Health-related quality of life and functional outcomes from a randomized-withdrawal study of long-term lisdexamfetamine dimesylate treatment in children and adolescents with attention-deficit/hyperactivity disorder

Abstract

Background: The stimulant prodrug lisdexamfetamine dimesylate (LDX) is an effective and generally well tolerated treatment for the symptoms of attention-deficit/hyperactivity disorder (ADHD). Positive impacts of LDX on health-related quality of life and functional impairment have previously been demonstrated in a 7-week, randomized, double-blind, placebo-controlled, phase III study in children and adolescents in Europe. Maintenance of these broad benefits, as well as symptomatic control, is a key goal of long-term management of ADHD.

Objective: Secondary objectives of this multinational study in children and adolescents with ADHD were to assess the long-term maintenance of effectiveness of LDX in improving health-related quality of life and reducing functional impairment, as gauged using the Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE: PRF) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P), respectively.

Methods: Patients aged 6-17 years with diagnosed ADHD and a baseline ADHD Rating Scale IV total score of at least 28 were enrolled from the previous European study and from US sites. Patients who completed an open-label LDX treatment period of at least 26 weeks were randomized (1:1) to continue on their optimized dose of LDX or to switch to placebo for a 6-week, double-blind, withdrawal period. Parents completed CHIP-CE: PRF and WFIRS-P questionnaires at weeks 0, 8 and 26 of the open-label period and at weeks 0 and 6 of the randomized-withdrawal period, or at early termination. The endpoint of each period was defined as the last visit with valid data. Effect sizes were the difference (LDX minus placebo) in least-squares (LS)-mean change from baseline to endpoint divided by root-mean-square error. P values were nominal and not adjusted for multiple comparisons.

Results: The open-label and randomized full analysis sets comprised 262 and 153 (LDX n = 76; placebo n = 77) patients, respectively. Mean pretreatment CHIP-CE: PRF T-scores were more than one standard deviation below the normative mean in four of the five domains, and there was significant improvement across all domains from baseline to endpoint of the open-label period. In the randomized-withdrawal period, LS-mean CHIP-CE: PRF T-scores deteriorated in all domains in the placebo group, but not in the LDX group. Compared with placebo, the effect of LDX was significant in the Risk Avoidance (effect size 0.829; p < 0.001), Achievement (0.696; p < 0.001) and Satisfaction (0.636; p < 0.001) domains. Mean pretreatment WFIRS-P scores were lowest in the Family domain and the Learning and School domain. WFIRS-P total score and scores in all domains improved significantly from baseline to endpoint of the open-label period. In the randomized-withdrawal period, LS-mean scores deteriorated in the placebo group but not in the LDX group. Compared with placebo, the effect of LDX was significant in the Family, Learning and School, and Risky Activities domains and in total (effect size 0.908; p < 0.001).

Conclusions: Using parent-rated instruments, long-term maintenance of the beneficial effect of LDX in multiple domains of health-related quality of life and functional impairment was demonstrated by comparison of treatment continuation and withdrawal under randomized, double-blind, placebo-controlled conditions.

Trial registration: ClinicalTrials.gov NCT00784654.

Figures

Fig. 1

SPD489-326 study design. CHIP-CE: PRF and WFIRS-P assessments were performed at the visits shown boxed, and/or at an early termination visit attended by patients who discontinued the study. aFor directly recruited patients only; other patients completed screening and washout as part of SPD489-325, the previous European, phase III study. bScreening and washout occurred 1–6 weeks before visit 1 for directly recruited patients. cSee Table 1 for definitions of baseline and endpoint in the open-label and randomized-withdrawal periods. dExtended dose-maintenance phase for patients enrolled under the original protocol. These patients may have attended one or more additional visits (shown in grey) before entering the fixed-dose period. eItalicized numbers show weeks of the randomized-withdrawal period. CHIP-CE: PRF Child Health and Illness Profile-Child Edition: Parent Report Form, R revised, WFIRS-P Weiss Functional Impairment Rating Scale-Parent Report

Fig. 2

CHIP-CE: PRF T-scores during the open-label period (n = 262). a Mean T-scores at open-label baseline and histogram showing mean change from open-label baseline to endpoint for CHIP-CE: PRF domains and subdomains. Error bars show 95 % CIs. Positive changes indicate improved HRQoL. ***p < 0.001, **p < 0.01, change at endpoint versus baseline (two-sided t test). P values are nominal and were not adjusted for multiple comparisons. b Mean CHIP-CE: PRF domain T-scores at baseline (BL), endpoint (EP), visit 6 (V6 8 weeks) and visit 3R (V3R ≥26 weeks) of the open-label period. Error bars show 95 % confidence intervals. These data were not subjected to statistical testing. Numbers of observations (n) are shown for each data point. A T-score of 43 or below indicates poor HRQoL in a domain or subdomain; a T-score of 57 or above indicates excellent HRQoL [20]. The horizontal axis is positioned at the normative mean (T-score of 50). BL baseline, CHIP-CE: PRF Child Health and Illness Profile-Child Edition: Parent Report Form, CI confidence interval, EP endpoint, HRQoL health-related quality of life, R revised, SD standard deviation, V visit

Fig. 3

Statistical analysis of changes in CHIP-CE: PRF T-scores from baseline to endpoint of the randomized-withdrawal period (n = 153). Histogram shows LS-mean change in CHIP-CE: PRF domain and subdomain T-scores from baseline to endpoint of the randomized-withdrawal period. Error bars show 95 % CIs. Effect size is the difference in LS-mean change (LDX minus placebo) divided by root-mean-square error. Positive changes indicate improved health-related quality of life. *p < 0.05, **p < 0.01, ***p < 0.001, change from baseline to endpoint (ad hoc analysis); †p < 0.05, ††p < 0.01, †††p < 0.001, LDX change versus placebo change (prespecified analysis). P values are nominal and were not adjusted for multiple comparisons. CHIP-CE: PRF Child Health and Illness Profile-Child Edition: Parent Report Form, LDX lisdexamfetamine dimesylate, LS least-squares

Fig. 4

WFIRS-P scores during the open-label period (n = 262). a Mean scores at open-label baseline and histogram showing mean change from open-label baseline to endpoint for WFIRS-P domain and total scores. Error bars show 95 % confidence intervals. Negative changes indicate reduced functional impairment. ***p < 0.001, **p < 0.01, change at endpoint versus baseline (two-sided t test). P values are nominal and were not adjusted for multiple comparisons. b Mean WFIRS-P domain and total scores at baseline (BL), endpoint (EP), visit 6 (V6 8 weeks) and visit 3R (V3R ≥26 weeks) of the open-label period. Error bars show 95 % CIs. These data were not subjected to statistical testing. Numbers of observations (n) are shown for each data point. Higher scores indicate more severe functional impairment. BL baseline, CI confidence interval, EP endpoint, R revised, SD standard deviation, V visit, WFIRS-P Weiss Functional Impairment Rating Scale-Parent Report

Fig. 5

Statistical analysis of changes in WFIRS-P scores from baseline to endpoint of the randomized-withdrawal period (n = 153). Histogram shows LS-mean change in WFIRS-P domain and total scores from baseline to endpoint of the randomized-withdrawal period. Error bars show 95 % CIs. Effect size is the difference in LS-mean change (LDX minus placebo) divided by root-mean-square error. Positive changes indicate worsened functional impairment. *p < 0.05, **p < 0.01, ***p < 0.001, change from baseline to endpoint (ad hoc analysis); †p < 0.05, ††p < 0.01, †††p < 0.001, LDX change versus placebo change (prespecified analysis). P values are nominal and were not adjusted for multiple comparisons. LDX lisdexamfetamine dimesylate, LS least-squares, WFIRS-P Weiss Functional Impairment Rating Scale-Parent Report