1 Introduction
Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that is estimated to affect approximately 5 % of children and adolescents and 3 % of adults worldwide [
1‐
3]. ADHD is characterized by symptoms of inattention, hyperactivity and/or impulsivity and is associated with substantial functional impairment across the lifespan [
4,
5]. In addition, ADHD is associated with reduced health-related quality of life for both patients and their families [
6]. The prodrug stimulant lisdexamfetamine dimesylate (LDX) is an effective treatment for ADHD in children, adolescents and adults [
7‐
13] and is currently licensed as a first-line pharmacological therapy for ADHD in the US, Canada, Brazil and Australia. LDX is the only long-acting amfetamine formulation available in Europe, where it is licensed in several countries for the treatment of ADHD in children aged 6 years and over when the response to previous methylphenidate (MPH) therapy is considered clinically inadequate.
Instruments such as the ADHD Rating Scale IV (ADHD-RS-IV) [
14], the Swanson, Nolan and Pelham version IV (SNAP-IV) scale [
15,
16] and the Conners’ Parent Rating Scale-Revised (CPRS-R) [
17] may be used in routine clinical practice to assess symptoms in patients with ADHD, and changes in mean scores provide evidence of treatment-related improvements in symptoms. Considerable normative data are available for these scales and they have all demonstrated good reliability and discriminant validity in children and adolescents [
14,
18]. However, while informative, changes in mean rating-scale scores cannot describe the degree of symptom improvement experienced at an individual level. An alternative approach to assessing the efficacy of a medication in patients with ADHD is to conduct responder analyses in order to establish the proportion of patients who show a clinically relevant response to treatment, where clinical response is defined a priori. The value of responder analyses when assessing the benefits of pharmacological treatment options is recognized by the requirement of the European Medicines Agency (EMA) that clinical response outcomes be included in all European regulatory trials for new ADHD medications [
19]. Another approach to exploring clinical benefit at the level of the individual is to examine the numbers of patients who shift to a less severe Clinical Global Impressions (CGI)–Severity (CGI–S) category as a result of treatment.
The primary efficacy and safety outcomes from a head-to-head study of LDX and atomoxetine (ATX) in the treatment of ADHD have been reported (study SPD489-317; ClinicalTrials.gov identifier: NCT01106430) [
20]. This 9-week, double-blind, randomized study was conducted in children and adolescents who had previously responded inadequately to MPH. In this primary analysis, a single definition of clinical response was used—a CGI–Improvement (CGI–I) score of 1 or 2. The time to first clinical response (the primary study endpoint) was significantly shorter with LDX treatment than with ATX treatment (median, 12.0 days and 21.0 days, respectively;
p = 0.001), and the proportion of patients with a CGI–I score of 1 or 2 by the end of the 9-week study was significantly higher (81.7 and 63.6 %, respectively;
p = 0.001) [
20]. Owing to a lack of consensus within the published literature on the most appropriate definition of clinical response, we now report the results of further prespecified responder analyses from SPD489-317. These are based on multiple ADHD-RS-IV and CGI–I criteria that have been used in previous responder analyses to assess the efficacy of LDX or ATX treatment [
7,
21‐
27]. We also present shifts from baseline to week 9 in patients’ severity of illness based on CGI–S categories as an indication of remission.
4 Discussion
In these analyses of data from the first head-to-head, randomized, controlled trial of LDX and ATX, LDX treatment was consistently associated with statistically significantly higher rates of clinical response than ATX treatment in children and adolescents with ADHD and an inadequate response to MPH, irrespective of the ADHD-RS-IV or CGI–I criteria used to define response (p < 0.01 for all comparisons). In addition, the proportions of patients with a sustained response, defined as those who met response criteria throughout weeks 4–9, were also statistically significantly higher among patients receiving LDX than among those receiving ATX (p < 0.05 for all comparisons). Finally, after 9 weeks of treatment, the proportion of patients who had low levels of disease severity (CGI–S score of 1 or 2) was numerically higher among individuals receiving LDX than among those receiving ATX.
The present responder data, and those previously reported for this study which found that a significantly greater proportion of patients receiving LDX (81.7 %) than ATX (63.6 %) achieved a CGI–I score of 1 or 2 by visit 9 (
p < 0.01) [
20], are generally consistent with those observed in previous studies of LDX and ATX, despite differences in study designs and patient populations [
7,
20‐
23,
25‐
27]. Several other clinical trials have found LDX to be associated with significantly higher proportions of treatment responders than placebo irrespective of the age of the patients [
7,
20,
23,
25,
27]. When clinical response was defined as at least a 30 % reduction from baseline in ADHD-RS-IV total score, approximately 65 % of adult patients receiving LDX were categorized as responders after 4 weeks of treatment, compared with approximately 35 % of those receiving placebo [
7]. Three LDX studies used the combined response criteria of at least a 30 % reduction from baseline in ADHD-RS-IV total score and a CGI–I score of 1 or 2. First, a US-based study in children with ADHD found that 79.3 % of patients treated with LDX responded, compared with 29.2 % of those receiving placebo [
25]. Among the subgroup of study participants who had previously experienced an inadequate response to MPH treatment, response rates for LDX (78.9 %) were similar to those in the overall study population and to the responder rates observed for LDX in the present study, which was also conducted in patients with a history of inadequate response to MPH treatment [
20,
25]. Second, clinical response was examined post hoc in a 12-month, open-label LDX study in adults with ADHD, categorized according to their baseline CGI–S score (4, 5 or ≥6) [
23]. This study revealed numerically higher (a statistical analyses was not performed) proportions of clinical responders among individuals with more severe baseline illness than those with less severe baseline illness (CGI–S of 4, 78.9 %; CGI–S of 5, 83.5 %; CGI–S of ≥6, 88.4 %) [
23]. In addition, 71.3 % of patients had at least a 50 % reduction from baseline in ADHD-RS-IV total score [
23], a value which, despite differences in study design and population, is very similar to the results of the present 9-week, double-blind, paediatric study (LDX, 73.0 %). Third, 74.2 % of patients receiving LDX compared with 10.7 % of those receiving placebo met the combined response criteria in a 7-week European regulatory trial in children and adolescents with ADHD, and 78.0 and 14.4 %, respectively, had a CGI–I score of 1 or 2 at endpoint [
27]. As required by the EMA, this last study included an active comparator treatment (osmotic-release oral system MPH; OROS-MPH) to validate the study design and to contextualize the results. A post hoc comparison indicated that the proportion of patients who responded to LDX was significantly (
p < 0.05) larger than the proportion who responded to OROS-MPH (combined criteria, 55.9 %; CGI–I of 1 or 2, 60.6 %) [
27]. Given that this study was neither designed nor powered to provide a direct comparison between treatments, these findings should be considered as preliminary. The results of ongoing parallel-group studies in adolescents (ClinicalTrials.gov identifiers: NCT01552915 and NCT01552902) will provide definitive evidence of the relative benefits of LDX and MPH.
The results of the present responder analyses are also broadly consistent with those of previous studies of ATX. Pooled data from six randomized controlled trials of 6–9 weeks in duration in children and adolescents with ADHD (
N = 1,069) revealed that 60 % of patients had at least a 25 % reduction from baseline in ADHD-RS-IV total score, and 47 % had a decrease of at least 40 % [
21]. Another pooled analysis combined data from three Canadian open-label studies in children and predicted that 75 % of patients would achieve at least a 25 % reduction from baseline in ADHD-RS-IV total score after 7.2 weeks of ATX treatment [
22]. This finding is very similar to the results of the present study. A meta-analysis indicated that the proportions of patients with a clinically relevant response to ATX were not significantly different from the proportions responding to MPH treatment, when response was defined as a reduction of at least 40 % (53.6 vs. 54.4 %) or at least 25 % (69.0 vs. 70.0 %) from baseline in ADHD-RS-IV total score, or as achieving a CGI–S score of 1 or 2 (18.2 vs. 24.3 %) [
24]. However, it should be noted that only one of the seven studies included in the meta-analysis compared ATX with a long-acting MPH formulation (OROS-MPH), and in that study the clinical response to OROS-MPH was superior to that of ATX [
26].
Responder analyses allow the degree of clinically meaningful symptom improvement in individual patients to be established. Despite the recognized benefits of responder analyses, a consensus has not been reached on the most appropriate criteria to use when assessing clinical response to ADHD medication and, as described above, various response criteria have been used in studies assessing the efficacy of LDX and ATX. In the present study, increasing the degree of change in ADHD-RS-IV total score required for response resulted in a decrease in responder rates. Response rates based on a CGI–I score of 1 or 2 [
20] appeared to correspond with an ADHD-RS-IV total score reduction of between 30 and 50 %. This is slightly lower than findings from a previous analysis of two LDX studies in paediatric populations, where reductions from baseline in ADHD-RS-IV total score of 80, 52 and 27 % correspond to CGI–I scores of 1 (very much improved), 2 (much improved) and 3 (minimally improved), respectively, perhaps due to differences in study design. The authors of that study suggested that on the basis of these results, a reduction in ADHD-RS-IV total score of at least 50 % should be used to define clinical response [
30].
Despite a continued lack of consensus on the appropriate threshold to use when defining a clinically relevant response to treatment, it was clear in the present head-to-head study that the relative benefits of LDX compared with ATX treatment remained similar irrespective of which response criterion was used. This finding is consistent with a meta-analysis of 32 clinical trials that concluded that both short- and long-acting psychostimulants were significantly more effective than non-stimulants [
31]. The present study also examined sustained response, revealing that a significantly larger proportion of patients receiving LDX than those receiving ATX met continued response criteria throughout weeks 4–9. This is the first study of either LDX or ATX to determine sustained response, an obviously desirable outcome in the clinical setting.
A criticism of responder analyses is that they do not take into account patients’ baseline disease severity. Therefore, individuals with severe baseline symptoms may meet clinical response criteria at study endpoint despite significant residual symptoms and/or impairment. To address this, some studies have assessed the proportions of patients whose symptoms reduce to below a defined ‘remission’ threshold. However, a consensus has still to be reached on the most appropriate criterion to be used to define remission. In previous studies of LDX and ATX, an ADHD-RS-IV score of 18 or less [
22,
23,
25] or a CGI–S score of 2 or less [
22,
32] were used to define remission. In the present study, CGI–S scores (based on LOCF) revealed that 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI–S score of 2 or less by week 9. These values are consistent with those observed in a pooled analysis of three open-label studies which concluded that the probability of children achieving a CGI–S score of 2 or less was 8 % after 4 weeks of ATX treatment and 47 % after 12 weeks of ATX treatment [
22].
Safety outcomes from this study have previously been published [
20]. In summary, similar proportions of patients in both treatment groups reported TEAEs (LDX, 71.9 %; ATX, 70.9 %). In addition, changes in mean vital signs and ECG parameters, and in the frequency of outliers and potentially clinically important observations, were generally similar between treatment groups [
20].
The strengths of this study include its double-blind, randomized, parallel-group, dose-optimized design, and the large international patient population. In addition, the results are particularly pertinent in Europe, given the recent approval of LDX in several European countries for the treatment of children and adolescents in whom previous MPH treatment was clinically inadequate; under these circumstances, the choice of medication in most countries will be between LDX and ATX. It is unclear whether this highly selected patient population, who were required to meet multiple inclusion and exclusion criteria relating to their previous exposure and/or response to ADHD medication, would have been more likely to respond to one treatment arm than the other. However, similarities in the results of this and other studies suggest that these inclusion/exclusion criteria do not unduly favour either treatment arm. In addition, the details of the study design, as described in the paediatric investigation plan, were agreed with the EMA. A potential limitation of this study is the 9-week duration which might have limited the potential benefits of ATX. Indeed, a meta-analysis of pooled data from ATX studies (
N = 601) indicated that the response to ATX continued to grow for as long as 12 weeks, although most of the improvement occurred during the first 4 weeks and any subsequent further improvement occurred in conjunction with increasing mean ATX dose [
33]. There is also evidence to suggest that higher doses of ATX than used in the present study and recommended in the product’s prescribing information (up to 1.8 mg/kg) may result in higher levels of efficacy of ATX [
34,
35]. In addition, there is some evidence that ATX is more effective when administered twice daily than once daily, as used in the present study [
34]. Finally, although there are only three available LDX doses, a greater variety of doses are available for ATX. Therefore, the length of the dose-optimization period of the study may not have permitted all ATX doses to be fully explored, which may have affected patient outcomes in the ATX treatment group.
Acknowledgements
This study was supported by funding from Shire. The authors thank the patients and their parents, and the investigators who took part in the study. Esther Cardo, David R. Coghill, Ralf W. Dittmann and Peter Nagy were principal investigators in this clinical study. Colleen S. Anderson, Beatriz Caballero, Richard Civil, Ralf W. Dittmann and Paul Hodgkins contributed to the study design. Ben Adeyi was responsible for the statistical analysis. All authors were involved in the discussion and interpretation of the data, critically revised the article and approved the manuscript before submission. Dr Tamzin Gristwood and Dr Eric Southam of Oxford PharmaGenesis™ Ltd provided writing and editing assistance, collated the comments of the authors and edited the manuscript for submission, with funding from Shire. Ben Adeyi, Colleen S. Anderson and Beatriz Caballero are employees of Shire and own stock/stock options. Richard Civil is a former employee of Shire. Paul Hodgkins is a former employee of Shire and a current employee of Vertex Pharmaceuticals. The following authors have received compensation for serving as consultants or speakers, or they, or the institutions they work for, have received research support or royalties from the companies or organizations indicated: Esther Cardo (Eli Lilly, Health Spanish Ministry Research Fund, Ministry of Education Grant Research, Shire, UCB); David R. Coghill (Flynn Pharma, Janssen-Cilag, Lilly, Medice, Novartis, Otsuka, Oxford University Press, Pfizer, Schering-Plough, Shire, UCB, Vifor Pharma); Ralf W. Dittmann (Ferring, Janssen-Cilag, Lilly, Otsuka, Shire, German Research Foundation [DFG], German Ministry of Education and Research [BMBF], Ministry of Health/German Regulatory Body [BfArM], European Union [EU FP7 program], US National Institute of Mental Health (NIMH), and he is a former employee and stockholder of Eli Lilly and Co.); Peter Nagy (Tourette Syndrome Association of USA, Hungarian Ministry of Education, National Development Agency of Hungary, Otsuka, Shire).