Efficacy and tolerability of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: sex and age effects and effect size across the day

<p>Abstract</p> <p>Background</p> <p>Efficacy and safety profiles by sex and age (6-9 vs 10-12 years) and magnitude and duration of effect by effect size overall and across the day of lisdexamfetamine dimesylate (LDX) vs placebo were assessed.</p> <p>Methods</p> <p>This study enrolled children (6-12 years) with attention-deficit/hyperactivity disorder (ADHD) in an open-label dose optimization with LDX (30-70 mg/d) followed by a randomized, double-blind, placebo-controlled, 2-way crossover phase. Post hoc analyses assessed interaction between sex or age and treatment and assessed effect sizes for Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) and Permanent Product Measure of Performance (PERMP) scales and ADHD Rating Scale IV measures. No corrections for multiple testing were applied on time points and subgroup statistical comparisons.</p> <p>Results</p> <p>129 participants enrolled; 117 randomized. Both sexes showed improvement on all assessments at postdose time points; females showed less impairment than males for SKAMP and PERMP scores in treatment and placebo groups at nearly all times. Both age groups improved on all assessments at postdose time points. Children 10-12 years had less impairment in SKAMP ratings than those 6-9 years. Treatment-by-sex interactions were observed at time points for SKAMP-D, SKAMP total, and PERMP scores; no consistent pattern across scales or time points was observed. LDX demonstrated significant improvement vs placebo, by effect size, on SKAMP-D from 1.5-13 hours postdose. The overall LS mean (SE) SKAMP-D effect size was -1.73 (0.18). In the dose-optimization phase, common (≥2%) treatment-emergent adverse events (TEAEs) in males were upper abdominal pain, headache, affect lability, initial insomnia, and insomnia; in females were nausea and decreased weight. During the crossover phase for those taking LDX, higher incidence (≥2% greater) was observed in males for upper abdominal pain and insomnia and in females for nausea and headache. Overall incidence of TEAEs in age groups was similar.</p> <p>Conclusion</p> <p>Apparent differences in impairment level between sex and age groups were noted. However, these results support the efficacy of LDX from 1.5 hours to 13 hours postdose in boys and girls with medium to large effect sizes across the day with some variability in TEAE incidence by sex.</p> <p>Trial Registration Number</p> <p>ClinicalTrials.gov Identifier: <a href="http://clinicaltrials.gov/ct2/show/NCT00500149">NCT00500149</a>.</p

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

BackgroundLisdexamfetamine 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.MethodsChildren 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.ResultsA 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 &lt; .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).ConclusionIn 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 registrationOfficial 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

A systematic review of the safety of lisdexamfetamine dimesylate

BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants

Efficacy of lisdexamfetamine dimesylate throughout the day in children and adolescents with attention-deficit/hyperactivity disorder:results from a randomized, controlled trial

Lisdexamfetamine dimesylate (LDX) is a long-acting, prodrug stimulant therapy for patients with attention-deficit/hyperactivity disorder (ADHD). This randomized placebo-controlled trial of an optimized daily dose of LDX (30, 50 or 70 mg) was conducted in children and adolescents (aged 6–17 years) with ADHD. To evaluate the efficacy of LDX throughout the day, symptoms and behaviors of ADHD were evaluated using an abbreviated version of the Conners’ Parent Rating Scale-Revised (CPRS-R) at 1000, 1400 and 1800 hours following early morning dosing (0700 hours). Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment, but the study was not designed to support a statistical comparison between LDX and OROS-MPH. The full analysis set comprised 317 patients (LDX, n = 104; placebo, n = 106; OROS-MPH, n = 107). At baseline, CPRS-R total scores were similar across treatment groups. At endpoint, differences (active treatment − placebo) in least squares (LS) mean change from baseline CPRS-R total scores were statistically significant (P < 0.001) throughout the day for LDX (effect sizes: 1000 hours, 1.42; 1400 hours, 1.41; 1800 hours, 1.30) and OROS-MPH (effect sizes: 1000 hours, 1.04; 1400 hours, 0.98; 1800 hours, 0.92). Differences in LS mean change from baseline to endpoint were statistically significant (P < 0.001) for both active treatments in all four subscales of the CPRS-R (ADHD index, oppositional, hyperactivity and cognitive). In conclusion, improvements relative to placebo in ADHD-related symptoms and behaviors in children and adolescents receiving a single morning dose of LDX or OROS-MPH were maintained throughout the day and were ongoing at the last measurement in the evening (1800 hours)

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

The Author(s) 2014. This article is published with open access at Springerlink.com Objectives A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and ato-moxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactiv-ity 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. Methods In this 9-week, double-blind, active-controlled study, patients aged 6–17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients \70 kg: 0.5–1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients C70 kg: 40, 80 or 100 mg/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 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (C25, C30 or C50 %) 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. Results A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p \ 0.01) 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 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also signifi-cantly (p \ 0.05) higher among LDX-treated patient

An observational study of once-daily modified-release methylphenidate in ADHD: the effect of previous treatment on ADHD symptoms, other externalising symptoms and quality-of-life outcomes

Methylphenidate (MPH) is the most commonly prescribed stimulant for children with ADHD. Data on the effects of different MPH formulations in real-life settings are scarce, and the role of previous therapy on treatment outcome when switching medications has not been well studied. OBSEER was an observational study designed to evaluate the effectiveness and safety of Equasym XL® in routine care. This study assessed whether the improvements reported with Equasym XL® are influenced by the degree of symptom control achieved with the previous medication. Patients enrolled in OBSEER were stratified by prior treatment (none, MPH-immediate release [IR] once daily [o.d.] [MPH-IR o.d.], MPH-IR repeated [MPH-IR >o.d.] and MPH-MR [modified release] excluding Equasym XL®), and changes in ADHD and other externalising symptoms (CGI-S, FBB-ADHD and DAYAS) and quality of life (QoL, KINDL) were evaluated during treatment with Equasym XL®. A total of 782 patients were analysed. Significant group-by-time interactions were found for all symptom variables analysed, indicating that effects varied by previous medication. For CGI-S and FBB-ADHD total scores, the greatest reductions in ADHD symptoms were observed in the treatment-naïve subgroup, followed (in order) by MPH-IR o.d., MPH-IR >o.d. and MPH-MR. A similar profile was seen for DAYAS ratings for all periods of the day except the evening, when there were no significant differences between subgroups. Similarly, the treatment-naïve and MPH-IR o.d. subgroups showed the greatest improvements in KINDL ratings. Although effects were greatest for treatment-naïve patients, improvements were also observed in the prior treatment subgroups for symptoms and QoL. This suggests that a change to Equasym XL® may be beneficial in patients with suboptimal effects on prior medication

Assessment of daily profiles of ADHD and ODD symptoms, and symptomatology related to ADHD medication, by parent and teacher ratings

DAYAS is a new two-part rating scale that assesses: (1) ADHD and ODD symptoms (externalising symptom ratings) and (2) symptomatology potentially related to ADHD medication (potentially medication-related symptoms) in real-world settings at different time periods throughout a normal school day. Data from a proof-of-concept study and two observational trials (Medikinet® retard [methylphenidate] and the Equasym XL® [methylphenidate] OBSEER study) evaluated: (1) validity of weekly externalising symptom ratings using DAYAS, in place of daily ratings; (2) reliability and internal consistency of DAYAS ratings for externalising symptoms and potentially medication-related symptoms; and (3) convergent and divergent validity of the externalising symptom ratings with existing validated scales. From the proof-of-concept study, daily scores by period of day and during the whole day correlated strongly with equivalent weekly scores (r = 0.83–0.92). Internal consistency of externalising symptom rating scales calculated from pooled data were acceptable or good by period of day (Cronbach’s alpha = 0.68–0.90) and very high for whole day scores (Cronbach’s alpha = 0.88–0.95). Internal consistency of the rating scale for potentially medication-related symptoms was also good for both teacher and parent ratings. From OBSEER data, correlations between FBB-ADHD total symptom scores and ratings on both parent and teacher versions of DAYAS were high (r = 0.73 and r = 0.84, respectively). Correlations between DAYAS and SDQ were highest for the SDQ subscales hyperactivity and conduct problems and substantially lower for pro-social behaviour, peers and emotional problems. The DAYAS rating scale had good internal consistency, and DAYAS scores correlated well with existing validated scales and the SDQ subscales hyperactivity and conduct problems. Weekly DAYAS scores (whole day and by period of day) could be considered a suitable replacement for daily assessment scores

Efficacy of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder previously treated with methylphenidate: a post hoc analysis

<p>Abstract</p> <p>Background</p> <p>Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral psychiatric disorder that afflicts children, with a reported prevalence of 2.4% to 19.8% worldwide. Stimulants (methylphenidate [MPH] and amphetamine) are considered first-line ADHD pharmacotherapy. MPH is a catecholamine reuptake inhibitor, whereas amphetamines have additional presynaptic activity. Although MPH and amphetamine can effectively manage ADHD symptoms in most pediatric patients, many still fail to respond optimally to either. After administration, the prodrug stimulant lisdexamfetamine dimesylate (LDX) is converted to l-lysine and therapeutically active d-amphetamine in the blood. The objective of this study was to evaluate the clinical efficacy of LDX in children with ADHD who remained symptomatic (ie, nonremitters; ADHD Rating Scale IV [ADHD-RS-IV] total score > 18) on MPH therapy prior to enrollment in a 4-week placebo-controlled LDX trial, compared with the overall population.</p> <p>Methods</p> <p>In this post hoc analysis of data from a multicenter, randomized, double-blind, forced-dose titration study, we evaluated the clinical efficacy of LDX in children aged 6-12 years with and without prior MPH treatment at screening. ADHD symptoms were assessed using the ADHD-RS-IV scale, Conners' Parent Rating Scale-Revised short form (CPRS-R), and Clinical Global Impressions-Improvement scale, at screening, baseline, and endpoint. ADHD-RS-IV total and CPRS-R ADHD Index scores were summarized as mean (SD). Clinical response for the subgroup analysis was defined as a ≥ 30% reduction from baseline in ADHD-RS-IV score and a CGI-I score of 1 or 2. Dunnett test was used to compare change from baseline in all groups. Number needed to treat to achieve one clinical responder or one symptomatic remitter was calculated as the reciprocal of the difference in their proportions on active treatment and placebo at endpoint.</p> <p>Results</p> <p>Of 290 randomized participants enrolled, 28 received MPH therapy at screening, of which 26 remained symptomatic (ADHD-RS-IV > 18). ADHD-RS-IV total scores, changes from baseline, clinical responsiveness, and rates of symptomatic remission in this subgroup were comparable to the overall population. The safety and tolerability profiles for LDX were comparable to other stimulants currently available.</p> <p>Conclusion</p> <p>In this analysis, children with significant clinical ADHD symptoms despite MPH treatment improved during treatment with LDX and experienced similar improvements in their symptoms as the overall study population.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00556296">NCT00556296</a></p

An observational study of once-daily modified-release methylphenidate in ADHD: effectiveness on symptoms and impairment, and safety

ADHD affects over 5% of children worldwide. It is typically treated with stimulant medications, and methylphenidate (MPH) is the most commonly prescribed. This study investigated the effectiveness, on symptoms and impairment, and safety of Equasym XL®, a combination of 30% immediate-release and 70% modified-release MPH, in the treatment of ADHD in daily clinical practice. This open-label, observational, post-marketing surveillance study was conducted in 169 centres in Germany. Eligible patients, aged 6–17 years, were diagnosed with ADHD and about to begin treatment with Equasym XL®. Effectiveness was assessed by physicians using the clinical global impression (CGI) severity and improvement scales; teachers and parents completed questionnaires evaluating ADHD symptoms and behavioural problems (DAYAS, FBB-ADHD and SDQ-P). Assessments were carried out at baseline, after 1–3 and 6–12 weeks of treatment. Of 852 enrolled patients, 822 were evaluable; 25.30% were treatment naïve, 69.84% had previously received different MPH formulations, and 4.87% had received other medications. ADHD symptoms improved from baseline to last visit for the majority of patients for all outcome measures. According to physician ratings of core ADHD symptoms, 75.73% of patients showed improvements on the CGI-Improvement scale, 17.77% had no change, and 6.50% worsened. In teacher and parent ratings, the effectiveness of Equasym XL® was rated better than prior therapy at all measured time points across the day, particularly late morning (teachers) and early afternoon (parents). Equasym XL® was generally well tolerated; only 3.16% of patients permanently discontinued treatment due to adverse events. Equasym XL® is effective and well tolerated in daily clinical practice

Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies

<p>Abstract</p> <p>Background</p> <p>The relatively short durations of the initial pivotal randomized placebo-controlled trials involving atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder (ADHD) provided limited insight into the time courses of ADHD core symptom responses to this nonstimulant, selective norepinephrine reuptake inhibitor. The aim of this analysis was to evaluate time courses of treatment responses or remission, as assessed by attainment of prespecified scores on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scales, during up to 1 year of atomoxetine treatment in children with ADHD.</p> <p>Methods</p> <p>Using pooled data from three Canadian open-label studies involving 338 children ages 6-11 years with ADHD who were treated with atomoxetine for 3, 6 and 12 months, and survival analysis methods for interval-censored data, we estimated the time to: 1) improvement and robust improvement defined by ≥25% and ≥40% reductions from baseline ADHDRS-IV-PI total scores, respectively; and 2) remission using two definitions: a final score of ADHDRS-IV-PI ≤18 or a final score of CGI-ADHD-S ≤2.</p> <p>Results</p> <p>The median time to improvement was 3.7 weeks (~1 month), but remission of symptoms did not occur until a median of 14.3 weeks (~3.5 months) using the most stringent CGI-ADHD-S threshold. Probabilities of robust improvement were 47% at or before 4 weeks of treatment; 76% at 12 weeks; 85% at 26 weeks; and 96% at 52 weeks. Probabilities of remission at these corresponding time points were 30%, 59%, 77%, and 85% (using the ADHDRS-IV scale) and 8%, 47%, 67%, and 75% (using the CGI-ADHD-S scale). The change from atomoxetine treatment month 5 to month 12 of -1.01 (1.03) was not statistically significant (<it>p </it>= .33).</p> <p>Conclusions</p> <p>Reductions in core ADHD symptoms during atomoxetine treatment are gradual. Although approximately one-half of study participants showed improvement at 1 month of atomoxetine treatment, remission criteria were not met until about 3 months. Understanding the time course of children's responses to atomoxetine treatment may inform clinical decision making and also influence the durations of trials comparing the effects of this medication with other ADHD treatments.</p> <p>Trial Registrations</p> <p>clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00191633">NCT00191633</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00216918">NCT00216918</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00191880">NCT00191880</a>.</p