Table 1.
Summary of efficacy and safety studies of lisdexamfetamine dimesylate in adults with ADHD.
| Reference | Study design, duration | Study population: no. of patients (N), regimens | Primary efficacy end points/assessments and selected secondary results | Adverse events |
|---|---|---|---|---|
| Adler et al22 | R, DB, PC, PG; 4-wk study: forced dose titration × 3 wk, followed by 1-wk maintenance | N = 420 (18-55 y) LDX: 30 mg/d (119) LDX: 50 mg/d (117) LDX: 70 mg/d (122) placebo (62) for 4 wk |
ADHD-RS-IV total score improvement from baseline, LDX vs placebo: LDX: 30 mg/d: −16.2 vs −8.2 LDX: 50 mg/d: −17.4 vs −8.2 LDX: 70 mg/d: −18.6 vs −8.2 (all, P’s < .0001) CGI-I score: significantly improved from baseline for all three LDX doses (57%, 62%, and 61%) vs placebo (29%) (all, P’s < .01) |
For all doses of LDX most common vs placebo: decreased appetite (27% vs 2%), dry mouth (26% vs 3%) insomnia (19% vs 5%. Others: diarrhea (7% vs 0%), nausea (7% vs 0%), anorexia (5% vs 0%), anxiety (5% vs 0%) |
| Weisler et al28 | OL, single-arm, MC (extension of Adler et al22) | N = 349 (18-55 y) LDX: 30 mg/d (61) LDX: 50 mg/d (113) LDX: 70 mg/d (175) |
Mean change in ADHD-RS-IV total score from baseline to end of study period: −24.8 (P < .0001) CGI-I: 84% improvement PSQI: overall mean change from baseline to end point: −1.3 (P < .0001) |
LDX at 30, 50, and 70 mg doses: upper respiratory tract infection (3%, 7%, 19%), insomnia (4%, 11%, 14%), headache (7%, 7%, 11%), dry mouth (5%, 7%, 11%), decreased appetite (5%, 6%, 7%), decreased weight (1%, 3%, 4%) |
| Wigal et al24 | 4-wk OL dose optimization followed by R, DB, MC, PC: 2-wk crossover | N = 142 (18-55 y) Dose optimization phase: LDX: 30 mg/d (28) LDX: 50 mg/d (70) LDX: 70 mg/d (44) Later: N = 127 LDX/placebo (63) Placebo/LDX (64) |
PERMP total (post-dose average): difference from LDX and placebo: 23.4 (P < .0001). PERMP total score significantly greater for LDX from 2 to 14 h vs placebo (P < .001) ADHD-RS-IV total scores mean change at dose-optimization end point was −11.5 (P < .0001) CGI-I score improved with LDX (76.5%) vs placebo (23.1%) (P < .0001) |
LDX vs placebo: fatigue (1% vs 12%), upper respiratory tract infection (2% vs 8%), decreased appetite (4% vs 2%), dry mouth (4% vs 1%), headache (2% vs 3%) |
| Brams et al29 | Patients maintained on LDX for >6 mo: 3-wk OL phase, followed by a 6-wk R, DB, withdrawal phase | N = 116 (18-55 y) LDX: 30, 50, 70 mg/d (56) Placebo (60) |
Symptom relapse: LDX (8.9%) vs placebo (75%) (P < .0001) ADHD-RS-IV scores: LS mean change from baseline of withdrawal phase to end point: LDX (1.6 [1.39]) vs placebo (16.8 [1.35]) (P < .0001) LDX vs placebo: LS mean difference in adjusted change from baseline of withdrawal phase: −15.2 (−19.1 to −11.4) |
LDX during OL phase, LDX during withdrawal phase vs placebo: headache (3%, 14% vs 5%), increased appetite (0%, 2% vs 3%), insomnia (2%, 5% vs 5%), upper respiratory tract infection (3%, 9% vs 0%) |
| Mattingly et al30 | Post hoc analysis of Weisler et al28 | N = 342 (18-55 y) Predominant ADHD subtypes: Inattention (n = 93) Hyperactivity/impulsivity (n = 13) Combined (n = 236) |
ADHD-RS-IV mean (SD) change from baseline to end point for predominantly inattention −19.3 (9.48), hyperactivity/impulsivity −24.0 (7.22), and combined symptom clusters −27.3 (11.78) subgroups, respectively | As reported previously |
| Biederman et al31 | R, DB, PC, PG: 6 wk | N = 61 (18-26 y) LDX: 30-70 mg/d (31) Placebo (30) |
LDX vs placebo: ADHD-RS-IV total score improvement from baseline: −18.4 vs −5.4, CGI-I: 68% vs 27%, and GAF: 7.5 vs 2.9 (all, P’s < .001) LDX vs placebo: faster reaction times (P = .026), reduced likelihood of having collision in driving simulator (23% vs 47%) (P = .048) |
LDX vs placebo: decreased appetite (61% vs 7%), mucosal dryness (29% vs 3%), tension/jitteriness (26% vs 7%), insomnia (23% vs 3%), headache (16% vs 3%) LDX vs placebo from baseline to end point: change in pulse (15.8 vs −0.6, P < .0001)and QTc interval (9.7 vs 0.6, P = .01) |
| DuPaul et al32 | DB, PC, CO: 5 wk: 5 phases, each 1 wk: no-drug baseline, placebo, LDX at doses: 30, 50, 70 mg | N = 40 (18-23 y) LDX: 30-70 mg/d (24) Controls (without ADHD) (26) |
CAARS: for all LDX doses, ratings significantly lower than baseline for inattention/memory problems, hyperactivity/restlessness, and ADHD index (P < .01) CTP-II: significant main effects for dosage for commission errors, hit reaction time-standard error (P = .02) BRIEF-A: for all LDX doses, significant improvement (P < .01) CVLT-II: significant linear trends for 4 scores (P ≤ .02) SCL-90-R: significant linear and cubic trends in decrease scores with increasing dosage for most scores (P ≤ .02) SAS-SR: no significant effects noted on social functioning EESC-C: no significant main effects (no dosage impact on affect or emotional expression) |
Most commonly reported adverse side effects include decreased appetite and trouble sleeping (percentages not available) No significant changes in SBP or pulse; mild increase in SBP (not clinically significant) |
| Adler et al23 | R, DB, MC, PC,PG: 10 wk | N = 159 (18-55 y) LDX: 30-70 mg/d (79) Placebo (80) |
ADHD-RS-IV total score improvement from baseline: LDX vs placebo (−21.4 vs −10.3, P < .0001) Reductions from baseline in mean BRIEF-A GEC T-scores: LDX vs placebo (−22.3 vs −11.2, P < .0001 CGI-I score: improved vs placebo (P < .0125) |
Most common LDX vs placebo: decreased appetite (33% vs 6%), dry mouth (32% vs 8%), headache (25% vs 3%), insomnia (13% vs 4%). Other: diarrhea (8% vs 3%), anorexia (5% vs 0%), nausea (3% vs 6%) |
| Adler et al33 | Post hoc analysis of Adler et al. (2013) | As above | From baseline to week 10, LDX vs placebo: greater improvement on all AIM-A global multi-item domain scales (all, P’s < .0302) Improvements for total AAQoL score (LS mean difference: 21.0) |
As reported above |
| Adler et al25 | R, OL,12 wk: 4-wk optimization period, followed by 8-wk maintenance phase | N = 40 (18-55 y) LDX: 30-70 mg/d |
ADHD-RS: significant decrease in total scores from baseline (47%, P < .001) ASRS: decrease in total scores (42%, P < .001) TASS: decrease in total scores in-clinic and in evening (47% and 53%, respectively, P < .001) AMRS: reductions of 53% in-clinic assessment and 61% in evening, P < .001 IA and HI subscale scores: significant improvement (P < .005) WRAADDS: improvement with 39% in-clinic and 79% evening reductions (P < .001) AMSES: smooth effect throughout day with no differences in doses noted |
For all doses of LDX most common adverse events: insomnia (80%), headache (53%), loss of appetite (53%), and dry mouth (43%) |
| Adler et al27 | SB (patient-blind), PC, crossover, 14 wk: 1-wk washout, LDX × 5 wk followed by placebo × 3 wk, then OL with MAS-IR × 5 wk | N = 21 (19-55 y) LDX: 30-70 mg/d MAS-IR (10-15 mg 3 times daily) |
ADHD-RS total score: decrease from baseline (LDX: 49%, MAS-IR 45%) NS ADHD-RS IA and HI scores: decreased for LDX (50%, 47%) and for MAS IR (47%, 43%) NS CGI-S score: LDX (32%) vs MAS-IR (24%) (P < .02) Improvements noted with both LDX and MAS-IR but NS differences between the two agents: BRIEF, PSQI |
Both LDX and MAS-IR well tolerated: dry mouth, anxiety, jitteriness, fatigue, and insomnia. No clinically significant changes in weight, blood pressure, pulse |
| Ginsberg et al34 | Post hoc analysis of Adler et al22 and Weisler et al28 | As previously reported | From baseline to endpoint 82%, 85%, and 88% very much/much improved (CGI-I of 1 or 2) in CGI-S categories of 4, 5, and ≥6 Greater baseline symptom severity having increased mean change in ADHD symptoms (P < .0001) CGI-S score 4, 5, ≥6 scores: clinical response in 79%, 84%, and 88%, respectively, and symptomatic remission criteria in 64%, 65%, and 72%, respectively |
Upper respiratory tract infection (22%), insomnia (20%), headache (17%), dry mouth (17%), decreased appetite (14%), irritability (11%) |
| Martin et al26 | R, DB, PC, 3-period crossover (7 d each) | N = 18 (18-55 y) LDX: 50 mg/d, MAS-IR 20 mg/d, and placebo × 7 d each in randomized order |
Improvement in PoA scores for LDX and MAS-IR vs placebo (3 to 16 h post dose on day 7, with maximum improvement 5 h post dose) CAARS scores unchanged with LDX and MAS-IR (vs placebo) at all postdose time points CDR-CBT: little change following LDX or MAS-IR (vs placebo) |
LDX, MAS-IR, placebo: dry mouth (33%, 24%, 18%), decreased appetite (16.7%, 24%, 6%), increased heart rate (11%, 0%, 0%), dyspnea (6%, 12%, 0%), headache (5.6%, 5.9%, 17.6%) |
| Waxmonsky et al35 | 3-wk OL, LDX titration trial, followed by phase 1 DB, PC (within-subjects evaluation), then phase 2 parent-blinded treatment of LDX or placebo × 4 wk | N = 30 parent (mean age: 40.7 y)-child/adolescent (5-12 y) dyads LDX: 30, 50, or 70 mg/d |
Change in rate of parenting behaviors coded during the parent-child interaction tasks Phase 1—reduction in negative talk by parents (P = .0066), reduction in children’s negative behaviors in homework phase (P = .0154) Phase 2—increases in praise by parents, reductions in parental commands, reduction in children’s inappropriate behaviors (all, P’s < .05) ADHD-RS total score: decrease from baseline in parental ADHD symptoms vs placebo (P < .005) |
LDX 30, 50, 70 mg: loss of appetite (56%, 61%, 69%), headaches (36%, 28%, 31%), dry mouth (30%, 33%, 56%), trouble sleeping (20%, 22%, 31%), irritability (16%, 17%, 25%), buccal-lingual movement (16%, 28%, 25%) Decreased weight over time (P < .05), no significant group differences in cardiovascular parameters |
Abbreviations: AAQoL, Adult ADHD Quality of Life Scale; ADHD-RS-IV, ADHD Rating Scale Version IV; AIM-A, Adult ADHD Impact Module; AMRS, Adult ADHD Medication Rebound Scale; ASRS, ADHD Self-Report Scale; BADDS, Brown Attention-Deficit Disorder Scale; BRIEF-A, Behavior Rating Inventory of Executive Functioning-Adult Version; CAARS, Connors’ Adult ADHD Rating Scales-Short form; CDR-CBT, Cognitive Drug Research Computerized Battery of Tests; CGI, Clinical Global Impression scores; CGI-I, Clinical Global Impression Improvement scores; CGI-S, Clinical Global Impression Severity of Illness Scale; CTP-II, Connors’ Continuous Performance Test; CVLT-II, California Verbal Learning Test-second edition; DB, double blind; DBP, diastolic blood pressure EESC-C: Expression and Emotion Scale-College Student Version; GAF, Global assessment of functioning scale; GEC, Global Executive Composite; HI, hyperactivity/impulsivity symptoms; IA, inattentive symptoms; LDX, lisdexamfetamine dimesylate; LS, least squares; MAS-IR, mixed amphetamine salts immediate release; MC, multicenter; NS, non significant; OL, open label; PC, placebo-controlled; PERMP, Permanent Product Measure of Performance; PG, parallel group; PoA, power of attention; PSQI, Pittsburgh Sleep Quality Index; R, randomized; SAS-SR, Social Adjustment Scale-Self Report; SB, single-blind; SBP, systolic blood pressure; SCL-90-R, Symptom Checklist 90-Revised; SKAMP, Swanson, Kotkin, Agler, M-Flynn, and Pelham; TASS, Time-Sensitive ADHD Symptom Scale; WRAADDS: Wender-Reimherr Adult Attention Deficit Disorder Scale.