Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder

Abstract

Background: Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD.

Methods: In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an "optimal" LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission.

Results: Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits.

Conclusion: In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months.

Trial registration: Clinical Trial Numbers: NCT00334880 and NCT01070394CLINICAL TRIAL REGISTRY: clinicaltrials.gov.

Figure 1

Kaplan-Meier plot: time to median clinical response from baseline in the short-term study by LDX treatment group (efficacy population, n=414). Log rank P-value: <.0001. P-value indicates overall significant effect among the treatment groups and was not specifically tested between any individual dose groups. Abbreviations: d=day; LDX=lisdexamfetamine dimesylate.

Figure 2

Kaplan-Meier plot: time to median symptomatic remission from baseline in the short-term study by LDX treatment group (efficacy population, n=414). Log rank P-value: <.0001. P-value indicates overall significant effect among the treatment groups and was not specifically tested between any individual dose groups. Abbreviations: d=day; LDX=lisdexamfetamine dimesylate.

Figure 3

Percentage of participants optimized to each dose, among participants who completed dose optimization (n=327). Percentages have been rounded; total tally may not equal 100%. Abbreviations: d=day; LDX=lisdexamfetamine dimesylate.

Figure 4

Percentage of participants who achieved clinical response and maintained clinical response and Kaplan-Meier time course (inset) of attainment (a) and loss (b) of clinical response from baseline in the long-term study for all LDX treatment groups. For attainment (a), log rank P-value: .0115; time to first clinical response was calculated from first day of study for participants who entered the maintenance phase of the study (n=327), response status at the start of the long-term study was not determined, and first on-treatment assessment of Attention-Deficit/Hyperactivity Disorder Rating Scale IV and Clinical Global Impressions-Improvement were at week 1; P-value indicates overall significant effect among the treatment groups and was not specifically tested between any individual dose groups. For loss (b), log rank P-value: .5531; time to loss of clinical response during the maintenance phase was calculated for participants who met criteria for response (n=278) at week 4 (visit 5); P-value indicates overall significant effect among the treatment groups and was not specifically tested between any individual dose groups. Abbreviation: LDX=lisdexamfetamine dimesylate.

Figure 5

Percentage of participants who achieved symptomatic remission and maintained symptomatic remission and Kaplan-Meier time course (inset) of attainment (a) and loss (b) of symptomatic remission in the long-term study for all LDX treatment groups. For attainment (a), log rank P-value: .0012; time to first symptomatic remission was calculated from the first day of the study for participants who entered the maintenance phase of the study (n=327), remission status at the start of the long-term study was not determined, and first on-treatment assessment of Attention-Deficit/Hyperactivity Disorder Rating Scale IV was at week 1; P-value indicates overall significant effect among the treatment groups and was not specifically tested between any individual dose groups. For loss (b), log rank P-value: .0385; time to loss of symptomatic remission during the maintenance phase was calculated for participants who met criteria for remission (n=213) at week 4 (visit 5); P-value indicates overall significant effect among the treatment groups and was not specifically tested between any individual dose groups. Abbreviation: LDX=lisdexamfetamine dimesylate.