Contents

Focus Points
Abstract
Introduction
Methods
       • Study Designs
       • Subjects
       • Efficacy Measures
       • Safety Measures
       • Statistical Analysis
Results
       • Subject Demographics
       • Efficacy
       • Safety
Discussion
Conclusion
References

 

Dr. Lasser is Senior Director, Dr. Dirks is Associate Director, and Dr. Babcock is Associate Director of Scientific Publications, all in the Clinical Development and Medical Affairs Department at Shire Development Inc. in Wayne, Pennsylvania. Mr. Adeyi is Associate Director of Global Biostatistics in the Biostatistics and Statistical Programming Department at Shire Development Inc.

Disclosures: Dr. Lasser, Mr. Adeyi, and Dr. Babcock are Shire employees and own stocks and/or stock options from Shire. Dr. Dirks is a Shire employee and owns stocks and/or stock options from Johnson & Johnson and Shire.

Acknowledgments: Clinical research was funded by Shire Development Inc. Authors directed writing assistance from Huda Ismail Abdullah, PhD, and Michael Pucci, PhD, employees of Health Learning Systems. Editorial assistance in the form of proofreading, copy editing, and fact checking was also provided by Health Learning Systems, part of CommonHealth. Health Learning Systems was funded by Shire Development Inc. for support in writing and editing this manuscript. Although the sponsor was involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, ultimate interpretation, and decision to submit it for publication in Primary Psychiatry were made by the authors independently.

Please direct all correspondence to: Robert Lasser, MD, Senior Director, Clinical Development and Medical Affairs, Shire Development Inc., 725 Chesterbrook Blvd, Wayne, PA 10987; Tel: 484-595-8383; Fax: 484-595-8679; E-mail: rlasser@shire.com.


Focus Points

• This post hoc, matched group analysis using data from two similar short-term trials examined the efficacy and safety of lisdexamfetamine dimesylate (LDX) and mixed amphetamine salts extended release (MAS XR) compared with their respective placebo groups for the treatment of adults with attention-deficit/hyperactivity disorder (ADHD).
• 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, as indicated by greater improvements in ADHD Rating Scale IV total scores and Clinical Global Impressions ratings.
• Both LDX and MAS XR demonstrated safety profiles consistent with stimulant use.
• LDX may offer efficacy advantages and a safety profile comparable with MAS XR for adult ADHD; however, this should be confirmed with appropriate comparative trials.

 

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, double-blind trials in adults with attention-deficit/hyperactivity disorder (ADHD) were analyzed. This post hoc analysis examined active treatment groups and placebo with approximately equivalent 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<.0001); MAS XR was -5.56 (20 mg/day) and -8.80 (40 mg/day) ( P≤.047). Common TEAEs with these stimulants included dry mouth, decreased appetite, and insomnia. TEAE percent differences (all doses minus placebo) rates for either study were similar (slightly more with MAS XR).
Discussion: LDX had numerically larger ADHD-RS-IV score improvements than MAS XR. Both stimulants appeared similar in safety and tolerability.
Conclusion: LDX may offer efficacy advantages and a safety profile comparable with MAS XR for adult ADHD; but this should be confirmed with appropriate comparative trials.

Introduction

Psychostimulants are pharmacotherapeutic mainstays for children and adults with attention-deficit/hyperactivity disorder (ADHD).1,2 Efficacy and safety of both methylphenidate-(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 adherence2,4 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 colleagues6 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 trials14-19 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 l-lysine 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 trial25 and in a laboratory school study26 in children from 1.5–12 hours post dose. A classroom, crossover children’s study indicated that the percent coefficient of variance for Tmax, Cmax, 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

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, 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 <28 were excluded from the analysis (see “Statistical Analysis” section).

Efficacy Measures

The primary efficacy measure in both studies was the total score of the ADHD-RS-IV.32 This is a validated rating instrument as used in the MAS XR study,33 but in the LDX trial, a newer version of the scale with adult prompts was administered.34 In both trials, the ADHD-RS-IV was administered at baseline and all postbaseline study weeks by trained and qualified clinical investigators. Originally designed to assess ADHD symptomatology in children, the ADHD-RS-IV for adults consists of 18 items based on DSM-IV-TR ADHD criteria. Each item is scored on a 4-point Likert scale from 0 (no symptoms) to 3 (severe symptoms), with total scores ranging from 0 to 54.

A secondary efficacy measure common to both trials were two of the Clinical Global Impressions (CGI) scales.35 The CGI scales provide clinician-rated assessment of global symptom severity and improvements over time. In both trials, the CGI-Severity (CGI-S) assessed baseline symptom severity on a scale from 1 (no symptoms) to 7 (very severe symptoms). As a measure of symptom improvement over time relative to baseline, clinicians completed the CGI-Improvement (CGI-I; LDX trial) or the CGI-Change (CGI-C; MAS XR trial) at all postbaseline weeks. For both scales, clinicians rated changes over time from 1 (very much improved) to 7 (very much worse). Although they are named differently, the CGI-I and CGI-C were identically worded instruments.

Safety Measures

In both trials, safety was assessed via the recording of adverse events (AEs) from baseline to the end of the trial. If the AEs occurred postrandomization, they were considered treatment-emergent AEs (TEAEs). Coding terminology for AEs in the LDX trial was based on Medical Dictionary for Regulatory Activities (MedDRA), Version 9.1,36 while Coding Symbols for the Thesaurus of Adverse Reaction Terms (COSTART) dictionary (Version 5.0),37 was used for the MAS XR trial. Both MedDRA and COSTART are standardized dictionaries that facilitate classification of AEs. Compared with COSTART, the newer MedDRA dictionary is more hierarchical, contains more terms, and is multiaxial in nature. Other safety measures in the trials included assessments of systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse, and electrocardiograms.

Statistical Analysis

This is a qualitative matched-group assessment of subjects who exceeded similar thresholds on the ADHD-RS-IV and were exposed to approximately equivalent doses of amphetamine base for a similar length of time. As an inclusion criterion, subjects in the LDX clinical trial were required to have a baseline ADHD-RS-IV total score ≥28. Although no such entry requirement existed in the MAS XR trial, for the purposes of this analysis, subjects with baseline ADHD-RS-IV total scores <28 were excluded. While 50 and 70 mg of LDX contained ~14.8 and 20.8 mg of d-amphetamine, respectively (data on file, Shire Development Inc.), 20 and 40 mg of MAS XR contained ~12.5 and 25 mg of total amphetamine base equivalence, respectively.23 Given that the amounts of amphetamine base in 50 and 70 mg/day LDX are approximately equivalent to those in 20 and 40 mg/day MAS XR, respectively, data from subjects in these treatment groups were included in the present analysis. In contrast, data from subjects randomized to treatment with 30 mg/day LDX and 60 mg/day MAS XR were excluded, since no similar dose groups were available for assessment. Although the amounts of amphetamine base were comparable, it should be noted that they were not exactly equal. For the first equivalency dose match, the amount of amphetamine base difference was 2.3 mg with LDX versus MAS XR; for the second equivalency dose match, the amphetamine base difference was 4.2 mg for MAS XR versus LDX.

LDX and MAS XR treatment groups were compared directly with their respective placebo groups. No direct quantitative comparisons between the LDX and MAS XR studies were performed because these post hoc analyses were an exploratory effort. Dunnett test was used to compare ADHD-RS-IV total scores between each active treatment dosage group and the placebo group in the same clinical trial. CGI scores were also compared between active treatment and placebo groups using Dunnett test. To further enable indirect comparisons across studies, effect sizes were calculated for each stimulant dose. The effect sizes provide a standardized assessment of treatment effect, and the calculations followed the method described by Curtin and colleagues.38 For presentation of TEAE data, when multiple MedDRA terms mapped to a single COSTART term, the COSTART terminology from the TEAEs of the MAS XR study were harmonized with the LDX study. The harmonization was conducted by recoding the MAS XR verbatim terminology, 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 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

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.

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 were significantly lower (indicating greater improvement) for both LDX dose groups compared with 3.2 (1.19) in the placebo group (P<.0001; Table 2). A CGI-I score of 3 indicates “minimally improved” while a score of 2 corresponds to “much improved.”35 At endpoint, the mean (SD) CGI-C scores were 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 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 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 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.

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 clinical 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, 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 colleagues44 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 abuse9; 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 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, 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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