Peter Nagy

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

ObjectivesThe 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).MethodsThis 9-week, head-to-head, randomized, double-blind, active-controlled study (SPD489-317; ClinicalTrials.gov NCT01106430) enrolled patients (aged 6–17xa0years) 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 70xa0mg) or ATX (patients <70xa0kg, 0.5–1.2xa0mg/kg with total daily dose not to exceed 1.4xa0mg/kg; patients ≥70xa0kg, 40, 80 or 100xa0mg). 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.ResultsOf 267 patients randomized (LDX, nxa0=xa0133; ATX, nxa0=xa0134), 200 (74.9xa0%) completed the study. The median time to first clinical response [95xa0% confidence interval (CI)] was significantly shorter for patients receiving LDX [12.0xa0days (8.0–16.0)] than for those receiving ATX [21.0xa0days (15.0–23.0)] (pxa0=xa00.001). By week 9, 81.7xa0% (95xa0% CI 75.0–88.5) of patients receiving LDX had responded to treatment compared with 63.6xa0% (95xa0% CI 55.4–71.8) of those receiving ATX (pxa0=xa00.001). Also by week 9, the difference between LDX and ATX in least-squares mean change from baseline (95xa0% CI) was significant in favour of LDX for the ADHD-RS-IV total score [−6.5 (−9.3 to −3.6); pxa0<xa00.001; effect size 0.56], inattentiveness subscale score [−3.4 (−4.9 to −1.8); pxa0<xa00.001; effect size 0.53] and the hyperactivity/impulsivity subscale score [−3.2 (−4.6 to −1.7); pxa0<xa00.001; effect size 0.53]. TEAEs were reported by 71.9 and 70.9xa0% of patients receiving LDX and ATX, respectively. At endpoint, both treatments were associated with mean (standard deviation) increases in systolic blood pressure [LDX, +0.7xa0mmHg (9.08); ATX, +0.6xa0mmHg (7.96)], diastolic blood pressure [LDX, +0.1xa0mmHg (8.33); ATX, +1.3xa0mmHg (8.24)] and pulse rate [LDX, +3.6xa0bpm (10.49); ATX, +3.7xa0bpm (10.75)], and decreases in weight [LDX, −1.30xa0kg (1.806); ATX, −0.15xa0kg (1.434)].ConclusionsLDX 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.

Cardiovascular Effects of Stimulant and Non-Stimulant Medication for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis of Trials of Methylphenidate, Amphetamines and Atomoxetine

BackgroundMany children and adolescents with attention deficit/hyperactivity disorder (ADHD) are treated with stimulant and non-stimulant medication. ADHD medication may be associated with cardiovascular effects. It is important to identify whether mean group effects translate into clinically relevant increases for some individual patients, and/or increase the risk for serious cardiovascular adverse events such as stroke or sudden death.ObjectivesTo evaluate potential cardiovascular effects of these treatments, we conducted a systematic review and meta-analysis of the effects of methylphenidate (MPH), amphetamines (AMP), and atomoxetine (ATX) on diastolic and systolic blood pressure (DBP, SBP) and heart rate (HR) in children and adolescents with ADHD.MethodsWe conducted systematic searches in electronic databases (PsychINFO, EMBASE and Medline) to identify published trials which involved individuals who were (i) diagnosed with ADHD and were aged between 0–18xa0years; (ii) treated with MPH, AMP or ATX and (iii) had their DBP and SBP and/or HR measured at baseline (pre) and the endpoint (post) of the study treatment. Studies with an open-label design or a double-blind randomised control design of any duration were included. Statistical analysis involved calculating differences between pre- and post-treatment measurements for the various cardiovascular parameters divided by the pooled standard deviation. Further, we assessed the percentage of clinically relevant increased BP or HR, or documented arrhythmias.ResultsEighteen clinical trials met the inclusion criteria (10 for MPH, 5 for AMP, and 7 for ATX) with data from 5837 participants (80.7% boys) and average duration of 28.7xa0weeks (range 4–96xa0weeks). All three medications were associated with a small, but statistically significant pre–post increase of SBP (MPH: standard mean difference [SMD] 0.25, 95% confidence interval [CI] 0.08–0.42, pxa0<xa00.01; AMP: SMD 0.09, 95% CI 0.03–0.15, pxa0<xa00.01; ATX: SMD 0.16, 95% CI 0.04–0.27, pxa0=xa00.01). MPH did not have a pre–post effect on DBP and HR. AMP treatment was associated with a small but statistically significant pre–post increase of DBP (SMD 0.16, CI 0.03–0.29, pxa0=xa00.02), as was ATX treatment (SMD 0.22, CI 0.10–0.34, pxa0<xa00.01). AMP and ATX were associated with a small to medium statistically significant pre–post increase of HR (AMP: SMD 0.37, CI 0.13–0.60, pxa0<xa00.01; ATX: SMD 0.43, CI 0.26–0.60, pxa0<xa00.01). The head-to-head comparison of the three medications did not reveal significant differences. Sensitivity analyses revealed that AMP studies of <18xa0weeks reported higher effect sizes on DBP compared with longer duration studies (F(1)xa0=xa019.55, pxa0=xa00.05). Further, MPH studies published before 2007 reported higher effect sizes on SBP than studies after 2007 (F(1)xa0=xa05.346, pxa0=xa00.05). There was no effect of the following moderators: type of medication, doses, sample size, age, gender, type of ADHD, comorbidity or dropout rate. Participants on medication reported 737 (12.6%) other cardiovascular effects. Notably, 2% of patients discontinued their medication treatment due to any cardiovascular effect. However, in the majority of patients, the cardiovascular effects resolved spontaneously, medication doses were changed or the effects were not considered clinically relevant. There were no statistically significant differences between the medication treatments in terms of the severity of cardiovascular effects.ConclusionsStatistically significant pre–post increases of SBP, DBP and HR were associated with AMP and ATX treatment in children and adolescents with ADHD, while MPH treatment had a statistically significant effect only on SBP in these patients. These increases may be clinically significant for a significant minority of individuals that experience larger increases. Since increased BP and HR in general are considered risk factors for cardiovascular morbidity and mortality during adult life, paediatric patients using ADHD medication should be monitored closely and regularly for HR and BP.

Functional outcomes from a head-to-head, randomized, double-blind trial of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder and an inadequate response to methylphenidate

Attention-deficit/hyperactivity disorder (ADHD) is associated with functional impairments in multiple domains of patients’ lives. A secondary objective of this randomized, active-controlled, head-to-head, double-blind, dose-optimized clinical trial was to compare the effects of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) on functional impairment in children and adolescents with ADHD. Patients aged 6–17xa0years with an ADHD Rating Scale IV total score ≥28 and an inadequate response to methylphenidate treatment (judged by investigators) were randomized (1:1) to once-daily LDX or ATX for 9xa0weeks. Parents/guardians completed the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at baseline and at weekxa09 or early termination. p values were nominal and not corrected for multiple comparisons. Of 267 randomized patients, 200 completed the study (LDX 99, ATX 101). At baseline, mean WFIRS-P total score in the LDX group was 0.95 [standard deviation (SD) 0.474; 95xa0% confidence interval (CI) 0.87, 1.03] and in the ATX group was 0.91 (0.513; 0.82, 1.00). Scores in all WFIRS-P domains improved from baseline to endpoint in both groups, with least-squares mean changes in total score of −0.35 (95xa0% CI −0.42, −0.29) for LDX and −0.27 (−0.33, −0.20) for ATX. The difference between LDX and ATX was statistically significant (pxa0<xa00.05) for the Learning and School (effect size of LDX vs ATX, 0.43) and Social Activities (0.34) domains and for total score (0.27). Both treatments reduced functional impairment in children and adolescents with ADHD; LDX was statistically significantly more effective than ATX in two of six domains and in total score.

Treatment Response and Remission in a Double-Blind, Randomized, Head-to-Head Study of Lisdexamfetamine Dimesylate and Atomoxetine in Children and Adolescents with Attention-Deficit Hyperactivity Disorder

ObjectivesA secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously.MethodsIn this 9-week, double-blind, active-controlled study, patients aged 6–17xa0years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70xa0mg/day) or ATX (patients <70xa0kg: 0.5–1.2xa0mg/kg/day, not to exceed 1.4xa0mg/kg/day; patients ≥70xa0kg: 40, 80 or 100xa0mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50xa0%. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (≥25, ≥30 or ≥50xa0%) or a Clinical Global Impressions (CGI)–Improvement (CGI–I) score of 1 or 2 throughout weeks 4–9. CGI–Severity (CGI–S) scores were also assessed, as an indicator of remission.ResultsA total of 267 patients were enrolled (LDX, nxa0=xa0133; ATX, nxa0=xa0134) and 200 completed the study (LDX, nxa0=xa099; ATX, nxa0=xa0101). By week 9, significantly (pxa0<xa00.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25xa0% (90.5 vs. 76.7xa0%), 30xa0% (88.1 vs. 73.7xa0%) or 50xa0% (73.0 vs. 50.4xa0%). Sustained response rates were also significantly (pxa0<xa00.05) higher among LDX-treated patients (ADHD-RS-IV ≥25, 66.1xa0%; ADHD-RS-IV ≥30, 61.4xa0%; ADHD-RS-IV ≥50, 41.7xa0%; CGI–I, 52.0xa0%) than among ATX-treated individuals (ADHD-RS-IV ≥25, 51.1xa0%; ADHD-RS-IV ≥30, 47.4xa0%; ADHD-RS-IV ≥50, 23.7xa0%; CGI–I, 39.3xa0%). Finally, by week 9, 60.7xa0% of patients receiving LDX and 46.3xa0% of those receiving ATX had a CGI–S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI–S category.ConclusionsBoth LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI–S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies.

Reports of Perceived Adverse Events of Stimulant Medication on Cognition, Motivation, and Mood: Qualitative Investigation and the Generation of Items for the Medication and Cognition Rating Scale

Abstract Objective: There is no questionnaire to specifically monitor perceived adverse events of methylphenidate (MPH) on cognition, motivation, and mood. The current study therefore had two goals. First, to harvest accounts of such putative events from transcripts of interviews in samples enriched for such potential experiences. Second, to use the derived data to generate items for a new questionnaire that can be used for monitoring such events in medication trials or routine clinical care. Methods: Following a literature search aimed at identifying associations between MPH and cognition and/or motivation, a qualitative semistructured interview was designed to focus specifically on the domains of cognition (i.e., reasoning, depth/breadth of thinking, intellectual capacity, and creativity) and motivation (i.e., drive, effort, and attitudes toward rewards/incentives). Interviews were conducted with 45 participants drawn from the following four groups: (a) clinicians, child and adolescent psychiatrists, and pediatricians specializing in attention-deficit/hyperactivity disorder (ADHD) (nu2009=u200915); (2) teachers, with experience of teaching at least 10 medicated children with ADHD (nu2009=u200910); (3) parents of children with ADHD (nu2009=u20098) treated with MPH; and (4) adolescents/adults with ADHD (nu2009=u200912). Purposeful sampling was used to selectively recruit ADHD participants whose histories suggested a degree of vulnerability to MPH adverse events. Data were analyzed using a deductive approach to content analysis. Results: While we probed purposefully for cognitive and motivational adverse events, a third domain, related to mood, emerged from the reports. Therefore, three domains, each with a number of subdomains, were identified from the interview accounts: (i) Cognition (six subdomains; attention/concentration, changes in thinking, reduced creativity, sensory overload, memory, slower processing speed); (ii) motivation (four subdomains; loss of intrinsic motivation for goal-directed activities, external locus of control, lack of effort/engagement in daily tasks, increased focus on incentives); and (iii) mood (three subdomains; dampening of spontaneity/flat affect, mood dysregulation, increased anxiety/edginess). On the basis of these reports, 34 items were specified and incorporated into a prototype questionnaire, which was piloted and refined on the basis of field-testing. Conclusions: Items were identified that capture potential/perceived cognitive, motivational, and mood-related adverse events of MPH. The items generated will allow us to further develop and psychometrically examine their prevalence, and the extent to which they are associated with medication adherence, treatment outcome, impairment, and other reported adverse events (e.g., loss of appetite/cardiovascular effects).

Association of Risk of Suicide Attempts With Methylphenidate Treatment

Importance Patients with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk of attempting suicide. Stimulants, such as methylphenidate hydrochloride, are the most common treatment for ADHD, but the association between their therapeutic use and suicide is unclear. Objective To investigate the association between methylphenidate and the risk of suicide attempts. Design, Setting, and Participants A population-based, electronic medical records database from the Hong Kong Clinical Data Analysis & Reporting System was used to identify 25 629 individuals aged 6 to 25 years who were treated with methylphenidate between January 1, 2001, and December 31, 2015. Those who had attempted suicide were included in the analysis. A self-controlled case series design was used to control for time-invariant characteristics of the patients. Main Outcomes and Measures Relative incidence of suicide attempt during periods when patients were exposed to methylphenidate compared with nonexposed periods. Results Among 25 629 patients with methylphenidate prescriptions, 154 had their first recorded suicide attempt within the study period; of these individuals, 111 (72.1%) were male; mean (SD) age at baseline was 7.15 (2.19) years. The overall incidence of suicide attempts during methylphenidate treatment was 9.27 per 10 000 patient-years. An increased risk of suicide attempts was detected during the 90-day period before methylphenidate was initiated, with an incidence rate ratio (IRR) of 6.55 (95% CI, 3.37-12.72). The IRR remained elevated during the first 90 days of treatment (IRR, 3.91; 95% CI, 1.62-9.42) before returning to baseline levels during ongoing treatment (IRR, 1.35; 95% CI, 0.77-2.38). When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of suicide attempts was not elevated (IRR, 0.78; 95% CI, 0.26-2.35). Conclusions and Relevance The incidence of suicide attempts was higher in the period immediately before the start of methylphenidate treatment. The risk remained elevated immediately after the start of methylphenidate treatment and returned to baseline levels during continuation of methylphenidate treatment. The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment. Therefore, this study’s results do not support a causal association between methylphenidate treatment and suicide attempts.

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

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management.ObjectivesOur objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.MethodsParticipants (aged 6–17xa0years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70xa0mg/day for 104xa0weeks. 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.ResultsOf 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 169.0xa0days; weight decrease, 29.0 and 225.0xa0days; insomnia, 17.0 and 42.8xa0days; and headache, 22.0 and 2.0xa0days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4–12xa0weeks. Psychiatric TEAEs were infrequent: psychosis and mania (nxa0=xa01), suicidal events (suicidal ideation, nxa0=xa02; suicide attempt, nxa0=xa01), and aggression events (aggression, nxa0=xa014; anger, nxa0=xa02; hostility, nxa0=xa01). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0xa0bpm (95% confidence interval [CI] 5.7–8.2); systolic blood pressure (SBP), 3.4xa0mmHgxa0(95% CI 2.2–4.5); and diastolic blood pressure (DBP), 3.2xa0mmHg (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 (−0.6xa0ms [95% CI −2.3 to 1.2]; range −50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1xa0kg (95% CI 1.5–2.8); height, 6.1xa0cm (95% CI 5.6–6.7); and body mass index (BMI), −0.5xa0kg/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.ConclusionsThe 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 IdentifierNCT01328756.

Randomized, Double-Blind, Placebo-Controlled Acute Comparator Trials of Lisdexamfetamine and Extended-Release Methylphenidate in Adolescents With Attention-Deficit/Hyperactivity Disorder

BackgroundPsychostimulants are considered first-line pharmacotherapy for youth with attention-deficit/hyperactivity disorder (ADHD), but questions remain regarding the comparative efficacy of amphetamine- and methylphenidate-based agents.ObjectiveOur objective was to describe two acute randomized, double-blind, placebo-controlled, head-to-head studies of lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) in adolescents with ADHD.MethodsAdolescents (13–17xa0years) diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria were enrolled in an 8-week flexible-dose study [LDX 30–70xa0mg/day (nxa0=xa0186 randomized); OROS-MPH 18–72xa0mg/day (nxa0=xa0185 randomized); placebo (nxa0=xa093 randomized)] or a 6-week forced-dose study [LDX 70xa0mg/day (nxa0=xa0219 randomized); OROS-MPH 72xa0mg/day (nxa0=xa0220 randomized); placebo (nxa0=xa0110 randomized)]. Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) total score changes from baseline (primary endpoint) at week 8 (flexible-dose study) or week 6 (forced-dose study) were assessed with mixed-effects models for repeated measures. Secondary endpoints included improvement on the dichotomized Clinical Global Impressions–Improvement scale (CGI-I; key secondary endpoint) and changes from baseline on the ADHD-RS-IV subscales. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs.ResultsLeast squares (LS) meanxa0±xa0standard error of the mean (SEM) ADHD-RS-IV total score changes from baseline to end of treatment were −17.0xa0±xa01.03 with placebo, −25.4xa0±xa00.74 with LDX, and −22.1xa0±xa00.73 with OROS-MPH in the forced-dose study and −13.4xa0±xa01.19 with placebo, −25.6xa0±xa00.82 with LDX, and −23.5xa0±xa00.80 with OROS-MPH in the flexible-dose study. LS meanxa0±xa0SEM treatment difference for the change from baseline significantly favored LDX over OROS-MPH in the forced-dose [−3.4xa0±xa01.04, pxa0=xa00.0013, effect size (ES) −0.33] but not the flexible-dose (−2.1xa0±xa01.15, pxa0=xa00.0717, ES −0.20) study. The percentage of improved participants on the dichotomized CGI-I at end of treatment was significantly greater with LDX than with OROS-MPH in the forced-dose study (81.4 vs. 71.3%, pxa0=xa00.0188) but not the flexible-dose study (LDX 83.1%, OROS-MPH 81.0%, pxa0=xa00.6165). The LS meanxa0±xa0SEM treatment differences for change from baseline on the ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscales nominally favored LDX in the forced-dose study (hyperactivity/impulsivity subscale −1.3xa0±xa00.49, nominal pxa0=xa00.0081, ES −0.27; inattentiveness subscale −2.0xa0±xa00.63, nominal pxa0=xa00.0013, ES −0.33), but there were no significant differences between active treatments in the flexible-dose study. In both studies, LDX and OROS-MPH were superior to placebo for all efficacy-related endpoints (all nominal pxa0<xa00.0001; ES range −0.43 to −1.16). The overall frequency of TEAEs for LDX and OROS-MPH, respectively, were 66.5 and 58.9% in the forced-dose study and 83.2 and 82.1% in the flexible-dose study. TEAEs occurring in ≥ 5% of participants that were also reported at two or more times the rate of placebo were decreased appetite, decreased weight, insomnia, initial insomnia, dry mouth, and nasopharyngitis (LDX and OROS-MPH), irritability and dizziness (LDX only), and increased heart rate (OROS-MPH only) in the forced-dose study and decreased appetite, decreased weight, insomnia, and dizziness (LDX and OROS-MPH) and dry mouth and upper abdominal pain (LDX only) in the flexible-dose study. Meanxa0±xa0standard deviation (SD) increases from baseline in vital signs (systolic and diastolic blood pressure, pulse) were observed in the forced-dose study [LDX 1.6xa0±xa09.65 and 3.3xa0±xa08.11xa0mmHg, 6.7xa0±xa012.78 beats per minute (bpm); OROS-MPH 2.6xa0±xa010.15 and 3.3xa0±xa09.13xa0mmHg, 7.6xa0±xa012.47 bpm] and the flexible-dose study (LDX 2.4xa0±xa09.46 and 2.8xa0±xa08.41xa0mmHg, 4.7xa0±xa011.82xa0bpm; OROS-MPH 0.4xa0±xa09.90 and 2.2xa0±xa08.64xa0mmHg, 6.0xa0±xa010.52xa0bpm) at the last on-treatment assessment.ConclusionsLDX was superior to OROS-MPH in adolescents with ADHD in the forced-dose but not the flexible-dose study. Safety and tolerability for both medications was consistent with previous studies. These findings underscore the robust acute efficacy of both psychostimulant classes in treating adolescents with ADHD.ClinicalTrials.gov registry numbersNCT01552915 and NCT01552902.

Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study

Introduction Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites. Methods and analysis 3 cohorts of children and adolescents (aged 6–17) living in the UK, Germany, Italy and Hungary are being recruited: Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time. Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication. Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2. All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score. Ethics and dissemination Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The studys website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public. Trial registration number NCT01470261.

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

BackgroundStimulant 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.ObjectiveThe 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.MethodsChildren and adolescents aged 6–17xa0years with attention-deficit/hyperactivity disorder took open-label lisdexamfetamine dimesylate (30, 50 or 70xa0mg/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.ResultsThe safety analysis population comprised all enrolled participants (Nu2009=u2009314) 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 2.1xa0kg (standard deviation 5.83) and height of 6.1xa0cm (standard deviation 4.90), and a body mass index decrease of 0.5xa0kg/m2 (standard deviation 1.72). Mean weight, height and body mass index z-scores decreased over the first 36xa0weeks 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 (−u20090.51, −u20090.24 and −u20090.59, respectively; nominal pu2009<u20090.0001). The proportion of participants with a z-score of <u2009−u20091 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.ConclusionsFindings from this comprehensive examination of growth outcomes associated with lisdexamfetamine dimesylate treatment over 2xa0years 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 identifierNCT01328756.