Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD: A Phase IV, 2-Year, Open-Label Study in Europe

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management.

Objectives: Our objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.

Methods: Participants (aged 6-17 years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70 mg/day for 104 weeks. Safety monitoring included treatment-emergent adverse events (TEAEs), vital signs, electrocardiography, and growth. The TEAEs decreased appetite, weight decrease, insomnia events (including insomnia, initial insomnia, middle insomnia, and terminal insomnia), headache, and psychiatric TEAEs were pre-defined as being of special interest. Efficacy was assessed as a secondary objective using the ADHD Rating Scale IV (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale, and the CGI-Severity (CGI-S) scale.

Results: Of 314 participants enrolled, 191 completed the study. TEAEs were reported in 89.8% of participants, led to discontinuation in 12.4%, and were reported as serious in 8.9%. TEAEs that were reported by ≥5% of participants and considered by investigators as related to LDX were decreased appetite (49.4%), weight decrease (18.2%), insomnia (13.1%), initial insomnia (8.9%), irritability (8.6%), nausea (6.7%), headache (5.7%), and tic (5.1%). The median time to first onset and duration, respectively, of TEAEs of special interest were as follows: decreased appetite, 13.5 and 169.0 days; weight decrease, 29.0 and 225.0 days; insomnia, 17.0 and 42.8 days; and headache, 22.0 and 2.0 days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4-12 weeks. Psychiatric TEAEs were infrequent: psychosis and mania (n = 1), suicidal events (suicidal ideation, n = 2; suicide attempt, n = 1), and aggression events (aggression, n = 14; anger, n = 2; hostility, n = 1). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0 bpm (95% confidence interval [CI] 5.7-8.2); systolic blood pressure (SBP), 3.4 mmHg (95% CI 2.2-4.5); and diastolic blood pressure (DBP), 3.2 mmHg (95% CI 2.2-4.2). Pre-defined thresholds for a potentially clinically important (PCI) high pulse rate were met at one or more visits by 22 participants (7.0%), for PCI high SBP were met by 45 children (22.4%) and 17 adolescents (15.2%), and for PCI high DBP were met by 78 children (38.8%) and 24 adolescents (21.4%). The mean QT interval corrected using Fridericia's formula (QTcF) decreased from baseline to LOTA (-0.6 ms [95% CI -2.3 to 1.2]; range -50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1 kg (95% CI 1.5-2.8); height, 6.1 cm (95% CI 5.6-6.7); and body mass index (BMI), -0.5 kg/m2 (95% CI -0.7 to -0.3). There was a general shift to lower z score categories for height, weight, and BMI from baseline to LOTA. The mean change in ADHD-RS-IV from baseline to LOTA was -25.8 (95% CI -27.0 to -24.5) for total score, -12.6 (95% CI -13.4 to -11.9) for the hyperactivity/impulsivity subscale score, and -13.1 (95% CI -13.8 to -12.4) for the inattention subscale score. At LOTA, 77.9% of participants had a CGI-I score of 1 or 2. In addition, 77.3 and 69.2% of participants were classified as treatment responders, based on a CGI-I score of 1 or 2 and a ≥30% or ≥50% reduction from baseline in ADHD-RS-IV total score, respectively.

Conclusions: The safety profile of LDX in this longer-term study was similar to that reported in previous studies. The efficacy of LDX was maintained throughout the 2-year study period. 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 funded by Shire International GmbH. Shire International GmbH also funded open access.

Conflicts of interest

BC and BY are employees of Shire and own 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 organizations indicated: TB (Actelion, Hexal Pharma, Lilly, Medice, Novartis, Otsuka, Shire, and Vifor Pharma); DRC (Eli Lilly, Janssen-Cilag, Medice, Novartis, Oxford University Press, Shire, and Vifor Pharma); PN (Lilly, Otsuka, and Shire); IHO (Alicia Koplowitz Foundation, Eli Lilly, Forest, Janssen-Cilag, Junta de Andalucía, Roche, Shire, Shire Pharmaceuticals Iberica S.L., and Sunovion); CAS (Alicia Koplowitz Foundation, Editorial Médica Panamericana, Eli Lilly, EUNSA [University of Navarra Press], Fundación Caja Navarra, Janssen, Mayo Eds, Medice/Juste, NeuroTech Solutions, Rubiò, Shire, Sociedad Vasco-Navarra de Psiquiatría, University of Navarra Research Projects [PIUNA], and Wolters Kluwer); AZ (Angelini, EduPharma, Lilly, Lundbeck, Otsuka, Oxford University Press, Roche, Shire, Takeda and Vifor Pharma).

Ethical 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 they took part in the study.

Figures

Fig. 1

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

Fig. 2

Patient disposition. aThe safety population comprised all enrolled participants who received at least one dose of LDX during the study. bThe FAS comprised all participants who received one dose of LDX and had at least one on-treatment post-baseline efficacy assessment; all 14 participants from a single study site were excluded from the efficacy analyses because of a serious violation of Good Clinical Practice. cThe number of participants refers to individuals in the enrolled population who completed the study. A total of 191 participants who were included in the FAS completed the study. dAccording to the protocol, lack of efficacy (in the opinion of the investigator) was to be reported as an adverse event. Five additional patients discontinued because of investigator-perceived lack of efficacy; according to the protocol, these should have been recorded as treatment-emergent adverse events. FAS full analysis set, LDX lisdexamfetamine dimesylate

Fig. 3

Incidence of treatment-emergent adverse events identified by the sponsor as of special interest: a decreased appetite, b weight decrease, c insomnia, and d headache (safety population). Percentages are based on the number of participants in the safety population who received lisdexamfetamine dimesylate for the given week. TEAE treatment-emergent adverse event

Fig. 4

a Mean ADHD-RS-IV total score, b inattention subscale score, and c hyperactivity/impulsivity subscale score by visit (full analysis set). ADHD-RS-IV ADHD Rating Scale IV, BL baseline, LOTA last on-treatment assessment, n number of participants with an ADHD-RS-IV score at that week, SD standard deviation