Comparative Efficacy and Safety of Lisdexamfetamine Dimesylate ...

ORIGINAL RESEARCH
Primary Psychiatry. 2010;17(9):44-54
R. Lasser, B. Dirks, B. Adeyi, T. Babcock
Comparative Efficacy and Safety of Lisdexamfetamine
Dimesylate and Mixed Amphetamine Salts Extended Release
in Adults With Attention-Deficit/Hyperactivity Disorder
Robert Lasser, MD, Bryan Dirks, MD, Ben Adeyi, MS, and Thomas Babcock, DO
ABSTRACT
Objective: To qualitatively compare the efficacy and safety of
lisdexamfetamine dimesylate (LDX) and mixed amphetamine salts
extended release (MAS XR) using data from two similar trials.
Methods: Two randomized, 4-week, forced-dose escalation, dou-
ble-blind trials in adults with attention-deficit/hyperactivity
disorder (ADHD) were analyzed. This post hoc analysis examined
active treatment groups and placebo with approximately equiva-
lent amphetamine base quantities (50 and 70 mg/day LDX; 20
and 40 mg/day MAS XR). Efficacy measures included the ADHD
Rating Scale IV (ADHD-RS-IV). Safety assessments included
treatment-emergent adverse events (TEAEs), vital signs, and
electrocardiograms.
Results: Placebo-adjusted difference in least squares mean change
from baseline with LDX for ADHD-RS-IV total score was -9.16
(50 mg/day) and -10.42 (70 mg/day) ( P

(MPH) and d-amphetamine-based stimulants were demonstrated
in controlled clinical trials. 2-4 Although efficacy and
tolerability profiles of both preparations share a high degree of
similarity, 2 subtle differences exist. 5 Their putative mechanisms
of action differ and individuals may exhibit different responses to
both stimulants, 2,5,6 suggesting an alternative formulation could
be prescribed for subjects responding inadequately to one. 1
Long-acting formulations generally have similar efficacy and tolerability
versus multidose immediate-release (IR) stimulants. 2,4,7,8
Once-daily dosing with long-acting formulations may enhance
convenience and adherence 2,4 as well as decrease potential abuse
and diversion. 4,9-12 Comparative data evaluating long-acting formulations
for ADHD treatment are limited, especially in adults.
Pelham and colleagues 6 evaluated relative efficacies of four formulations
in children, including sustained-release MPH and
d-amphetamine formulations. Another pediatric ADHD study
compared efficacy and safety of lisdexamfetamine dimesylate
(LDX) versus placebo with mixed amphetamine salts extended
release (MAS XR) as a reference arm (eg, no direct comparison
with LDX). 13 Several clinical trials 14-19 compared efficacy of different
long-acting MPH formulations in children, but the authors of
this article are unaware of comparative efficacy trials of stimulants
in adults. Direct head-to-head trials are required for clinicians to
comprehensively compare long-acting formulations, but in their
absence, we can only rely on indirect, qualitative comparisons.
LDX is a long-acting, amphetamine-based stimulant approved
for ADHD in adults. LDX is the first prodrug stimulant. After
oral ingestion, therapeutically inactive LDX is converted to llysine
and active d-amphetamine, which is responsible for the
therapeutic effect. The conversion of LDX into active d-amphetamine
occurs primarily in the blood. The combination of l-lysine
and d-amphetamine created a new chemical entity with a prodrug
technology of delivery of d-amphetamine. 20 In adults, LDX
demonstrated significant efficacy versus placebo in a 4-week
pivotal trial, 21 and from 2–14 hours post dose in a randomized,
controlled, simulated workplace environment trial. 22
MAS XR is also a long-acting, amphetamine-based stimulant
approved for ADHD in adults. 23 MAS XR is a once-daily,
extended-release, single-entity amphetamine product that contains
equal proportions of IR and enteric-coated delayed-release
beads. 24 The capsule contains two types of drug-containing beads
that were designed to give double-pulsed delivery of amphetamine
to prolong release. 23 MAS XR has demonstrated efficacy
with various doses versus placebo in a 4-week, randomized trial 25
and in a laboratory school study 26 in children from 1.5–12 hours
post dose. A classroom, crossover children’s study indicated that
the percent coefficient of variance for T max, C max, and area under
the curve-last for LDX-treated subjects was lower than those for
MAS XR-treated subjects, suggesting lower intersubject variability
with LDX and potentially more consistent drug delivery
among subjects. 13 Both treatments demonstrated a safety profile
consistent with long-acting stimulant use. 4,21,27,28
Comparative Efficacy and Safety of LDX and MAS XR in Adults With ADHD
LDX and MAS XR are controlled substances and carry warnings
for potential abuse. Head-to-head abuse liability studies
have not been conducted between the products. Oral LDX
capsules contain no free d-amphetamine and are not likely
affected by simple mechanical manipulation (eg, crushing and
simple extraction). 29 In contrast, mechanical manipulation may
be possible with beaded technology, such as MAS XR, in which
active d- and l-amphetamine are contained in the capsule and
can be made accessible. Oral and intravenous (IV) abuse liability
studies have been conducted with LDX only, 29,30 and not with
MAS XR; therefore, no definitive conclusions can be made
regarding comparative abuse-related drug-liking effect between
these two treatments. However, unlike IR d-amphetamine, IV
LDX did not produce significant subjective abuse-related liking
in adult substance abusers compared with placebo. 30 LDX
(50 and 100 mg) taken orally had reduced abuse-related liking
effects compared with IR d-amphetamine (40 mg equivalent
amphetamine-base dose to LDX 100 mg). At higher doses of
LDX (150 mg), subject abuse-related liking scores were similar
between LDX and IR d-amphetamine (40 mg). 29
Absence of direct head-to-head data motivated the present
post hoc analysis of matched groups that qualitatively explores
the safety and efficacy of both stimulants using data from two
separate clinical trials in adults. 21,25 This qualitative assessment
was designed to compare the efficacy and safety profiles of
LDX and MAS XR in a short-term, randomized, placebo-
controlled clinical trial setting.
METHODS
Study Designs
The study designs of both clinical trials in the present analysis
have been described previously. 21,25 Briefly, both were multicenter,
randomized, double-blind, placebo-controlled, parallel-group,
forced-dose escalation clinical trials. At baseline, subjects were
randomized to receive stimulant (one of three dosages of LDX
or MAS XR) or placebo and began a 4-week treatment period.
In the LDX trial, subjects randomized to receive active treatment
(LDX 30, 50, or 70 mg/day) initiated therapy at 30 mg/day
with weekly adjustment to randomized dose. In the MAS XR
clinical trial, subjects randomized to receive active treatment
(MAS XR 20, 40, or 60 mg/day) initiated therapy at 20 mg/day
with weekly adjustment to their randomized dose.
Subjects
Each clinical trial enrolled adults who met Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision, 31 criteria for a primary diagnosis of ADHD. In the
LDX trial, subjects were required to be 18–55 years of age,
Primary Psychiatry 45
© MBL Communications Inc. September 2010

R. Lasser, B. Dirks, B. Adeyi, T. Babcock
whereas in the MAS XR trial only a lower age limit of 18 years
was specified. Exclusion criteria in both trials included comorbid
psychiatric conditions with significant symptoms, pregnancy,
seizures, tic disorders, Tourette’s syndrome, hypertension, cardiac
conditions, a positive drug screen, history of substance abuse, or
use of any prescription/investigational medication (except that
used to treat ADHD within 30 days of screening). Each study
relied on clinical diagnosis of ADHD based on a structured diagnostic
interview. The LDX study had the additional requirement
that a baseline severity in clinician-rated ADHD Rating Scale IV
(ADHD-RS-IV) be met for entry. The present analyses included
only data from a subgroup of enrolled subjects in each trial who
were matched for baseline ADHD severity and randomized
to approximately equivalent doses of delivered amphetamine
base content. Subjects in the MAS XR study with baseline
ADHD-RS-IV total scores

using the MedDRA dictionary (Version 9.1) and reporting all
TEAEs with a subject incidence ≥5%, using MedDRA preferred
terminology. Vital signs were summarized by treatment group.
Categorical analysis using outlier criteria was performed for SBP
(≥150 mm Hg), DBP (≥95 mm Hg), pulse (change to ≥ mean+2
SD), QT interval (>480 msec), and QT interval corrected using
Fridericia’s formula (QTcF; >480 msec).
RESULTS
Subject Demographics
Using the above selection criteria, the LDX trial comprised
301 subjects, including 239 randomized to receive LDX. In
the MAS XR trial data set, 128 subjects were included, with 83
randomized to receive MAS XR. All subjects enrolled and randomized
for this subgroup analysis were included in the safety
analysis. Within each trial, the demographic characteristics of
the subjects were similar (Table 1). The mean age of subjects
in the LDX clinical trial was slightly younger than those in the
Comparative Efficacy and Safety of LDX and MAS XR in Adults With ADHD
MAS XR trial. The proportion of men in each treatment group
in the LDX trial (51.6%–56.4%) was slightly less than that
observed in the MAS XR trial (59.5%–70.7%).
Efficacy
TABLE 1
DEMOGRAPHIC CHARACTERISTICS OF SUBJECTS FROM LDX AND MAS XR TRIALS
LDX 50 mg/day
(n=117)
Within each study, active treatment groups and placebo exhibited
similar mean baseline ADHD-RS-IV total scores, although baseline
scores in the LDX clinical trial were slightly higher than those in
the MAS XR trial and endpoint scores were decreased versus baseline
in both trials (Figure 1). In each clinical trial, active treatment
was associated with significantly greater improvements from baseline
in ADHD-RS-IV total score at endpoint (last valid postbaseline
assessment) than placebo (Figure 2). Moreover, within these
subgroups, the placebo-adjusted least squares mean (SE) ADHD-
RS-IV total score change from baseline at endpoint for the placebo
cohorts was -8.1 (1.40) and -7.4 (1.89) in the LDX and MAS XR
trials, respectively. The ADHD-RS-IV treatment effect size was
larger for both LDX doses when compared with approximately
equivalent doses of MAS XR (Table 2); however, no statistical
comparisons were performed.
LDX Trial MAS XR Trial
LDX 70 mg/day
(n=122) Placebo (n=62)
MAS XR
20 mg/day (n=41)
MAS XR
40 mg/day (n=42) Placebo (n=45)
Age (years) mean (SD) 34.2 (10.0) 35.8 (10.5) 35.2 (10.9) 38.9 (11.5) 37.3 (10.0) 39.6 (11.8)
Age category (years), n (%)
18-29
30-39
40-49
≥50
Sex, n (%)
Male
Female
Ethnicity/race, n (%)
White
Black
Hispanic
Asian
Native American
Other
45 (38.5)
31 (26.5)
33 (28.2)
8 (6.8)
66 (56.4)
51 (43.6)
99 (84.6)
3 (2.6)
11 (9.4)
2 (1.7)
1 (0.9)
1 (0.9)
40 (32.8)
37 (30.3)
31 (25.4)
14 (11.5)
63 (51.6)
59 (48.4)
108 (88.5)
2 (1.6)
8 (6.6)
1 (0.8)
0
3 (2.5)
22 (35.5)
15 (24.2)
19 (30.6)
6 (9.7)
32 (51.6)
30 (48.4)
48 (77.4)
4 (6.5)
6 (9.7)
0
2 (3.2)
2 (3.2)
10 (24.4)
12 (29.3)
11 (26.8)
8 (19.5)
29 (70.7)
12 (29.3)
36 (87.8)
2 (4.9)
2 (4.9)
1 (2.4)
0
0
11 (26.2)
15 (35.7)
11 (26.2)
5 (11.9)
25 (59.5)
17 (40.5)
38 (90.5)
1 (2.4)
2 (4.8)
0
1 (2.4)
0
10 (22.2)
12 (26.7)
14 (31.1)
9 (20.0)
29 (64.4)
16 (35.6)
39 (86.7)
2 (4.4)
2 (4.4)
1 (2.2)
0
1 (2.2)
Weight (lb) mean (SD) 173.1 (37.8) 174.3 (37.3) 181.3 (39.1) 183.9 (31.8) 185.6 (55.3) 186.3 (42.6)
Height (in) mean (SD) 67.6 (3.6) 67.4 (3.7) 67.9 (3.7) 68.2 (3.5) 67.5 (3.7) 67.7 (4.0)
ITT population, n 117 120 62 39 42 43
Safety population, n 117 122 62 41 42 45
LDX=lisdexamfetamine dimesylate; MAS XR=mixed amphetamine salts extended release; SD=standard deviation; ITT=intention to treat.
Lasser R, Dirks B, Adeyi B, Babcock T. Primary Psychiatry. Vol 17, No 9. 2010.
Primary Psychiatry 47
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R. Lasser, B. Dirks, B. Adeyi, T. Babcock
In the LDX trial, subjects randomized to the placebo
group had a mean (SD) baseline CGI-S score of 4.7 (.73)
and in the MAS XR trial a score of 4.6 (.62). On the CGI-S
scale, a score of 4 represents “moderately ill” while a score of
5 represents “markedly ill.” 35 In the LDX trial at endpoint,
Dunnett test determined that the mean (SD) CGI-I scores
FIGURE 1
MEAN (SD) ADHD-RS-IV SCORES AT BASELINE AND ENDPOINT*
Mean (SD) ADHD-RS-IV Total Score
54
48
42
36
30
24
18
12
6
0
LDX
50 mg/day
LDX Placebo MAS XR MAS XR Placebo
70 mg/day
20 mg/day 40 mg/day
LDX Study MAS XR Study
* Endpoint=last valid postbaseline assessment.
ADHD-RS-IV=Attention-Deficit/Hyperactivity Disorder Rating Scale IV; LDX=lisdexamfetamine
dimesylate; MAS XR=mixed amphetamine salts extended release.
Baseline Endpoint
Lasser R, Dirks B, Adeyi B, Babcock T. Primary Psychiatry. Vol 17, No 9. 2010.
were significantly lower (indicating greater improvement) for
both LDX dose groups compared with 3.2 (1.19) in the placebo
group (P

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
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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

DISCUSSION
This study is the first to qualitatively assess two long-acting,
amphetamine-based stimulants, LDX and MAS XR, in
adults. Using groups derived from registration trials that were
matched on baseline severity of ADHD symptoms, duration
of treatment, and approximately comparable amphetamine
doses, a post hoc matched-group assessment was conducted.
In these clinical trials, LDX and MAS XR had similar TEAEs.
Common TEAEs ≥10% in the present analysis of both studies
included dry mouth, decreased appetite, insomnia, and
headache. The common differences of the percent incidence
of all active treatment doses minus placebo TEAEs in both trials
were decreased appetite, insomnia, and dry mouth. These
are consistent with TEAEs observed with other long-acting
stimulants in adults. 39,40 Although most TEAEs in both clini-
TABLE 5
MEAN (SD) SBP, DBP, AND PULSE AT BASELINE AND AT ENDPOINT*
Vital Sign, mean (SD)
LDX
50 mg/day (n=117)
Comparative Efficacy and Safety of LDX and MAS XR in Adults With ADHD
cal trials were mild or moderate in severity, the incidence of
severe TEAEs was twice as low in LDX-treated subjects than in
MAS XR-treated subjects. As expected for stimulant therapies,
LDX and MAS XR were associated with weight loss over a
4-week treatment period. The degree of weight loss was lower
in LDX treatment groups versus MAS XR treatment groups
when assessing groups with approximately equivalent amounts
of amphetamine base. Within each trial, the degree of weight
loss appeared to demonstrate a dose response.
Although LDX and MAS XR were associated with increases
in BP parameters and pulse, such changes were modest and not
clinically meaningful. Given that the doses of LDX and MAS
XR included in the present analysis have approximately equivalent
amounts of amphetamine base, the mechanisms underlying
the observed differences in cardiovascular effects are unclear.
Subgroup post hoc analysis results for vital signs (SBP, DBP,
LDX Trial MAS XR Trial
LDX
70 mg/day (n=122) Placebo (n=62)
MAS XR
20 mg/day (n=41)
MAS XR
40 mg/day (n=42) Placebo (n=45)
SBP, mm Hg Baseline 118.3 (9.8) 115.5 (10.0) 116.4 (10.3) 121.3 (10.8) 117.4 (13.5) 117.4 (10.7)
Endpoint 118 (10.0) 117.3 (10.2) 116.0 (10.8) 122.8 (12.3) 120.0 (13.0) 116.6 (10.7)
DBP, mm Hg Baseline 74.8 (8.3) 73.6 (8.1) 74.1 (8.2) 77.6 (8.7) 74.9 (9.8) 76.8 (8.4)
Endpoint 75.7 (8.2) 75.5 (8.5) 75.2 (8.2) 80.6 (9.5) 79.2 (7.6) 79.8 (8.5)
Pulse, bpm Baseline 72.4 (8.9) 69.8 (9.2) 70.9 (9.6) 73.1 (9.5) 73.6 (9.1) 71.8 (8.9)
Endpoint 76.0 (11.5) 75.6 (10.4) 70.9 (8.1) 77.1 (11.1) 79.6 (9.8) 72.2 (9.5)
*Endpoint=last valid postbaseline measurement.
SD=standard deviation; SBP=systolic blood pressure; DBP=diastolic blood pressure; LDX=lisdexamfetamine dimesylate; MAS XR=mixed amphetamine salts extended release; bpm=beats
per minute.
Lasser R, Dirks B, Adeyi B, Babcock T. Primary Psychiatry. Vol 17, No 9. 2010.
TABLE 6
OUTLIER CRITERIA MET BY PARTICIPANTS AT ENDPOINT*
Outlier Criteria
LDX 50 mg/day
(n=117)
LDX Trial MAS XR Trial
LDX 70 mg/day
(n=122) Placebo (n=62)
MAS XR
20 mg/day (n=41)
MAS XR
40 mg/day (n=42) Placebo (n=45)
SBP ≥150 mm Hg 0 0 0 2 1 0
DBP ≥95 mm Hg 0 0 0 1 0 1
Pulse ≥mean + 2 SD bpm 3 4 3 6 4 3
QT interval >480 msec 0 0 0 0 0 0
QTcF >480 msec 0 0 0 0 0 0
*Endpoint=last valid postbaseline assessment.
LDX=lisdexamfetamine dimesylate; MAS XR=mixed amphetamine salts extended release; SBP=systolic blood pressure; DBP=diastolic blood pressure; SD=standard deviation;
bpm=beats per minute; QTcF=QT interval corrected using Fridericia’s formula.
Lasser R, Dirks B, Adeyi B, Babcock T. Primary Psychiatry. Vol 17, No 9. 2010.
Primary Psychiatry 51
© MBL Communications Inc. September 2010

R. Lasser, B. Dirks, B. Adeyi, T. Babcock
and pulse) from the LDX and MAS XR analysis were consistent
with what has been observed in their respective studies; the mean
(SD) change from baseline at endpoint for both LDX and MAS
XR were consistent with their respective primary study (data not
shown). Another possibility for the difference was that this post
hoc analysis of the selected groups may introduce some bias. A
difference between these agents is the absence of l-amphetamine
from LDX and its presence in MAS XR (both d- and l- isoforms),
which may play an essential role in this slight cardiovascular
difference between treatments. 41-43 Studies comparing the
cardiovascular effects of d- and l-amphetamine have not yielded
clear answers; however, many sources suggest that l-amphetamine
may have greater peripheral and cardiovascular effects and
that d-amphetamine is more potent as a central stimulant. 41,44 In
a small clinical trial in children with ADHD, Arnold and colleagues
44 found no significant differences in effects on BP and
heart rate, but it was also assessed at the third week of treatment.
Unlike changes in BP parameters, increases in pulse were very
similar between equivalent (ie, similar total amphetamine base)
doses of LDX and MAS XR with only minimally higher rates
observed with MAS XR. In neither study did treatment result in
clinically significant changes in QT interval.
Both LDX and MAS XR were associated with significant
reductions (versus placebo) in ADHD core symptoms as
assessed by ADHD-RS-IV total scores. Significant improvements
were also observed on clinician ratings of global
improvement as assessed by CGI score. At approximately
equivalent amphetamine doses, LDX resulted in numerically
greater improvements in ADHD-RS-IV and CGI than MAS
XR. The ADHD-RS-IV treatment effect size and CGI-I/CGI-
C was larger for both LDX doses when compared qualitatively
with approximately equivalent doses of MAS XR. The ADHD-
RS-IV total score effect sizes suggest that both LDX doses demonstrated
effect sizes that are considered large; effects sizes for
MAS XR were medium. The CGI effect sizes for LDX were
medium and large for both LDX doses (50 and 70 mg/day),
respectively, and medium for both doses of MAS XR (20 and
40 mg/day). These differences in effect sizes may be due to the
relative sample sizes of LDX groups that were almost twice as
large as the MAS XR group as well as relative placebo responses
across both studies. When comparing placebo-adjusted
comparisons (eg, effect size) for each stimulant, the reader is
reminded that the placebo cohort used for comparison differed
in each study. While no direct comparisons of these placebo
groups were performed, the placebo effect appears greater in
the LDX trial. This was indicated by the greater decrease in
ADHD-RS-IV total score change from baseline at endpoint
for the placebo cohort in the LDX trial. Overall, a qualitative
assessment would imply a slightly better improvement with
LDX versus MAS XR when compared with placebo.
The present analysis suggests that, at approximately comparable
doses, LDX was more efficacious than MAS XR and
had lower incidence of the differences (all active treatment
doses [for either trial] minus placebo) in the percent of AEs
and any percent differences of AEs versus MAS XR, although
prospective and quantitative comparison studies are required to
confirm these results. The results of this analysis are consistent
with short-term controlled clinical trials evaluating the safety
and efficacy of LDX and MAS XR in children and adolescents
with ADHD that also demonstrated significant improvements
versus placebo in both ADHD-RS-IV total score and CGI ratings.
28,45 Furthermore, although the present analysis used data
from a pair of short-term trials, the effectiveness of both LDX
and MAS XR for the treatment of ADHD in adults has been
demonstrated in long-term trials. 46,47
Other considerations in terms of assessing potential differences
between both treatment regimens should be noted. The
mode of therapeutic action for amphetamines in the treatment
of ADHD is thought to be due to the block of reuptake of
norepinephrine and dopamine into the presynaptic neuron
and their increased release into the extraneuronal space. LDX,
the parent drug, does not bind to the sites responsible for the
reuptake of the neurotransmitters. 48 Thus, although there are
similarities between LDX and MAS XR, they are different
in terms of mechanism of action (prodrug versus mechanical
release) and their pharmacokinetic profiles (LDX has a more
predictable pharmacokinetic profile).
Although pharmacokinetic studies of MAS XR in adults
indicated consistency in terms of bioavailability, 49-51 the prodrug
mechanism of LDX may provide a more consistent pharmacokinetic
profile. In a clinical trial in healthy adults, LDX demonstrated
low inter- and intrasubject variability, offering consistent
time to maximum d-amphetamine concentration. 52 With prodrug
LDX administration, d-amphetamine plasma concentrations
increased linearly and in a dose-dependent manner,
with no indication of enzyme saturation in healthy adults and
showed reliable delivery over a wide range of doses. 52 The prodrug
mechanism requires intrinsic enzymatic cleavage of intact
LDX to active d-amphetamine and is independent of exogenous
formulation/drug-release delivery systems such as MAS XR. 53
Mechanically formulated delayed-release beads can be crushed,
so they are more easily susceptible to abuse 9 ; enteric-coated beads
can be affected by gastric pH, since they have a pH-sensitive,
release-delaying polymer layer and overcoating. 54 Variations in
pH did not affect the solubility profile of LDX, and increases in
pH beyond this range only slightly reduced solubility. 55 Hence,
the absorption of LDX versus MAS XR is not readily altered or
converted by enzymes that simulated conditions of the gastrointestinal
tract and is consistent with intact LDX absorption. 20
It has also been suggested that LDX is absorbed intact by active
transport in the small intestine. 20 Although, changes in urinary
pH alter the elimination of either drug, with urinary alkalinization
decreasing excretion and acidification increasing excretion,
23,48 d-amphetamine is not available until after metabolism
Primary Psychiatry 52
© MBL Communications Inc. September 2010

of LDX. Prescribing information for LDX, unlike that for MAS
XR, does not warn about the effects of alterations in gastric pH
on d-amphetamine absorption. 23,48
The findings of this matched group qualitative assessment of
two clinical trials must be viewed in light of several limitations.
To develop matched comparison groups, the data set from the
MAS XR trial was reduced in size and was smaller than the LDX
data set (n=128 vs. n=301), potentially allowing for variability as
a result of differences in sample size, although the original number
of participants in the MAS XR trial was ~250. 25 The nature
of effect sizes is to estimate the apparent magnitude of relationships
among data sets between treatment and placebo groups.
As such, effect sizes facilitate comparisons between studies of
various population sizes, limited study design differences, and
with similar or different outcome measures. 56 Nonetheless, since
the assessed population of the LDX trial was ~2-fold higher,
comparisons of study effect sizes and the differences between
TEAE frequencies should be considered as qualitative in nature.
Additionally, while the demographics of the groups analyzed are
intended to be comparable, the participants were not matched
by age, sex, or disease severity, which resulted in slight dissimilarities
among cohorts (eg, greater mean age of subjects in the
MAS XR trial). Differences in the inclusion/exclusion criteria
and the AE classification/coding systems of the trials should
also be recognized. Both studies largely excluded adults with
coexisting conditions including comorbid psychiatric disorders
and cardiovascular disease. As such, the populations studied may
not fully represent patients encountered in clinical practice. The
30 mg/day LDX and 60 mg/day MAS XR treatment groups
were excluded from this analysis because dose equivalents of
amphetamine base were not available across trials. Finally, precise
equivalent dosage strengths of different extended-release stimulants
remain unknown due to differences in their pharmacokinetic
profiles and mechanisms of delivery, and hence may not be
entirely comparable.
CONCLUSION
The efficacy and relative safety of long-acting amphetamine-
and MPH-based psychostimulants for the treatment of ADHD
are well documented. Although early research focused on
stimulant treatment for ADHD in children, recent studies have
demonstrated similar benefits in adults. The virtual nonexistence
of prospective head-to-head trials in this population makes
direct comparisons of long-acting stimulants impossible. In lieu
of such trials, clinicians are left to rely on indirect comparisons
such as the post hoc analysis presented here. In these short-term
clinical trials, both long-acting amphetamine-based stimulants,
LDX and MAS XR, were effective in the treatment of ADHD
in adults and provided significantly greater control of ADHD
symptoms than placebo. In this matched group qualitative
comparison, LDX demonstrated better efficacy than MAS XR,
Comparative Efficacy and Safety of LDX and MAS XR in Adults With ADHD
as indicated by greater improvements in ADHD-RS-IV total
scores and CGI ratings. Both LDX and MAS XR demonstrated
safety profiles consistent with stimulant use, although marginally
smaller changes in cardiovascular parameters and the incidence
of severe TEAEs were observed with LDX. Although not a substitute
for prospective and quantitative comparison studies, this
analysis suggests LDX may offer advantages over MAS XR for
the treatment of adults with ADHD. PP
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