditions were excluded. This may have selected for a study population that under-represents psychiatric comorbidities generally seen in ADHD populations [34].”
    • Also stated in: § Discussion · hedged
      “Other limitations that may affect the ability to generalize these findings include the uniformly high level of baseline severity of the study subjects, the lack of a group of subjects with inattentive type ADHD, and the under-representation of minority populations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Spencer TJ, Biederman J, Mick E: Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. J Pediatr Psychol. 2007, 32: 631-642. 10.1093/jpepsy/jsm005. source

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

    Study design and conductreasoning

    Strengths of the study included the use of a controlled laboratory school setting, ratings by trained investigators, dose optimization mimicking clinical practice, the blinded crossover design, and the reliability and validity of the SKAMP and PERMP scales.

    “Strengths of the study included the use of a controlled laboratory school setting, ratings by trained investigators, and dose optimization, which mimicked dose titration in clinical practice.”
    • Also stated in: § Discussion · plain
      “The blinded design of the crossover phase allowed a more valid assessment of patients at their optimized dosage of LDX versus placebo.”
    • Also stated in: § Discussion · plain
      “Reliability and validity of SKAMP and PERMP scales were other strengths as well as their inclusion as subjective and objective evaluations of efficacy, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    This study expanded and further refined findings from a previous laboratory school study due to a larger sample size (129 vs 52) and additional time points assessed predose and 13-hour measurements (-0.5 to 13 hours vs 1 to 12 hours).

    “This study expanded and further refined findings from a previous laboratory school study, due to a larger sample size (129 vs 52), and additional time points assessed predose and 13-hour measurements (-0.5 to 13 hours in this study vs 1 to 12 hours) [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 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: 970-976. 10.1016/j.biopsych.2007.04.015. source

  • May combine two claims.

    Premisecitation

    In healthy adult volunteers, intact LDX plasma concentrations reached their maximum at 1.1 hours after ingestion and then declined to 0 by 5 hours postdose.

    “In healthy adult volunteers, the plasma concentrations showed intact LDX levels reaching their maximum concentration at 1.1 hours after ingestion and then declined to 0 by 5 hours postdose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Krishnan SM, Stark JG: Multiple daily-dose pharmacokinetics of lisdexamfetamine dimesylate in healthy adult volunteers. Curr Med Res Opin. 2008, 24: 33-40. source

  • May combine two claims.

    Premisecitation

    In the previous laboratory school study, treatment effects were observed beginning at 2 hours postdose and continued until 12 hours postdose.

    “In the previous study, treatment effects were observed beginning at 2 hours postdose and continued until 12 hours postdose.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] 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: 970-976. 10.1016/j.biopsych.2007.04.015. source

  • May combine two claims.

    Interpretationown data

    This study demonstrated an onset of action for LDX at 1.5 hours, with duration of efficacy up to 13 hours postdose as assessed during the crossover treatment period.

    “This study demonstrated an onset of action for LDX at 1.5 hours (the first postdose time point measured), with duration of efficacy up to 13 hours postdose as assessed during the crossover treatment period.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mean plasma levels of d-amphetamine reached their maximum at 3.7 hours and did not approach 0 until 72 hours following the final dose.

    “However, mean plasma levels of d-amphetamine reached their maximum at 3.7 hours and did not approach 0 until 72 hours following the final dose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Krishnan SM, Stark JG: Multiple daily-dose pharmacokinetics of lisdexamfetamine dimesylate in healthy adult volunteers. Curr Med Res Opin. 2008, 24: 33-40. source

  • May combine two claims.

    Interpretationreasoning

    These findings suggest that LDX may provide effective symptom control in children with ADHD throughout the day and that continues to afterschool activities and family time.

    “These findings suggest that LDX may provide effective symptom control in children with ADHD throughout the day and that continues to afterschool activities and family time.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ADHD symptoms may extend beyond the school day and continue into afterschool activities and family interactions.
42 of 42

  • The paper relies on this without support.

    There is no carryover effect between the 1-week LDX and placebo treatment periods in the crossover design.

    “Subjects were randomized to receive daily LDX treatment (at the optimized dose) for 1 week followed by daily placebo capsules (identical in appearance to LDX capsules) for 1 week, or vice versa.”

  • The paper relies on this without support.

    The dose-optimization phase identifies a stable optimal dose that remains effective and tolerable during the double-blind phase.

    “Optimal dose was defined as the dose that produced a reduction in ADHD-RS-IV score ≥ 30% and CGI-Improvement (CGI-I) score of 1 or 2 and had tolerable side effects.”

  • The paper relies on this without support.

    The laboratory school setting is a valid analog for real-world classroom behavior and ADHD symptom control.

    “This randomized, double-blind, multicenter, placebo-controlled, dose-optimization, crossover, laboratory school study of LDX was conducted at 7 study sites in the United States.”

  • The paper relies on this without support.

    ADHD symptoms may extend beyond the school day and continue into afterschool activities and family interactions.

    “The symptoms of ADHD may extend beyond the school day and continue into afterschool activities and family interactions.”
4 of 4

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?

  • The profile of d-amphetamine delivery by LDX underlies the long daily duration of action of LDX in relieving the hyperactive, inattentive, and impulsive symptoms experienced by patients with ADHD.

    “The profile of d-amphetamine delivery by LDX underlies the long daily duration of action of LDX in relieving the hyperactive, inattentive, and impulsive symptoms experienced by patients with ADHD.3,4”

    From Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of&amp;nbsp;red blood cells (2014) · cites this paper as [3]

    The Discussion reports efficacy through 13 hours in school-aged children and says that this duration “seem[s] to follow” the known d-amphetamine pharmacokinetic profile. The paper did not collect pharmacokinetic data in this trial, so it supports the proposed explanation but not the claim’s unqualified causal wording or its extension to patients with ADHD generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In Wigal et al 13-hour laboratory school study of 117 children aged 6-12 years with ADHD, lisdexamfetamine produced statistically significant improvements on SKAMP deportment, SKAMP attention, and PERMP scales (P < 0.001) compared with placebo.

    “Statistically significant improvements were noted on the SKAMP deportment rating, SKAMP attention, and Permanent Product Measure of Performance scales (P < 0.001).”

    From Update on optimal use of lisdexamfetamine in the treatment of ADHD (2013) · cites this paper as [33]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • 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].”

    From 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 (2013) · cites this paper as [14]

Cites

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Related

Authors
the 311 Study Group, Wigal, S. B., Kollins, S. H., Childress, A. C., & Squires, L.
Affiliations
  • University of California, Irvine (US)
  • Duke Medical Center (US)
  • Center for Psychiatry and Behavioral Medicine (US)
Corresponding author
Wigal, Sharon B
ORCID
Venue
Child and Adolescent Psychiatry and Mental Health
Publisher
Springer Science and Business Media LLC
Published
2009-06-09
Volume
3
Issue
1
Pages
17-17
ISSN
1753-2000 (ISSN-L)
DOI
10.1186/1753-2000-3-17
PMC
PMC2704174
OpenAlex
W2023262882
Cited by
112
References
31
Citations by year
2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 11 · 2013: 19 · 2012: 13
FWCI
9.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Child and Adolescent Psychiatry and Mental Health (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Keywords
lisdexamfetamine dimesylate, attention deficit hyperactivity disorder, school-aged children, time course of drug effects, stimulant efficacy, deportment, attention, dose optimization, adverse events, stimulant side effects, classroom setting, pharmacokinetics, placebo-controlled crossover trial, adults

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.

Cited sources are checked by gpt-6-sol.

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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