Table 1.
Summary of clinical trials of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder
| Author | Study population: number of patients (n), patient age | Duration, study design | Primary efficacy measurements | Results | AEs |
|---|---|---|---|---|---|
| Biederman et al22 | n = 52, 6–12 years | 6 weeks, MC, R, DB, PC, and active-controlled three-treatment, three-period, crossover study in a controlled classroom environment. Three cohorts: each cohort received LDX 30, 50, or 70 mg; MAS XR 10, 20, or 30 mg; and placebo. |
LS mean of the average scores of SKAMP-D at endpoint. | Significant improvement noted for LDX (30, 50, and 70 mg combined doses) and MAS XR (10, 20, and 30 mg combined doses) in mean (SD) SKAMP-D score (both treatments 0.8 [0.1]) versus placebo (1.7 [0.1]) (both treatments P < 0.0001 versus placebo). | During the DB part of the study, AEs reported for LDX, MAS XR, and placebo, respectively, were: insomnia (8%, 2%, 2%), decreased appetite (6%, 4%, 0%), anorexia (4%, 0%, 0%), upper respiratory tract infection (2%, 2%, 0%), vomiting (0%, 2%, 4%), and upper abdominal pain (0%, 4%, 2%). Abdominal pain, headache, and labile affect were all reported as zero for all three treatment groups. |
| Wigal et al23 | n = 117, 6–12 years | 6 weeks, 4-week MC, laboratory school study, open-label, dose optimization LDX 30, 50, or 70 mg, followed by R, DB, PC, two-way crossover phase (1 week each × 2). | LS mean difference of SKAMP-D. | Significant improvement on SKAMP-D with LDX from 1.5 hours to 13 hours postdose compared to placebo (P < 0.005). Mean difference in LS means for SKAMP-D by optimized LDX dose groups: 30 mg, −0.70 (−0.88, −0.52); 50 mg, −0.68 (−0.84, −0.52); 70 mg, −0.96 (−1.30, −0.63). |
TEAEs during dose optimization and crossover phase, respectively, were: decreased appetite (47%, 6%), insomnia (27%, 4%), headache (17%, 5%), irritability (16%, 1%), upper abdominal pain (16%, 2%), and labile affect (10%, 0%). |
| Lopez et al28 | n = 52, 6–12 years | Post hoc analysis of Biederman et al’s22 trial. | CGI-I score of one at endpoint. | Significantly higher number of patients on LDX (32%) versus MAS XR (16%) (P < 0.0386) with “very much improved” CGI-I score (placebo was 2%). | NA |
| Biederman et al29 | n = 290, 6–12 years | 4 weeks, MC, R, DB, PC, FD titration, parallel groups: LDX 30, 50, or 70 mg versus placebo. | Mean change from baseline to endpoint in ADHD-RS-IV total score. | Significant improvement in ADHD-RS-IV noted with all doses of LDX versus placebo (−21.8, −23.4, −26.7, −6.2, respectively; all P < 0.001). Significant improvement noted in weekly ADHD-RS-IV total score change from baseline starting at week one (P < 0.001), with all three doses of LDX. |
AEs for LDX 30 mg, 50 mg, 70 mg, and placebo, respectively, were: decreased appetite (37%, 31%, 49%, 4%), insomnia (16%, 16%, 25%, 3%), upper abdominal pain (14%, 7%, 15%, 6%), headache (10%, 10%, 16%, 10%), irritability (11%, 8%, 10%, 0%), vomiting (7%, 5%, 14%, 4%), weight loss (6%, 3%, 19%, 1%), nausea (4%, 3%, 11%, 3%), dizziness (7%, 5%, 3%, 0%), nasopharyngitis (6%, 4%, 6%, 6%), nasal congestion (4%, 0%, 0%, 6%), cough (3%, 1%, 0%, 6%), and dry mouth (3%, 3%, 8%, 0%). |
| Lopez et al30 | n = 290, 6–12 years | Post hoc analysis of Biederman et al’s29 trial. | Improvements on the CPRS-R:S and its subscales (ADHD index, hyperactivity, oppositional, and cognition) analyzed at 10 am, 2 pm, and 6 pm. | Improvement from baseline for all doses of LDX at all times versus placebo: CPRS-R:S (P < 0.0001); CPRS-R:S ADHD Index (P < 0.0001); CPRS-R:S Hyperactivity (P < 0.0001); CPRS-R:S Cognition (P < 0.0001); and CPRS-R:S Oppositional at 10 am and 2 pm only (P < 0.01). |
NA |
| Jain et al31 | n = 290, 6–12 years | Post hoc analysis of Biederman et al’s29 trial to evaluate clinical efficacy of LDX in children with/without prior MPH treatment. | Dual criteria of ≥30% reduction in ADHD-RS-IV total score from baseline and a CGI-I score of one or two at endpoint. | Of 290 randomized patients, 28 received MPH treatment at screening, of which 26 remained symptomatic (nonremitters). Of nonremitters on prior MPH therapy, clinical response observed in 15 on LDX and three on placebo. NNT (95% CI) for one patient to achieve symptomatic remission and a clinical response, respectively, with LDX at treatment endpoint was 2.0 (1.21–6.63) (for both) in nonremitters on prior MPH versus 2.1 (1.74–2.72) and 1.8 (1.51–2.22) in the overall study population. |
Mean (SE) change from baseline at endpoint for LDX versus placebo: pulse 0.3 (1.20) to 4.1 (1.17) bpm versus −0.7 (1.17) bpm; SBP 0.4 (1.08) to 2.6 (1.05) mmHg versus 1.3 (1.05) mmHg; DBP 0.6 (0.93) to 2.3 (0.91) mmHg versus 0.6 (0.91) mmHg. |
| Wigal et al34 | n = 117, 6–12 years | Post hoc analysis of Wigal et al’s23 trial. | Effect size for SKAMP-D, interaction between sex or age and treatment. | LS mean postdose effect size of LDX on SKAMP-D: −1.73 (0.18). LS mean SKAMP scores for females improved more than for males in all measures at all time points. LS mean SKAMP scores for ages 10–12 years were lower (less impairment) versus ages 6–9 years. |
TEAEs in dose optimization phase in males and females, respectively, were: decreased appetite (48%, 45%), insomnia (31%, 16%), headache (18%, 13%), irritability (16%, 16%), upper abdominal pain (16%, 13%), labile affect (11%, 7%), and nausea (7%, 13%). TEAEs in crossover phase in males and females, respectively, were: decreased appetite (6%, 7%), insomnia (6%, 0%), headache (5%, 7%), irritability (1%, 0%), upper abdominal pain (2%, 0%), labile affect (0%, 0%), and nausea (1%, 4%). |
| Findling et al35 | n = 272, 6–12 years | 12 months, MC, open-label extension; LDX dose optimized to 30, 50, or 70 mg for the first 4 weeks, then maintained for 11 months. | Mean change from baseline to endpoint in ADHD-RS-IV total score. | At endpoint, LDX (all doses) showed a 60% improvement by decreasing ADHD-RS-IV total mean scores: −27.2 (13.0) compared with baseline (P < 0.0001); improvement in decreasing ADHD-RS inattentive and hyperactivity-impulsivity subscale scores −13.4 (7.0) and −13.8 (7.0), respectively, compared with baseline (both P < 0.001). Improvements in ADHD-RS-IV were consistent from week four onwards. |
With all doses of LDX, AEs were: decreased appetite (33%), weight loss (18%), headache (18%), insomnia (17%), upper abdominal pain (11%), upper respiratory tract infection (11%), irritability (10%), nasopharyngitis (10%), vomiting (9%), cough (7%), and influenza (6%). The majority of AEs occurred within the first 2 months; after 4 months, only decreased appetite and weight loss occurred in >5% of patients. |
| Findling et al36 | n = 318, 6–12 years | 7 weeks, MC, open-label, dose optimization and maintenance; LDX: 20, 30, 40, 50, 60, or 70 mg. | Mean change from baseline to endpoint in ADHD-RS-IV total score. | At endpoint, LDX (all doses) showed a 69% improvement by decreasing ADHD-RS-IV total mean scores −28.6 (10.9) compared with baseline (P < 0.0001). There were significant improvements in the inattention (−15.2) and hyperactivity/impulsivity subscales (−13.4) at endpoint (P < 0.0001). |
TEAEs (≥10% of patients) were: decreased appetite (43%), decreased weight (17%), irritability (16%), insomnia (16%), headache (14%), upper abdominal pain (13%), and initial insomnia (11%). Incidence of AEs highest at 20 mg dose (54%) and lowest at 70 mg dose (24%). |
| Turgay et al37 | n = 318, 6–12 years | Post hoc analysis of Findling et al’s36 trial. | BRIEF scores. | Mean (SD) change from baseline to endpoint with LDX all doses for: GEC −17.9 (12.5); BRI −15.4 (12.6); and MCI −17.6 (12.3) (all P < 0.0001). | As noted in Findling et al.36 |
| Wigal et al38 | n = 26, 6–12 years | 4–5 weeks, LDX dose optimization 30, 50, or 70 mg and open-label, laboratory school study (1 week). | Reading performance assessed via GORT-4. | Nonsignificant trend toward improvement in both reading and reading accuracy (P < 0.088 and P < 0.0679, respectively). | NA |
| Findling et al39 | n = 314, 13–17 years | 4 weeks, MC, R, DB, PC, FD, parallel-groups with LDX 30, 50, or 70 mg versus placebo. | Mean change from baseline to endpoint in ADHD-RS-IV total score. | Mean change from baseline to endpoint in ADHD-RS-IV total scores were −18.3 (1.25), −21.1 (1.28), −20.7 (1.25) for LDX 30, 50, or 70 mg versus placebo −12.8 (1.25) (P < 0.0056 versus placebo for each). | TEAE (≥5%) for LDX 30, 50, or 70 mg and placebo were: decreased appetite (37%, 27%, 37%, 3%), headache (12%, 17%, 15%, 13%), insomnia (9%, 10%, 14%, 4%), decreased weight (4%, 9%, 15%, 0%), irritability (8%, 3%, 10%, 4%), nasopharyngitis (3%, 5%, 1%, 1%), and upper respiratory tract infection (3%, 5%, 5%, 8%). Mean (SE) change from baseline at endpoint for vital signs with LDX 30, 50, or 70 mg and placebo: SBP −0.8 (1.22), 0.3 (1.01), 1.7 (1.21), and 2.2 (1.04) mmHg; DBP −0.5 (1.05), 0.4 (0.84), 3.4 (0.80), and 0.5 (0.97) mmHg, pulse 5.0 (1.18), 3.8 (1.37), 5.4 (1.27), and 0.8 (1.36) bpm. |
| Childress et al40 | n = 269, 13–17 years | 52 weeks, 4-week study from Findling et al,39 then 48-week open-label extension. | Mean change from baseline to endpoint in ADHD-RS-IV total score. | Mean change from baseline to endpoint in ADHD-RS-IV total score was −26.2 (9.75) (P < 0.001). | TEAEs (≥5%) were: upper respiratory tract infections (21.9%), decrease in appetite (21.1%), headache (20.8%), weight loss (16.2%), irritability (12.5%), insomnia (12.1%), nasopharyngitis (7.2%), influenza (6.8%), dizziness (5.3%), and dry mouth (5.3%). |
| Childress et al41 | n = 269, 13–17 years | Post hoc analysis of Childress40 trial. | Changes in YQOL-R from baseline to endpoint. | Mean YQOL-R transformed total perceptual score improved from 79.8 (11.28) at baseline to 83.9 (11.0) at endpoint (P < 0.001). | As noted in Childress et al.42 |
| Coghill et al42 | n = 336, 6–17 years | 7 weeks, MC, R, DB, PC, parallel groups: LDX 30, 50, or 70 mg or OROS-MPH 18, 36, or 54 mg versus placebo. | Mean change from baseline to endpoint in ADHD-RS-IV total score. | Significant difference between both active treatment groups and placebo from baseline in ADHD-RS-IV total scores (LDX −18.6, OROS-MPH −13, both P < 0.001). | TEAEs (≥10%) were: decreased appetite, headache, insomnia, decreased weight, nausea, and anorexia. |
| Katic et al43 | n = 318, 6–12 years | Post hoc analysis of Findling et al’s36 trial. | EESC total scores. | At endpoint, significant mean change from baseline in EESC total score −7.4 (18.3) (P < 0.0001); and for each subscale: −2.1 (9.6) for positive emotions (P < 0.0002); −2.5 (7.7) for emotional flatness (P < 0.0001); and −2.8 (5.2) for emotional lability (P < 0.0001). | Higher incidence of labile affect and aggression among patients with worsening of EESC total scores. |
| Wigal et al46 | n = 27, 6–12 years | Post hoc analysis of Wigal et al’s38 trial. | Safety profile of LDX on cardiovascular measurements. | Changes in physiological measures for stimulant-naïve patients versus prior stimulant exposed patients: pulse 1.62 versus −4.57 bpm; SBP 5.38 versus −4.14 mmHg; DBP 1.00 versus 0.57 mmHg; PR interval 0.46 versus 1.00 msec; QRS duration 1.54 versus 0.57 msec; QT interval 1.38 versus 10.00 msec; heart rate-corrected QT interval 5.15 versus −0.57 msec. | Frequency of most significant (P < 0.05) AEs for stimulant-naïve and prior stimulant exposed patients, respectively, were: trouble sleeping (77%, 21%), stomach pain (62%, 21%), dizziness (0%, 29%), and hyperfocus (31%, 0%). |
| Giblin and Strobel50 | n = 24, 6–12 years | 7 weeks, 3-week, open-label, LDX dose optimization 30, 50, or 70 mg, followed by 4 weeks R, DB. | Change from baseline to endpoint in LPS via PSG. | PSG data: mean change from baseline to endpoint not significant from placebo and LDX-treated patients for LPS, WASO, and TST. Significant only for NAW in LDX-treated patients compared to placebo (P < 0.0001). Mean improvement with LDX in ADHD-RS-IV of 28.7 from baseline(P < 0.0001). |
All TEAEs were mild or moderate. The most common for LDX versus placebo were: headache (five versus one), increased pulse (five versus zero), and increased blood pressure (two versus one). |
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ADHD-RS-IV, Attention-Deficit/Hyperactivity Disorder Rating Scale Version IV; AE, adverse event; bpm, beats per minute; BRI, Behavioral Regulation Index; BRIEF, Behavior Rating Inventory of Executive Function; CGI-I, Clinical Global Impression-Improvement; CI, confidence interval; CPRS-R:S, Conners’ Parent Rating Scale, Revised Short Version; DB, double-blind; DBP, diastolic blood pressure; EESC, Expression and Emotion Scale for Children; FD, forced-dose; GEC, Global Executive Composite; GORT-4, Gray Oral Reading Test-4; LDX, lisdexamfetamine dimesylate; LPS, latency to persistent sleep; LS, least squares; MAS XR, extended-release mixed amphetamine salts; MC, multicenter; MCI, Metacognition Index; MPH, methylphenidate; msec, milliseconds; NA, not available; NAW, number of awakenings; NNT, number needed to treat; OROS-MPH, osmotic release oral system methylphenidate; PC, placebo-controlled; PSG, polysomnography; R, randomized; SBP, systolic blood pressure; SD, standard deviation; SE, standard error; SKAMP-D, Swanson, Kotkin, Agler, M-Flynn, and Pelham-Deportment scale; TEAE, treatment-emergent adverse event; TST, total sleep time; WASO, wake time after sleep onset; YQOL-R, Youth Quality of Life-Research Version.