Comparative Efficacy and Safety of Lisdexamfetamine Dimesylate ...

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significantly lower in both MAS XR groups compared with 3.4 (1.00) in the placebo group (P≤.0027; Table 2). Effect sizes for treatment with LDX and MAS XR as assessed by the global improvement scales are presented in Table 2. In the LDX trial, a post hoc analysis of dichotomized CGI-I difference in improved (very much improved [CGI-I=1] and much improved [CGI-I=2]) versus placebo was significant for both doses of LDX, at all weeks and at endpoint (P≤.0005 for each). The percentage of subjects for 50 and 70 mg/day LDX, respectively, at week 1 was 24.7% and 27.9%; at week 2 was 32.5% and 34.2%; at week 3 was 35.1% and 38.9%; at week 4 was 32.9% and 33.3%; and at endpoint was 32.5% and 31.8%. For the MAS XR trial, the analysis indicated that the categorical CGI-I difference in improved versus placebo was not significant for the 20 mg/day dose of MAS XR at all weeks and at endpoint. With the 40 mg/day dose of MAS XR, the percentage of subjects that had a difference in improved versus placebo was significant only at weeks 2 and 4, and at endpoint (P≤.0210 for each). The CGI-I difference for the 40 mg/day dose of MAS XR at week 2 was 27.3%; at week 4 was 29.2%; and at endpoint was 29.1%. Safety The harmonization of AE terminology resulted in the reclassification of the verbatim item mapping to the COSTART “anorexia” to the MedDRA “decreased appetite” or “anorexia.” The verbatim terms mapping to the COSTART “insomnia” was TABLE 3 Comparative Efficacy and Safety of LDX and MAS XR in Adults With ADHD reclassified to the MedDRA “initial insomnia” or “insomnia.” In the LDX clinical trial, 80.3% of subjects in the active treatment groups experienced at least one TEAE compared with 58.1% of those receiving placebo (Table 3). The most common (≥10%) TEAEs reported by subjects receiving LDX were dry mouth (28%), decreased appetite (25.5%), headache (21.3%), and insomnia (19.2%). In the MAS XR clinical trial, 80.7% of subjects experienced at least one TEAE compared with 53.3% of those receiving placebo. After harmonization, the most common (≥10%) TEAEs reported by subjects receiving MAS XR were dry mouth (33.7%), decreased appetite (26.5%), insomnia (21.7%), headache (20.5%), and weight loss (14.5%; Table 4). The difference in percent incidence of all active treatment doses for either trial minus placebo TEAEs for both stimulants were dry mouth, decreased appetite, and insomnia; MAS XR all doses included headache and weight loss. In the LDX trial 22.2% of subjects and in the MAS XR trial 27.4% of subjects experienced at least one difference in percent incidence of all active treatment doses minus placebo TEAEs. In both trials, most TEAEs were mild or moderate in severity. Severe TEAEs were reported by 4.2% (n=10) of subjects receiving LDX, with only severe fatigue (n=2; 0.8%) and severe insomnia (n=6; 2.5%) reported by more than one subject. Among subjects receiving MAS XR, 8.4% (n=7) experienced severe TEAEs, with only severe insomnia reported by more than one subject (n=3; 3.6%). Both stimulants were associated with small mean increases from baseline in SBP at endpoint (Table 5). LDX-treated TEAES REPORTED DURING LDX TRIAL BY ≥5% OF SUBJECTS IN EITHER LDX TREATMENT GROUP Body System Preferred Term (MedDRA 9.1) LDX 50 mg/day (n=117) n (%) LDX 70 mg/day (n=122) n (%) All LDX Doses (n=239) n (%) Placebo (n=62) n (%) Difference in % Incidence of All LDX Doses Minus Placebo (%) Any TEAE 90 (76.9) 102 (83.6) 192 (80.3) 36 (58.1) 22.2 Anorexia 8 (6.8) 6 (4.9) 14 (5.9) 0 5.9 Anxiety 7 (6.0) 9 (7.4) 16 (6.7) 0 6.7 Decreased appetite 33 (28.2) 28 (23.0) 61 (25.5) 1 (1.6) 23.9 Diarrhea 12 (10.3) 4 (3.3) 16 (6.7) 0 6.7 Dry mouth 29 (24.8) 38 (31.1) 67 (28.0) 2 (3.2) 24.8 Feeling jittery 4 (3.4) 9 (7.4) 13 (5.4) 0 5.4 Headache 22 (18.8) 29 (23.8) 51 (21.3) 8 (12.9) 8.4 Initial insomnia 7 (6.0) 7 (5.7) 14 (5.9) 2 (3.2) 2.7 Insomnia 20 (17.1) 26 (21.3) 46 (19.2) 3 (4.8) 14.4 Irritability 6 (5.1) 7 (5.7) 13 (5.4) 4 (6.5) -1.1 Nausea 7 (6.0) 8 (6.6) 15 (6.3) 0 6.3 Upper abdominal pain 7 (6.0) 1 (0.8) 8 (3.3) 1 (1.6) 1.7 Upper respiratory tract infection 6 (5.1) 7 (5.7) 13 (5.4) 3 (4.8) 0.6 TEAEs=treatment-emergent adverse events; LDX=lisdexamfetamine dimesylate; MedDRA=Medical Dictionary for Regulatory Activities. Lasser R, Dirks B, Adeyi B, Babcock T. Primary Psychiatry. Vol 17, No 9. 2010. Primary Psychiatry 49 © MBL Communications Inc. September 2010
R. Lasser, B. Dirks, B. Adeyi, T. Babcock subjects had a mean (SD) SBP increase from baseline at endpoint of 0.7 (9.2) mm Hg. At endpoint, subjects treated with MAS XR demonstrated a mean (SD) change in SBP from baseline of 2.1 (12.9) mm Hg. The maximum mean (SD) changes from baseline in SBP for the active treatment groups occurred at week 3 for LDX (1.5 [9.7] mm Hg) and at week 4 for MAS XR (2.2 [13.1] mm Hg). In their respective trials, both LDX and MAS XR were also associated with small mean increases from baseline in DBP at endpoint (Table 5). At endpoint, subjects treated with LDX exhibited a mean (SD) increase in DBP of 1.3 (7.5) mm Hg compared with 3.6 (9.9) mm Hg exhibited by MAS XR-treated subjects. The maximum mean (SD) change from baseline in DBP occurred at week 2 for LDX-treated subjects (1.9 [7.0] mm Hg) and at week 4 for MAS XR-treated subjects (3.6 [10.0] mm Hg). The lower dose of LDX (ie, 50 mg) was actually associated with a mean (SD) 0.3 (9.1) mm Hg decrease in SBP, while both doses of MAS XR were associated with increases in SBP at endpoint. Similarly, while both stimulants resulted in minimal increases in DBP at endpoint, the mean (SD) elevations associated with 70 mg/day LDX were ~2.5 times less than observed in subjects receiving 40 mg/day MAS XR (1.7 [6.9] mm Hg versus 4.3 [8.7] mm Hg). In both trials, stimulant treatment was associated with mean increases in pulse (Table 5). The placebo-treated cohorts demonstrated virtually no mean (SD) change in pulse from baseline at TABLE 4 endpoint: 0 (9.2) beats per minute (bpm) and 0.4 (11.3) bpm for placebo cohorts in the LDX and MAS XR trials, respectively. At endpoint, LDX and MAS XR were associated with mean (SD) increases in pulse of 4.6 (10.7) bpm and 4.9 (11.4) bpm, respectively. For the combined active treatment groups, the maximal mean (SD) increases in pulse were observed at week 3: 5.7 (10.4) bpm for LDX and 6.0 (13.5) bpm for MAS XR. Overall, participants rarely met outlier criteria (Table 6). Blood pressure (BP) outlier criteria were not met at endpoint by any subject receiving LDX. Moreover, no subject in the present analysis had a QT or QTcF interval >480 msec at any LDX or MAS XR treatment week, nor did any subject demonstrate a prolongation of QTcF of 60 msec or more from baseline at any study week. Consistent with the short-term safety profile of stimulants, in the present analysis both LDX and MAS XR were associated with dose-dependent decreases in weight. In the LDX trial, subjects receiving placebo exhibited a mean (SD) increase in weight from baseline of 0.4 (2.9) lb at endpoint. In contrast, subjects receiving 50 and 70 mg LDX exhibited mean (SD) changes in weight of -3.1 (6.5) lb and -4.3 (4.5) lb, respectively. At endpoint of the MAS XR trial, the mean (SD) change in weight from baseline was -2.1 (4.0) lb and -6.4 (4.9) lb in the 20 and 40 mg/day dose groups, respectively, compared with 0.4 (4.9) lb increase in the placebo group. TEAES REPORTED DURING MAS XR TRIAL BY ≥5% OF SUBJECTS IN EITHER MAS XR TREATMENT GROUP Body System Preferred Term (MedDRA 9.1) MAS XR 20 mg/day (n=41) n (%) MAS XR 40 mg/day (n=42) n (%) All MAS XR Doses (n=83) n (%) Placebo (n=45) n (%) Difference in % Incidence of All MAS XR Doses Minus Placebo (%) Any TEAE 32 (78.0) 35 (83.3) 67 (80.7) 24 (53.3) 27.4 Agitation 3 (7.3) 2 (4.8) 5 (6.0) 1 (2.2) 3.8 Anorexia 0 3 (7.1) 3 (3.6) 0 3.6 Anxiety 4 (9.8) 2 (4.8) 6 (7.2) 3 (6.7) 0.5 Decreased appetite 9 (22.0) 13 (31.0) 22 (26.5) 1 (2.2) 24.3 Diarrhea 3 (7.3) 3 (7.1) 6 (7.2) 0 7.2 Dizziness 2 (4.9) 3 (7.1) 5 (6.0) 0 6.0 Dry mouth 10 (24.4) 18 (42.9) 28 (33.7) 3 (6.7) 27.0 Fatigue 2 (4.9) 3 (7.1) 5 (6.0) 3 (6.7) -0.7 Headache 7 (17.1) 10 (23.8) 17 (20.5) 3 (6.7) 13.8 Initial insomnia 3 (7.3) 2 (4.8) 5 (6.0) 0 6.0 Insomnia 10 (24.4) 8 (19.0) 18 (21.7) 4 (8.9) 12.8 Irritability 2 (4.9) 1 (2.4) 3 (3.6) 5 (11.1) -7.5 Palpitation 4 (9.8) 1 (2.4) 5 (6.0) 0 6.0 Weight loss 3 (7.3) 9 (21.4) 12 (14.5) 0 14.5 TEAEs=treatment-emergent adverse events; MAS XR=mixed amphetamine salts extended release; MedDRA=Medical Dictionary for Regulatory Activities. Lasser R, Dirks B, Adeyi B, Babcock T. Primary Psychiatry. Vol 17, No 9. 2010. Primary Psychiatry 50 © MBL Communications Inc. September 2010
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