Cognitive Function of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate

Abstract

Background: SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404.

Objective: The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Methods: Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant.

Results: All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%).

Conclusions: Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required. CLINICALTRIALS.

Gov identifier: NCT01328756.

Conflict of interest statement

Funding

The study was funded by Shire Development LLC. Writing and editing assistance for this paper was provided by Oxford PharmaGenesis, funded by Shire International GmbH. Shire International GmbH also funded open access.

Conflict of interest

Caleb Bliss and Brigitte Robertson are employees of Shire and own stocks or stock options. The following authors have received compensation for serving as consultants or speakers for, or they or the institutions they work for have received research support or royalties from, the companies or organisations indicated: Tobias Banaschewski (Actelion, CIP Medien, Hexal Pharma, Hogrefe, Kohlhammer, Lilly, Lundbeck, Medice, Novartis, Oxford University Press, Shire and Vifor Pharma); David R. Coghill (Eli Lilly, Janssen-Cilag, Medice, Novartis, Oxford University Press, Shire and Vifor Pharma); Alessandro Zuddas (Angelini, EduPharma, Janssen, Lilly, Lundbeck, Oxford University Press, Roche, Servier and Shire).

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Each patient’s parent/legal guardian provided written informed consent, and assent was obtained from each participant (as applicable) before taking part in the study.

Figures

Fig. 1

SPD489-404 study design. Cambridge Neuropsychological Test Automated Battery (CANTAB) assessments were carried out at baseline (week 0), at weeks 4, 24, 48, 72 and 104 of the open-label treatment period and/or at the early termination (ET) visit. LDX lisdexamfetamine dimesylate

Fig. 2

Delayed Matching to Sample outcomes: a, b key and c, d additional variables. Dashed lines indicate the mean at baseline (week 0). Arrows show the direction of improvement; higher per cent correct and lower median reaction time indicate better cognitive function. Annotated percentages indicate potentially clinically significant changes from baseline (key variables only; parts a and b). Groupwise summary data are shown in Online Resource 1. LOTA last on-treatment assessment, SD standard deviation

Fig. 3

Spatial Working Memory outcomes: a key and b additional variables. Dashed lines indicate the mean at baseline (week 0). Arrows show the direction of improvement; fewer between-search errors indicate better cognitive function. Annotated percentages indicate potentially clinically significant changes from baseline (key variable only; part a). Groupwise summary data are shown in Online Resource 2. LOTA last on-treatment assessment, SD standard deviation

Fig. 4

Stop Signal Task outcomes: a key and b additional variables. Dashed lines indicate the mean at baseline (week 0). Arrows show the direction of improvement; lower reaction time and lower reaction time standard deviation (SD) on ‘go’ trials indicate better cognitive function. Annotated percentages indicate potentially clinically significant changes from baseline (key variable only; part a). Groupwise summary data are shown in Online Resource 3. LOTA last on-treatment assessment

Fig. 5

Reaction Time outcomes: a, b key and c, d additional variables. Dashed lines indicate the mean at baseline (week 0). Arrows show the direction of improvement; lower reaction time, lower reaction time standard deviation (SD) and lower premature response errors indicate better cognitive function. No potentially clinically significant changes from baseline were identified (key variables only; parts a and b). Groupwise summary data are shown in Online Resource 4. LOTA last on-treatment assessment