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

Abstract

Background: Stimulant medications for the treatment of attention-deficit/hyperactivity disorder have a history of safe and effective use; however, concerns exist that they may adversely affect growth trajectories in children and adolescents.

Objective: The objective of this study was to evaluate the longer-term effects of lisdexamfetamine dimesylate on weight, height, body mass index and pubertal development in children and adolescents with attention-deficit/hyperactivity disorder.

Methods: Children and adolescents aged 6-17 years with attention-deficit/hyperactivity disorder took open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) in this open-label 2-year safety and efficacy study. Safety evaluations included treatment-emergent adverse events, measurement of weight, height and body mass index, and self-reported pubertal status using Tanner staging.

Results: The safety analysis population comprised all enrolled participants (N = 314) and 191 (60.8%) completed the study. Weight decrease was reported as a treatment-emergent adverse event in 63 participants (20.1%) and two participants (0.6%) discontinued the study as a result of treatment-emergent adverse events of weight decrease. Growth retardation of moderate intensity was reported as a treatment-emergent adverse event for two participants. From baseline to the last on-treatment assessment, there were increases in mean weight of 2.1 kg (standard deviation 5.83) and height of 6.1 cm (standard deviation 4.90), and a body mass index decrease of 0.5 kg/m2 (standard deviation 1.72). Mean weight, height and body mass index z-scores decreased over the first 36 weeks of the study and then stabilised. Changes from baseline to the last on-treatment assessment in mean z-scores for weight, height and body mass index were significantly less than zero (- 0.51, - 0.24 and - 0.59, respectively; nominal p < 0.0001). The proportion of participants with a z-score of < - 1 ranged from 5.1% (baseline) to 22.1% (week 84) for weight, 8.2% (baseline) to 12.6% (week 96) for height, and 8.3% (baseline) to 28.8% (week 96) for body mass index. Thirteen participants (4.1%) shifted to a weight below the fifth percentile at the last on-treatment assessment from a higher weight category at baseline. At the last on-treatment assessment, most participants remained at their baseline Tanner stage or had shifted higher.

Conclusions: Findings from this comprehensive examination of growth outcomes associated with lisdexamfetamine dimesylate treatment over 2 years were consistent with previous studies of stimulant medications. Whilst mean weight and height increased over the course of the study, there was a small but transient reduction in mean weight, height and body mass index z-scores. A small increase in the proportion of participants in the lowest weight and body mass index categories highlights the importance of the regular monitoring of weight and height. There was no evidence of delayed onset of puberty. CLINICALTRIALS.

Gov identifier: NCT01328756.

Conflict of interest statement

Funding

This 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

Brian Yan is an employee of Shire and owns stock 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, Medice, Novartis, Otsuka, Oxford University Press, Shire, Vifor Pharma); David R. Coghill (Eli Lilly, Janssen-Cilag, Medice, Novartis, Oxford University Press, Shire, Vifor Pharma); Mats Johnson (Eli Lilly, Evolan, Ginsana, PCM Scientific, New Nordic, Shire, Vifor Pharma); Peter Nagy (Lilly, Otsuka, Medice, Shire); Isabel Hernández Otero (Alicia Koplowitz Foundation, Eli Lilly, Forest, Janssen-Cilag, Junta de Andalucía, Roche, Shire, Shire Pharmaceuticals Iberica S.L., Sunovion); César A. Soutullo (Alicia Koplowitz Foundation, Editorial Médica Panamericana, Eli Lilly, Fundación Caja Navarra, Lundbeck, Mayo Eds, Medice/Juste, NeuroTech Solutions, Rubiò, Shire); and Alessandro Zuddas (Angelini, EduPharma, Lilly, Lundbeck, Otsuka, Oxford University Press, Roche, Shire, Takeda, Vifor Pharma).

Ethics approval

This study was approved by the appropriate ethics committees and was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments, as well as other applicable local ethical and legal requirements.

Consent to participate

Written informed consent was obtained from all individual participants included in the study. Informed consent and assent, where applicable, was documented (on an appropriate form approved by the ethics committee) by the dated signature of the participant and the participant’s legally authorised representative/parents, as applicable.

Figures

Fig. 1

SPD489-404 study design. ET early termination, LDX lisdexamfetamine dimesylate

Fig. 2

Changes from baseline (BL) in a weight, b height and c body mass index (BMI), and z-score box plots for d weight, e height and f BMI at each study visit and last on-treatment assessment (LOTA) [safety analysis population; N = 314]. In parts a–c, the filled diamond represents the mean, the box represents the standard deviation and the whiskers indicate the range (minimum, maximum). In parts d–f, the filled diamond represents the mean, the box represents the interquartile range, the whiskers indicate 1.5 times the interquartile range and the filled circle represents outliers (values outside 1.5 times the interquartile range). The z-scores were derived using Centers for Disease Control and Prevention growth charts [23]. For calculation of the BMI, for visits where height was not measured or if height was missing, the last observation carried forward value for height was used

Fig. 3

Proportions of participants in z-score categories for a weight, b height and c body mass index (BMI) by study visit and study week (safety analysis population; N = 314). BL baseline, LOTA last on-treatment assessment, SD standard deviation