Lisdexamfetamine dimesylate (LDX) was superior to osmotic-release oral system methylphenidate (OROS-MPH) for improving attention-deficit/hyperactivity disorder (ADHD) symptoms in a forced-dose study but not in a flexible-dose study. |
Both LDX and OROS-MPH are highly efficacious in treating adolescents with ADHD and are generally well tolerated, demonstrating that either stimulant class can be used with confidence. This may be important in cases of inadequate response or poor tolerability to one of the stimulant classes (as has previously been reported), although the sequencing of treatment was not assessed in these studies. |
The overall safety and tolerability profiles of LDX and OROS-MPH were consistent with previous reports. |
LDX may have a somewhat higher effect size than OROS-MPH at US FDA-approved doses, though with perhaps slightly numerically higher rates of adverse events. |
1 Introduction
2 Methods
2.1 Study Design and Treatment Regimens
2.1.1 Flexible-Dose Study
2.1.2 Forced-Dose Study
2.2 Study Population
2.3 Efficacy Endpoints
2.4 Safety and Tolerability Endpoints
2.5 Statistical Analyses
3 Results
3.1 Disposition and Demographics
Characteristic | Flexible-dose study (N = 459) | Forced-dose study (N = 547) | ||||
---|---|---|---|---|---|---|
Placebo (n = 91) | LDX (n = 184) | OROS-MPH (n = 184) | Placebo (n = 110) | LDX (n = 218) | OROS-MPH (n = 219) | |
Age, years | 14.8 ± 1.43 | 14.7 ± 1.38 | 14.7 ± 1.32 | 14.7 ± 1.37 | 14.6 ± 1.38 | 14.7 ± 1.42 |
Sex | ||||||
Male | 61 (67.0) | 122 (66.3) | 122 (66.3) | 76 (69.1) | 135 (61.9) | 150 (68.5) |
Female | 30 (33.0) | 62 (33.7) | 62 (33.7) | 34 (30.9) | 83 (38.1) | 69 (31.5) |
Ethnicity | ||||||
Hispanic/Latino | 16 (17.6) | 32 (17.4) | 45 (24.5) | 20 (18.2) | 45 (20.6) | 36 (16.4) |
Not Hispanic/Latino | 75 (82.4) | 152 (82.6) | 139 (75.5) | 90 (81.8) | 173 (79.4) | 183 (83.6) |
Race | ||||||
White | 67 (73.6) | 142 (77.2) | 136 (73.9) | 78 (70.9) | 168 (77.1) | 155 (70.8) |
Black/African American | 16 (17.6) | 30 (16.3) | 27 (14.7) | 22 (20.0) | 37 (17.0) | 51 (23.3) |
Native Hawaiian/Pacific Islander | 0 | 1 (0.5) | 1 (0.5) | 2 (1.8) | 0 | 0 |
Asian | 1 (1.1) | 1 (0.5) | 5 (2.7) | 0 | 4 (1.8) | 4 (1.8) |
American Indian or Alaska Native | 0 | 1 (0.5) | 1 (0.5) | 0 | 1 (0.5) | 2 (0.9) |
Other | 0 | 0 | 1 (0.5) | 1 (0.9) | 1 (0.5) | 1 (0.5) |
Multiple | 7 (7.7) | 9 (4.9) | 13 (7.1) | 7 (6.4) | 7 (3.2) | 6 (2.7) |
Weight, kg | 61.05 ± 13.325 | 61.69 ± 13.579 | 62.38 ± 13.142 | 60.28 ± 12.450 | 61.64 ± 12.571 | 63.10 ± 13.998 |
Height, cm | 165.52 ± 9.423 | 167.80 ± 10.080 | 167.03 ± 9.789 | 165.82 ± 10.174 | 166.60 ± 8.330 | 167.13 ± 9.791 |
BMI, kg/m2
| 22.13 ± 3.688 | 21.74 ± 3.457 | 22.20 ± 3.504 | 21.89 ± 4.277 | 22.07 ± 3.465 | 22.41 ± 3.703 |
ADHD subtype | ||||||
Predominantly inattentive | 41 (45.1) | 91 (49.5) | 62 (33.7) | 40 (36.4) | 70 (32.1) | 71 (32.4) |
Predominantly hyperactive/impulsive | 0 | 1 (0.5) | 4 (2.2) | 2 (1.8) | 2 (0.9) | 4 (1.8) |
Combined | 50 (54.9) | 92 (50.0) | 118 (64.1) | 68 (61.8) | 146 (67.0) | 144 (65.8) |
Baseline ADHD-RS-IV total score | 38.3 ± 6.89 | 36.6 ± 6.34 | 37.8 ± 6.06 | 36.1 ± 5.91 | 37.2 ± 6.46 | 36.9 ± 6.42 |
Baseline ADHD-RS-IV hyperactivity/impulsivity subscale scorea
| 15.8 ± 5.96 | 13.9 ± 6.06 | 15.4 ± 5.35 | 14.4 ± 5.72 | 15.4 ± 5.72 | 15.4 ± 5.29 |
Baseline ADHD-RS-IV inattentiveness subscale scorea
| 22.4 ± 2.93 | 22.7 ± 3.11 | 22.4 ± 3.24 | 21.7 ± 3.70 | 22.0 ± 3.35 | 21.6 ± 3.55 |
CGI-Sb
| ||||||
Borderline ill | 0 | 0 | 0 | 1 (0.9) | 0 | 0 |
Mildly ill | 0 | 1 (0.5) | 0 | 2 (1.8) | 4 (1.8) | 1 (0.5) |
Moderately ill | 48 (52.7) | 112 (60.9) | 103 (56.0) | 60 (54.5) | 93 (42.7) | 115 (52.5) |
Markedly ill | 36 (39.6) | 69 (37.5) | 75 (40.8) | 41 (37.3) | 106 (48.6) | 90 (41.1) |
Severely ill | 7 (7.7) | 2 (1.1) | 6 (3.3) | 6 (5.5) | 15 (6.9) | 13 (5.9) |
3.2 Drug Exposure and Treatment Compliance
3.3 Efficacy
3.3.1 ADHD-RS-IV Total Score
Placebo | LDX | OROS-MPH | |
---|---|---|---|
ADHD-RS-IV total score
| |||
Flexible-dose study | |||
n
| 67 | 139 | 152 |
LS mean ± SEM change from baseline at EOS | −13.4 ± 1.19 | −25.6 ± 0.82 | −23.5 ± 0.80 |
LS mean (95% CI) treatment differences at EOS | |||
LDX vs. OROS-MPH | – | −2.1 (−4.3, 0.2); DF = 414, t statistic = 1.81;
p = 0.0717; ES = −0.20 | |
Active vs. placeboa
| – | −12.2 (−15.1, −9.4); DF = 428, t statistic = 8.44;
p < 0.0001; ES = −1.16 | −10.1 (−13.0, −7.3); DF = 427, t statistic = −7.07;
p < 0.0001; ES = −0.97 |
Forced-dose study | |||
n
| 93 | 175 | 181 |
LS mean ± SEM change from baseline at EOS | −17.0 ± 1.03 | −25.4 ± 0.74 | −22.1 ± 0.73 |
LS mean (95% CI) treatment differences at EOS | |||
LDX vs. OROS-MPH | – | −3.4 (−5.4, −1.3); DF = 499, t statistic = 3.23;
p = 0.0013; ES = −0.33 | |
Active vs. placeboa
| – | −8.5 (−11.0, −6.0); DF = 491, t statistic = 6.67;
p < 0.0001; ES = −0.82 | −5.1 (−7.6, −2.6); DF = 492, t statistic = −4.04;
p < 0.0001; ES = −0.50 |
ADHD-RS-IV hyperactivity/impulsivity subscale score
| |||
Flexible-dose study | |||
n
| 67 | 139 | 152 |
LS mean ± SEM change from baseline at EOS | −5.5 ± 0.57 | −10.7 ± 0.39 | −10.1 ± 0.38 |
LS mean (95% CI) treatment differences at EOS | |||
LDX vs. OROS-MPHa
| – | −0.6 (−1.7, 0.5); DF = 406, t statistic = 1.08;
p = 0.2805; ES = −0.12 | |
Active vs. placeboa
| – | −5.2 (−6.6, −3.9); DF = 418, t statistic = 7.51;
p < 0.0001: ES = −1.05 | −4.6 (−6.0, −3.3); DF = 416, t statistic −6.75;
p < 0.0001; ES = −0.93 |
Forced-dose study | |||
n
| 93 | 175 | 181 |
LS mean ± SEM change from baseline at EOS | −7.1 ± 0.48 | −10.9 ± 0.35 | −9.6 ± 0.34 |
LS mean (95% CI) treatment differences at EOS | |||
LDX vs. OROS-MPHa
| – | −1.3 (−2.2, −0.3); DF = 496, t statistic = 2.66;
p = 0.0081; ES = −0.27 | |
Active vs. placeboa
| – | −3.8 (−4.9, −2.6); DF = 489, t statistic = 6.36;
p < 0.0001; ES = −0.79 | −2.5 (−3.6, −1.3); DF = 489, t statistic −4.19;
p < 0.0001; ES = −0.52 |
ADHD-RS-IV inattentiveness subscale score
| |||
Flexible-dose study | |||
n
| 67 | 139 | 152 |
LS mean ± SEM change from baseline at EOS | −7.9 ± 0.72 | −14.9 ± 0.50 | −13.4 ± 0.49 |
LS mean (95% CI) treatment differences at EOS | |||
LDX vs. OROS-MPHa
| – | −1.5 (−2.9, −0.1); DF = 421, t statistic = 2.18;
p = 0.0299; ES = −0.24 | |
Active vs. placeboa
| – | −7.0 (−8.7, −5.3); DF = 434, t statistic = 7.99;
p < 0.0001; ES = −1.10 | −5.5 (−7.2, −3.8); DF = 432, t statistic −6.31;
p < 0.0001; ES = −0.86 |
Forced-dose study | |||
n
| 93 | 175 | 181 |
LS mean ± SEM change from baseline at EOS | −9.8 ± 0.62 | −14.5 ± 0.45 | −12.5 ± 0.44 |
LS mean (95% CI) treatment differences at EOS | |||
LDX vs. OROS-MPHa
| – | −2.0 (−3.3, −0.8); DF = 502, t statistic = 3.23;
p = 0.0013; ES = −0.33 | |
Active vs. placeboa
| – | –4.7 (–6.2, –3.2); DF = 495, t statistic = 6.14;
p < 0.0001; ES = –0.76 | –2.7 (–4.2, –1.2); DF = 495, t statistic = –3.49;
p = 0.0005; ES = –0.43 |
CGI-I
| |||
Flexible-dose study | |||
n
| 89 | 178 | 184 |
Improved at EOS, n (%) | 31 (34.8) | 148 (83.1) | 149 (81.0) |
Not improved at EOS, n (%) | 58 (65.2) | 30 (16.9) | 35 (19.0) |
LDX vs. OROS-MPH | — | DF = 1, CMH statistic = 0.2508; p = 0.6165 | |
Active vs. placeboa
| — | DF = 1, CMH statistic = 60.0783; p < 0.0001 | DF = 1, CMH statistic = 56.6112; p < 0.0001 |
Forced-dose study | |||
n
| 106 | 210 | 216 |
Improved at EOS, n (%) | 53 (50.0) | 171 (81.4) | 154 (71.3) |
Not improved at EOS, n (%) | 53 (50.0) | 39 (18.6) | 62 (28.7) |
LDX vs. OROS-MPH | – | DF = 1, CMH statistic = 5.5157; p = 0.0188 | |
Active vs. placeboa
| – | DF = 1, CMH statistic = 32.6389;
p < 0.0001 | DF = 1, CMH statistic = 13.8434;
p = 0.0002 |
3.3.2 Dichotomized CGI-I Scores
3.3.3 ADHD-RS-IV Subscale Scores
3.4 Safety and Tolerability
3.4.1 Adverse Events
Flexible-dose study | Forced-dose study | ||||||
---|---|---|---|---|---|---|---|
Placebo (n = 91) | LDX (n = 184) | OROS-MPH (n = 184) | Placebo (n = 110) | LDX (n = 218) | OROS-MPH (n = 219) | ||
Any TEAE, n (%) | 58 (63.7) | 153 (83.2) | 151 (82.1) | Any TEAE, n (%) | 49 (44.5) | 145 (66.5) | 129 (58.9) |
Serious TEAEs | 0 | 1 (0.5) | 1 (0.5) | Serious TEAEs | 1 (0.9) | 1 (0.5) | 1 (0.5) |
Severe TEAEsa
| 2 (2.2) | 10 (5.4) | 7 (3.8) | Severe TEAEsa
| 1 (0.9) | 3 (1.4) | 6 (2.7) |
Study drug-related TEAEs | 28 (30.8) | 136 (73.9) | 122 (66.3) | Study drug-related TEAEs | 31 (28.2) | 117 (53.7) | 98 (44.7) |
TEAEs leading to discontinuation | 3 (3.3) | 14 (7.6) | 3 (1.6) | TEAEs leading to discontinuation | 1 (0.9) | 16 (7.3) | 15 (6.8) |
Fatal adverse events | 0 | 0 | 0 | Fatal adverse events | 0 | 0 | 0 |
Most frequently reported TEAEs (≥ 5% in any treatment group) | Most frequently reported TEAEs (≥ 5% in any treatment group) | ||||||
Decreased appetite | 7 (7.7) | 98 (53.3) | 77 (41.8) | Decreased appetite | 11 (10.0) | 69 (31.7) | 51 (23.3) |
Decreased weight | 1 (1.1) | 37 (20.1) | 24 (13.0) | Headache | 9 (8.2) | 33 (15.1) | 35 (16.0) |
Irritability | 9 (9.9) | 37 (20.1) | 14 (7.6) | Decreased weight | 0 | 23 (10.6) | 11 (5.0) |
Headache | 7 (7.7) | 28 (15.2) | 28 (15.2) | Insomnia | 3 (2.7) | 17 (7.8) | 17 (7.8) |
Insomnia | 0 | 16 (8.7) | 15 (8.2) | Dry mouth | 1 (0.9) | 16 (7.3) | 7 (3.2) |
Initial insomnia | 2 (2.2) | 15 (8.2) | 12 (6.5) | Dizziness | 0 | 12 (5.5) | 11 (5.0) |
Dry mouth | 1 (1.1) | 15 (8.2) | 11 (6.0) | Irritability | 7 (6.4) | 11 (5.0) | 15 (6.8) |
Nausea | 4 (4.4) | 14 (7.6) | 15 (8.2) | Nausea | 3 (2.7) | 11 (5.0) | 11 (5.0) |
Abdominal pain, upper | 4 (4.4) | 12 (6.5) | 10 (5.4) | Abdominal pain, upper | 2 (1.8) | 11 (5.0) | 8 (3.7) |
Dizziness | 1 (1.1) | 12 (6.5) | 8 (4.3) | ||||
Nasopharyngitis | 1 (1.1) | 11 (6.0) | 13 (7.1) | ||||
Somnolence | 4 (4.4) | 10 (5.4) | 6 (3.3) | ||||
Fatigue | 3 (3.3) | 10 (5.4) | 5 (2.7) | ||||
URTI | 8 (8.8) | 9 (4.9) | 6 (3.3) | ||||
Increased heart rate | 0 | 8 (4.3) | 11 (6.0) |
3.4.2 Vital Signs
Measure | Flexible-dose study | Forced-dose study | ||||
---|---|---|---|---|---|---|
Placebo (n = 89) | LDX (n = 179) | OROS-MPH (n = 184) | Placebo (n = 106) | LDX (n = 210) | OROS-MPH (n = 216) | |
SBP, mmHg | ||||||
Change from baseline at last on-treatment assessment | −0.8 ± 8.97 | 2.4 ± 9.46 | 0.4 ± 9.90 | −1.5 ± 9.75 | 1.6 ± 9.65 | 2.6 ± 10.15 |
SBP ≥ 135 mmHg and increase > 10 mmHg from baseline at any visit | 2 (2.2) | 5 (2.8) | 11 (6.0) | 0 | 3 (1.4) | 12 (5.6) |
DBP, mmHg | ||||||
Change from baseline at last on-treatment assessment | −1.2 ± 8.11 | 2.8 ± 8.41 | 2.2 ± 8.64 | −0.4 ± 8.17 | 3.3 ± 8.11 | 3.3 ± 9.13 |
DBP ≥ 85 mmHg and increase > 10 mmHg from baseline at any visit | 0 | 9 (5.0) | 11 (6.0) | 2 (1.9) | 14 (6.7) | 13 (6.0) |
Pulse, bpm | ||||||
Change from baseline at last on-treatment assessment | 0.3 ± 11.32 | 4.7 ± 11.82 | 6.0 ± 10.52 | 2.0 ± 10.99 | 6.7 ± 12.78 | 7.6 ± 12.47 |
Pulse ≥ 110 bpm and increase > 15 bpm from baseline at any visit | 0 | 10 (5.6) | 13 (7.1) | 1 (0.9) | 8 (3.8) | 15 (6.9) |
Weight, kg | ||||||
Change from baseline at last on-treatment assessment | 1.14 ± 1.884 | −1.96 ± 2.244 | −1.34 ± 2.133 | 0.95 ± 1.728 | −1.75 ± 2.070 | −1.07 ± 2.259 |
Decrease ≥ 7% from baseline at last on-treatment assessment | 0 | 27 (15.1) | 18 (9.8) | 0 | 17 (8.1) | 11 (5.1) |
z scorea
| 0.441 ± 0.9814 | 0.225 ± 1.0046 | 0.296 ± 1.0542 | 0.396 ± 0.9831 | 0.274 ± 0.9973 | 0.387 ± 1.0614 |
Median z scorea
| 0.750 | 0.250 | 0.250 | 0.250 | 0.250 | 0.500 |
BMI, kg/m2
| ||||||
Change from baseline at last on-treatment assessment | 0.44 ± 0.715 | −0.70 ± 0.820 | −0.47 ± 0.747 | 0.34 ± 0.629 | −0.64 ± 0.740 | −0.40 ± 0.785 |
BMI < 5th percentile for age and sex at last on-treatment assessment | 1 (1.1) | 6 (3.4) | 5 (2.7) | 2 (1.9) | 10 (4.8) | 4 (1.9) |
z scorea
| 0.520 ± 0.9264 | 0.096 ± 0.9902 | 0.285 ± 0.9766 | 0.401 ± 0.9665 | 0.236 ± 1.0070 | 0.363 ± 0.9929 |
Median z scorea
| 0.750 | 0.250 | 0.250 | 0.250 | 0.250 | 0.250 |