A Long-Term Open-Label Safety and EffectivenessTrial of Lisdexamfetamine Dimesylate in Adolescents

With Attention-Deficit/Hyperactivity Disorder

Robert L. Findling, MD, MBA,1 Andrew J. Cutler, MD,2,3 Keith Saylor, PhD,4 Maria Gasior, MD, PhD,5

Mohamed Hamdani, MS,6 M. Celeste Ferreira-Cornwell, PhD,7 and Ann C. Childress, MD8

Abstract

Objective: Information on psychostimulant treatment in long-term studies for attention-deficit/hyperactivity disorder

(ADHD) in adolescents is limited. This study aimed to assess the safety and effectiveness of lisdexamfetamine dimesylate

(LDX) over 52 weeks in adolescents with ADHD.

Methods: This open-label multicenter study enrolled eligible participants after their participation in a randomized, double-

blind, placebo-controlled 4 week trial in adolescents with ADHD. Following a 4 week dose-optimization phase, participants

were maintained on treatment for up to *48 weeks on an optimal dose. Safety assessments included treatment-emergent

adverse events (TEAEs), vital signs, laboratory findings, and electrocardiograms. Effectiveness measures included the

ADHD Rating Scale IV (ADHD-RS-IV; primary) and Clinical Global Impressions-Improvement (CGI-I). The Youth Quality

of Life-Research Version (YQOL-R) was also included in this study; raw scores are transformed to a 0–100 point scale.

Results: Of 269 enrolled (from the antecedent study), 265 (98.5%) were in the safety population and effectiveness population.

Common TEAEs (‡5%) with LDX included upper respiratory tract infection (21.9%), decreased appetite (21.1%), headache

(20.8%), decreased weight (16.2%), irritability (12.5%), insomnia (12.1%), nasopharyngitis (7.2%), influenza (6.8%),

dizziness (5.3%), and dry mouth (5.3%). At end point, for all LDX doses in the overall safety population, mean (SD) increase

from baseline in systolic blood pressure was 2.3 (10.53) mm Hg, diastolic blood pressure was 2.5 (8.37) mm Hg, and pulse rate

was 6.3 (12.74) bpm. No clinically meaningful electrocardiogram or vital sign changes were observed. At end point with LDX

treatment, the ADHD-RS-IV mean (SD) total score change from antecedent study baseline was -26.2 (9.75) (p < 0.001);

87.2% of participants were improved (CGI-I = 1 or 2). Baseline (antecedent study) mean (SD) YQOL-R perceptual total score

was 79.8 (11.28) and increased by 3.9 (9.73) at end point (p < 0.001).

Conclusions: LDX demonstrated a long-term safety profile similar to that of other long-acting psychostimulants and was

effective, as indicated by improvements in ADHD symptoms and participant-perceived YQOL, in adolescents with ADHD.

Clinical Trial Registration: NCT00764868, http://www.clinicaltrials.gov/ct2/show/NCT00764868?term = SPD489-306

&rank = 1

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a

childhood-onset neurobehavioral disorder with symptoms

often continuing into adolescence and beyond (Dulcan and the

Work Group on Quality Issues 1997; Green et al. 1999; American

Academy of Pediatrics Subcommittee on Attention-Deficit/

Hyperactivity Disorder and Committee on Quality Improvement

2001; Weisler 2005). The worldwide prevalence of adolescent

ADHD is estimated to be *2–4% (Polanczyk et al. 2007). How-

ever, worldwide data on prevalence stratified by age are limited,

and regional and national rates differ widely, ranging from *9

to *14% (Centers for Disease Control and Prevention 2010;

Merikangas et al. 2010). In a United States survey that reported

an *9% prevalence, *50% exhibited severe impairment

(Merikangas et al. 2010).

1Johns Hopkins Medicine and the Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland.2Florida Clinical Research Center, LLC, Bradenton, Florida.3Department of Psychiatry, University of Florida, Bradenton, Florida.4NeuroScience, Inc., Herndon, Virginia.Departments of 5Global Clinical Medicine, 6Biostatistics, and 7Clinical Programs, Shire Development LLC, Wayne, Pennsylvania.8Center for Psychiatry and Behavioral Medicine Inc., Las Vegas, Nevada.Funding: Clinical research was funded by the sponsor, Shire Development LLC.These data have been previously presented at the 2011 American Psychiatric Association meeting, May 14–18, 2011, in Honolulu, Hawaii.

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 23, Number 1, 2013ª Mary Ann Liebert, Inc.Pp. 11–21DOI: 10.1089/cap.2011.0088

11

Based on the percentage of adolescents who met the Diagnostic

and Statistical Manual of Mental Disorders, 4th ed., Text Revision

(DSM-IV-TR) (American Psychiatric Association 2000) ADHD

criteria, there are *3,500,000 in the United States with ADHD

(Schubiner and Katragadda 2008). Adolescents may exhibit less

hyperactivity than do children with ADHD. However, when com-

pared with their peers, adolescents with ADHD have increased

impulsivity (e.g., ‘‘making irresponsible choices’’), increased in-

attention, and a high rate of psychiatric comorbidities (Schubiner

and Katragadda 2008). When compared with treated adolescents,

untreated adolescents with ADHD had higher rates of academic

failure, emotional problems, earlier onset of substance abuse, de-

linquency, teenage pregnancy, sexually transmitted infections, and

poor driving records (Schubiner and Katragadda 2008).

There are several efficacious treatment options for ADHD.

Psychostimulant medications are the most commonly prescribed

and are recommended as first-choice ADHD treatment options by

various guidelines (Pliszka and AACAP Work Group on Quality

Issues 2007; Wolraich et al. 2007; Graham and Coghill 2008).

However, there are only a few long-term studies (Hoare et al. 2005;

Hammerness et al. 2009; Findling et al. 2010) to date that have

assessed the safety and effectiveness of psychostimulant use in

adolescents. Hence, there is a need for long-term studies assessing

psychostimulant use, especially long-acting formulations.

Lisdexamfetamine dimesylate (LDX), a long-acting prodrug

stimulant, is indicated by the United States Food and Drug Ad-

ministration for ADHD treatment of children (6–12 years), ado-

lescents (13–17 years), and adults. Two long-term, open-label LDX

studies conducted in children (Findling et al. 2008) and adults

(Weisler et al. 2009) with ADHD demonstrated a safety profile

consistent with that of other psychostimulant medications. In the

child study, mainly mild to moderate treatment-emergent adverse

events (TEAEs) were experienced by 78% of participants (Findling

et al. 2008). Common TEAEs with an incidence >5% with LDX

treatment included decreased appetite (33%), headache (18%),

decreased weight (18%), insomnia (17%), upper abdominal pain

(11%), upper respiratory tract infection (11%), irritability (10%),

nasopharyngitis (10%), vomiting (9%), cough (7%), and influenza

(6%). In the adult study, with all LDX doses, TEAEs (mainly mild

to moderate severity) were experienced by *88% of participants

(Weisler et al. 2009). TEAEs with an incidence ‡5% with any LDX

dose included upper respiratory tract infection (21.8%), insomnia

(19.5%), headache (17.2%), dry mouth (16.6%), decreased appetite

(14.3%), irritability (11.2%), anxiety (8.3%), nasopharyngitis

(7.4%), sinusitis (6.6%), decreased weight (6.0%), back pain

(5.4%), and muscle spasms (5.2%).

Additionally, LDX demonstrated efficacy in adolescents with

ADHD and a safety profile consistent with that of long-acting

psychostimulants in a randomized, double-blind, parallel-group,

placebo-controlled, forced-dose titration study (4 weeks) (Findling

et al. 2011). This is a first report of the long-term effects of LDX in

adolescents (aged 13–17 years) with at least moderately symp-

tomatic ADHD. Of note, this study included an examination of

adolescents’ perception of quality of life (QOL) during LDX

treatment.

Methods

Study design and participants

This open-label extension study was conducted across 45 sites in

the United States from November 2008 to April 2010. Adolescents

13–17 years of age (inclusive at the time of the antecedent study

entry) with a primary diagnosis of ADHD who participated in an

antecedent parallel-group, double-blind, placebo-controlled, fixed-

dose titration, short-term (4 weeks) LDX study (Findling et al.

2011) and were treated with LDX or placebo, were eligible to

participate in this long-term study, if they completed a minimum of

3 weeks of the antecedent study and were not terminated for non-

compliance, adverse events (AEs), or other safety reasons. Parti-

cipants remained blinded to prior treatment (placebo or LDX)

assignments in the present study, although it was an open-label

design. In order to preserve the blind of the antecedent study,

investigators in the present study were blinded to data from the

antecedent study; however, to facilitate patient management, a few

sites requested unblinded data after all participants had completed

participation in the antecedent study and after all treatment in the

current study had been initiated.

Key study inclusion criteria for the antecedent study included

being 13–17 years of age (inclusive) at the time of consent; a total

score of ‡ 28 on the ADHD Rating Scale IV (ADHD-RS-IV)

(DuPaul et al. 1998) at baseline; age-appropriate intellectual

function; blood pressure (BP) measurements £ 95th percentile for

age, sex, and height; and a negative pregnancy test for females.

Also included were participants with no clinically relevant abnor-

malities based on their medical history or physical examination,

and those and their parent(s) or legally authorized guardian(s) who

were willing and able to adhere to protocol requirements.

Key exclusion criteria for the antecedent study included co-

morbid psychiatric disorder and/or symptoms/conditions that might

contraindicate treatment with LDX and influence safety or effec-

tiveness analyses; a concurrent chronic or acute illness or an un-

stable medical condition that might confound the safety results;

clinically significant electrocardiogram (ECG) or history of serious

cardiac problems (e.g., cardiovascular disease, advanced arterio-

sclerosis, structural cardiac abnormality, cardiomyopathy, serious

heart rhythm abnormalities, coronary artery disease, and family

history of sudden cardiac death or ventricular arrhythmia) prior to

treatment; suicidal ideations; substance abuse; and/or allergy, hy-

persensitivity, and/or intolerance to amphetamine. Additionally,

participants who were nonresponsive to amphetamine in the ante-

cedent study or were receiving prohibited medications that have

central nervous system effects or affect performance (e.g., sedating

antihistamines, decongestant sympathomimetics) prior to the an-

tecedent study were not eligible to participate. Participants were

also not eligible to participate in this study if they were termi-

nated from the antecedent 4 week study because of noncompliance

and/or an AE for which continued treatment would be medically

contraindicated.

This study was designed to assess the safety and effectiveness of

a daily morning dose (30, 50, or 70 mg/day) of LDX in adolescents

with ADHD. It consisted of a 4 week dose-optimization phase

followed by a 48 week, open-label maintenance phase and a safety

follow-up phase. Regardless of prior treatment in the antecedent

study, all participants began this open-label study with a 30 mg/day

dose of LDX. During the optimization phase, beginning at week 0

and extending through week 4, participants were titrated to an

optimal dose of medication with site visits occurring every 7 days

(– 2 days). Titration was based on overall response, defined as

acceptable, ineffective, or intolerable. An acceptable response to

LDX treatment was defined as a ‡30% reduction in ADHD-RS-IV

total score from baseline (visit 0 of antecedent study) and a Clinical

Global Impressions-Improvement (CGI-I) rating of 1 or 2 with

tolerable side effects, whereas an ineffective response was defined

as not meeting these criteria. For an ineffective response, the LDX

12 FINDLING ET AL.

dose was titrated upward to the next dose strength. An intolerable

response was defined as occurrence of side effects that were

characterized as intolerable by the investigator, and the dose was

decreased to a lower dose (if available). If at the lower dose, in-

tolerable side effects persisted, the participant was removed from

the study. To obtain the optimal dose of LDX, the dose could be

decreased or increased by 20 mg/day increments (maximum dose

of 70 mg/day), based on investigator judgment. During the main-

tenance phase (48 additional weeks), participants returned for study

visits at 28 day intervals (– 5 days). The optimized LDX dose was

continued, or, if deemed necessary by the investigator, further

dose adjustments were possible. A safety follow-up telephone call

occurred 7 days (– 2 days) after the last LDX dose. Baseline de-

mographics were obtained during the antecedent trial. Baseline

safety and effectiveness assessments used for the current study

were those obtained at the baseline visit of the antecedent study.

Voluntarily signed informed consent was provided by a parent or

legally authorized guardian, and participants signed documentation

of assent to indicate that they were aware of the study procedures

and restrictions. This study was conducted in accordance with the

Declaration of Helsinki and Good Clinical Practice E6 according to

the International Conference on Harmonisation (ICH) guidelines.

In addition, the institutional review board of each institution re-

viewed and approved the informed consent form and the protocol.

Safety measures

Safety measures included reported AEs, physical examinations,

height and weight assessments, vital signs, a 12 lead ECG, and

clinical laboratory tests. AEs were coded using the Medical

Dictionary for Regulatory Activities Version 11.1 (MedDRA

2009). Ongoing AEs from the antecedent study were recorded as

medical history. All study AEs were recorded from the time of

signed informed consent to the follow-up call, were assessed for

relatedness and severity by the investigator at all study visits, and

were summarized by system organ class and preferred term for each

LDX dose group. If an AE increased in intensity relative to the

antecedent study during this open-label study, it was considered a

new TEAE. TEAEs were defined as AEs that started or worsened at

any time from the first day of LDX treatment in this study to the

third day (inclusive) after treatment had stopped. Whether an AE

was treatment related or considered serious was determined by the

investigator. Serious AEs (SAEs) were defined as clinical occur-

rences that were judged by the investigator to be ‘‘medically im-

portant’’ and that resulted in death, were life threatening, required

or prolonged hospitalization, resulted in persistent or significant

disability, or resulted in a congenital defect. A severe AE was

defined as an AE that was incapacitating, resulting in an inability to

work or complete usual activity.

Physical examinations were performed at week 4/end point of

the antecedent study, at week 52, and end point/early termination

(ET) of this study. Height was measured at week 4/end point of the

antecedent study and, in the current study, at week 4 of the dose-

optimization phase and at weeks 12, 20, 28, 36, 44, and 52/or ET

end point of the maintenance phase. Weight was measured and vital

signs (including sitting systolic BP [SBP], diastolic BP [DBP], and

pulse) obtained at all study visits. A 12 lead ECG was recorded at

week 4 and end point/ET of the antecedent study and at weeks 12,

24, 36, and 52 and at end point/ET of the maintenance phase.

Clinical laboratory tests were assessed at week 4/end point of the

antecedent study and at week 20 and week 52 and at end point/ET in

this study. The baseline values for height and weight, vital signs,

laboratory tests, and ECG were the baseline of the antecedent study,

and visit 1 values for the current study were those from week 4/end

point of the antecedent study. Clinical significance of ECG and

laboratory assessment results was determined by the investigator.

Medication adherence was assessed from week 1 to week 52 and at

end point/ET of the current study. Reasons for discontinuation

from the study were AEs, protocol nonadherence/participant non-

compliance, refusal to participate further, loss to follow-up, lack

of effectiveness, and other.

Effectiveness measures

The primary measure of effectiveness was the clinician-

reported ADHD-RS-IV (DuPaul 1998). The key effectiveness end

point of the study was the change from baseline (defined as baseline

from the 4 week study) of the ADHD-RS-IV total score at end point.

ADHD-RS-IV was also assessed at each postbaseline visit. The scale

consists of 18 items that evaluate ADHD symptom levels based on

current DSM-IV-TR criteria and is divided into two subscales (in-

attention and hyperactivity/impulsivity) of nine items each. Items are

scored on a four point scale that ranges from 0 (never, rarely) to 3

(very often). The range of possible scores is 0–54, with higher scores

indicating more impairment. The ADHD-RS-IV was completed by

the same rater at each visit, whenever possible, and information was

obtained from the participant’s parent/legal guardian.

The clinician-reported CGI evaluated global illness severity

(CGI-S) and improvement (CGI-I) over time (Guy 1976). The

CGI-S assessed global illness severity based on a seven point scale,

which ranges from 1 (normal, not at all ill) to 7 (among the most

extremely ill). The CGI-I, which evaluated global improvement

from week 1 of the dose-optimization phase up to 48 weeks or end

point/ET of the maintenance phase, is also based on a seven point

rating scale, ranging from 1 (very much improved) to 7 (very much

worse). Improvement was assessed relative to baseline of the an-

tecedent study. Clinician-reported scales (i.e., ADHD-RS-IV and

CGI), were completed when possible by the same rater (clinician)

experienced in evaluating adolescents with ADHD.

The QOL of adolescents participating in the study was assessed

using the Youth Quality of Life Instrument-Research Version

(YQOL-R) (YQOL-R 2002; Edwards et al. 2002; Patrick et al.

2002). The participant-reported YQOL-R is a validated, 56 item

instrument consisting of two modules: contextual items (potentially

verifiable by others) and perceptual items (known only to the par-

ticipant). The perceptual module is reported herein and is catego-

rized into four general domains (self, relationship, environment,

and general QOL). A total of five scores can be generated from the

perceptual items, a total perceptual score and four individual do-

main scores. The YQOL-R raw score is transformed to a 0–100

point scale to assist in result interpretation, with higher scores in-

dicating better QOL. The YQOL-R was completed by the partici-

pants at study entry, at week 28, and at week 52 and end point/ET of

the current study.

Safety analyses

Safety was reported for all enrolled participants who had taken at

least one dose of LDX treatment. The change from baseline in

safety parameters was from baseline of the antecedent study. End

point was defined as the last on-treatment visit after the first visit in

the current study. The last valid assessment after baseline was used

for participants with early termination.

Vital signs, ECG results, physical examination findings, and labo-

ratory evaluations were summarized using descriptive statistics. Outlier

EFFECTIVENESS/SAFETY OF LDX IN ADOLESCENTS 13

criteria were defined a priori. At end point/ET, numbers of participants

who met defined outlier criteria were recorded. Outlier criteria for SBP

included SBP ‡120 mm Hg and, separately, SBP ‡120 mm Hg that

constituted an increase from baseline of ‡10 mm Hg. Outlier criteria

for DBP included DBP ‡80 mm Hg and, separately, DBP ‡ 80 mm Hg

that constituted an increase from baseline of ‡10 mm Hg. Outlier cri-

teria for pulse rate included pulse ‡100 bpm and, separately, pulse

‡100 bpm that constituted an increase from baseline of ‡15 bpm.

Mean z scores for height and weight were determined based on

Centers for Disease Control and Prevention (CDC) (Centers for

Disease Control and Prevention 2000) reference values for these

measurements. Participants who took 80–100% of the LDX treat-

ment from visit to visit were considered clinically adherent to

treatment. Treatment compliance was assessed based on capsule

counts. The adherence rate was calculated as (number of capsules

dispensed - number of capsules returned)/(number of capsules

prescribed per day · number of days in treatment period) · 100.

Statistically, a participant was considered to be protocol compliant

if between 80% and 120% (inclusive) compliance with LDX

treatment was maintained throughout the study.

The clinician-administered Columbia-Suicide Severity Rating

Scale (C-SSRS) (Posner et al. 2009) was included after this study

was begun (week 24/next scheduled visit to week 52 and end point/

ET), and safety monitoring based on review of responses was used

to assess suicidal ideations and behaviors.

Effectiveness analyses

The effectiveness population (full analysis set [FAS]) was de-

fined as all enrolled participants who took at least one dose of LDX

treatment and had one postenrollment assessment of the primary

effectiveness measure (ADHD-RS-IV total score). Changes from

baseline (from antecedent 4 week study) in ADHD-RS-IV total

score at each visit and end point/ET were summarized and assessed

using a two-sided paired t test. The ADHD-RS-IV total and sub-

scale scores were summarized by visit and dose. The secondary

effectiveness outcome measures also included CGI-I and the

YQOL-R.

For analysis of CGI-I, scores were dichotomized into those

globally improved (CGI-I ratings of 1 [very much improved] or 2

[much improved]) and those not improved (CGI-I ratings of 3–7).

Summary statistics were presented at each postbaseline visit of this

study and at end point/ET. For the YQOL-R, only perceptual items

were included in the a priori statistical plan for analysis; paired

t tests were used to evaluate the change from baseline (4 week

antecedent double-blind study) to week 28, week 52, and end

point/ET.

Results

Participant disposition and demographics

Of the 314 participants who were enrolled and randomized in the

antecedent double-blind 4 week study, 310 participants received at

least one dose of LDX or placebo treatment and were included in

that study’s safety population. Of the 310 participants, 257 (82.9%)

completed the antecedent double-blind study. There were 269

participants from the antecedent study who enrolled in the current

study, of which 265 (98.5%) were included in the safety and FAS

populations. Of the 269 participants, 198 (73.6%) received LDX

treatment and 71 (26.4%) received placebo in the antecedent study;

randomization in the antecedent study was 1:1:1:1 for the LDX

30 mg/day, 50 mg/day, and 70 mg/day dose groups and placebo,

respectively (Findling et al. 2011). A total of 156 (58.0%)

FIG. 1. Participant disposition. aParticipants received treatment in the antecedent double-blind study. bA total of 14 participants werediscontinued in the prior LDX-treated group for other reasons: Pregnancy (n = 3), moved or were out of area (n = 6; one was sponsorrequested), took prohibited medication for an AE (n = 1), withdrew consent (n = 1), had a misuse/compliance issue with study drug(n = 1), met exclusion criteria (n = 1), and tested positive on urine drug screen (n = 1). Four participants were discontinued in the priorplacebo-treated group for other reasons: Moved or were out of area (n = 3) and tested positive on urine drug screen (n = 1). FAS, fullanalysis set; LDX, lisdexamfetamine dimesylate; TEAEs, treatment-emergent adverse events.

14 FINDLING ET AL.

participants completed the current study (Fig. 1). There were 41 of

310 (13.2%) participants from the antecedent study who did not

enroll in the current study. Of these 41 participants, 33 (10.6%)

were terminated early from the antecedent study and 8 (2.6%)

completed the antecedent study.

Demographic characteristics for the safety population are sum-

marized in Table 1. Overall, most participants were male (70.6%),

white (79.6%), and non-Hispanic or non-Latino (86.4%). At

baseline, the majority of participants were moderately or markedly

ill (95.1%), based on CGI-S ratings. Moreover, most participants

were diagnosed with inattention (34.7%) or combined (64.5%)

ADHD subtypes, and the mean (SD) time since initial ADHD di-

agnosis was 4.6 (4.14) years prior to the screening visit of the 4

week double-blind study. No apparent differences existed in

baseline and demographic characteristics between the LDX- and

placebo-treated groups.

Treatment dosing

There were 55 participants who had a final LDX dose of 30 mg/

day, 101 participants who had a final dose of 50 mg/day, and 109

who had a final dose of 70 mg/day. During the study, of 150 par-

ticipants who were titrated to a maximum dose of 70 mg/day, 109

participants had a final dose of 70 mg/day, whereas 34 and 7 par-

ticipants had been down-titrated to the 50 mg/day and 30 mg/day

dose levels, respectively. Of the 87 participants titrated to a max-

imum LDX dose of 50 mg/day, 67 were on that same dose at final

visit, and 20 were down-titrated to the 30 mg/day dose. At week 52

(n = 158), the percentage of participants in the 30 mg/day group was

20.9%, in the 50 mg/day group it was 38.6%, and in the 70 mg/day

group it was 40.5%.

Safety

Of the overall safety population, 230 (86.8%) participants ex-

perienced TEAEs; for participants who had previously received

LDX and placebo, 169 of 195 (86.7%) and 61 of 70 (87.1%),

respectively, reported TEAEs. Common TEAEs reported by ‡5%

of participants are summarized in Table 2. The incidence of TEAEs

‡5% by actual LDX dose suggests a dose-dependent increase in the

percentage of participants with TEAEs. Most TEAEs were mild to

moderate in severity. There were 13 (4.9%) participants who ex-

perienced 18 severe TEAEs (i.e., incapacitating AEs). These severe

TEAEs included dizziness (2), headache (2), migraine (2), ag-

gression (1), agitation (1), dermatitis contact (1), ectopic pregnancy

(1), hydrocele (1), joint sprain (1), pelvic fracture (1), pneumonia

(1), testicular torsion (1), traumatic liver injury (1), weight decrease

(1), and wrist fracture (1). There were no deaths during the study.

Moreover, there were 10 (3.8%) participants who reported 15 se-

rious TEAEs (i.e., clinical occurrences judged by the investigator to

be ‘‘medically important’’). These serious TEAEs included syn-

cope (4), aggression (2), ectopic pregnancy (1), hydrocele (1), joint

sprain (1), pelvic fracture (1), pneumonia (1), testicular torsion (1),

traumatic liver injury (1), vasovagal syncope (1), and wrist fracture

Table 1. Summary of Demographics and Baseline Characteristics in the Safety Population (n = 265)a

Antecedent 4-week study Overall

Baseline characteristics Subcategories LDX (n = 195) Placebo (n = 70) (n = 265)

Sex, n (%) Male 140 (71.8) 47 (67.1) 187 (70.6)Female 55 (28.2) 23 (32.9) 78 (29.4)

Race, n (%) White 152 (77.9) 59 (84.3) 211 (79.6)Black/African American 28 (14.4) 9 (12.9) 37 (14.0)Native Hawaiian/Other

Pacific Islander1 (0.5) 0 1 (0.4)

Asian 1 (0.5) 0 1 (0.4)Other 13 (6.7) 2 (2.9) 15 (5.7)

Ethnicity, n (%) Hispanic or Latino 26 (13.3) 10 (14.3) 36 (13.6)Non-Hispanic or non-Latino 169 (86.7) 60 (85.7) 229 (86.4)

Age (y), mean (SD) 14.6 (1.32) 14.4 (1.23) 14.5 (1.30)

Age group (y), n (%) 13–14 104 (53.3) 40 (57.1) 144 (54.3)15–17 91 (46.7) 30 (42.9) 121 (45.7)

Height (cm), mean (SD) 167.7 (9.03) 165.9 (10.00) 167.2 (9.31)

Weight (kg), mean (SD) 64.3 (13.07) 62.0 (13.73) 63.7 (13.25)

ADHD-RS-IV scores, mean (SD) Total 37.8 (6.95) 38.6 (7.16) 38.0 (7.00)Inattention subscale 22.5 (3.45) 22.9 (3.06) 22.6 (3.35)Hyperactivity/impulsivity

subscale15.3 (6.12) 15.7 (6.39) 15.4 (6.19)

CGI-S rating, mean (SD) 4.5 (0.59) 4.5 (0.63) 4.5 (0.60)

YQOL-R perceptual transformedscores, mean (SD)

Total perceptual 80.1 (11.33) 78.9 (11.17) 79.8 (11.28)Self domain 68.8 (10.56) 67.2 (11.34) 68.3 (10.77)Relationship domain 81.3 (14.15) 80.2 (12.71) 81.0 (13.77)Environment domain 82.4 (13.14) 83.6 (11.21) 82.7 (12.64)General QOL domain 87.9 (15.27) 84.7 (17.73) 87.1 (15.99)

aDemographics and baseline characteristics were carried forward from the antecedent 4 week double-blind study.ADHD-RS-IV, Attention-Deficit/Hyperactivity Disorder Rating Scale IV; CGI-S, Clinical Global Impressions-Severity; LDX, lisdexamfetamine

dimesylate; QOL, quality of life; SD, standard deviation; YQOL-R, Youth Quality of Life Instrument-Research Version.

EFFECTIVENESS/SAFETY OF LDX IN ADOLESCENTS 15

(1). No serious TEAEs were considered related to treatment except

for three syncopal episodes. In this trial, syncope was considered an

important medical event requiring reporting as an SAE; there were

5 such events (4 syncope, 1 vasovagal syncope) in four participants.

Of these 5 events, 2 (both syncope) were mild and 3 (2 syncope, 1

vasovagal syncope) were moderate, and all resolved without any

intervention or sequelae. Of the three moderate events, the one

episode of moderate vasovagal syncope occurred in a participant

treated with LDX who had a prior history of a structural cardiac

abnormality and mitral insufficiency by echocardiogram. On

sponsor-determined early termination (because of a protocol vio-

lation), the patient was not eligible for study participation and she

subsequently reported an SAE of syncope. Vasovagal syncope

occurred while taking 70 mg/day of LDX on day 21 of treatment in

the current study (participant had received 70 mg/day of LDX in the

antecedent study) and resolved without treatment. Per protocol, this

was considered a treatment-related and serious AE. TEAEs resulted

in early termination in 15 of 265 (5.7%) participants. These 15

participants had 19 TEAEs that led to early termination, including

depressed mood (3), insomnia (3), aggression (2), abdominal pain

(2), depression (1), ectopic pregnancy (1), increased BP (1),

irritability (1), paranoia (1), suicidal ideation (1), tic (1), visual

hallucination (1), and weight decrease (1).

SBP, DBP, and pulse rate for the overall safety population are

summarized in Table 3. There were increases from baseline (of the

antecedent study) in SBP, DBP, and pulse rate at weeks 12, 24, 36,

and 52 and at end point (Table 3). At end point, for all LDX doses in

the overall safety population, mean (SD) increase in SBP was 2.3

(10.53) mm Hg, DBP was 2.5 (8.37) mm Hg, and pulse rate was 6.3

(12.74) bpm from baseline (Table 3). For each LDX dose group,

moderate increases were observed in mean (SD) change from

baseline in SBP, DBP, and pulse rate with time. There was no clear

relationship between the various doses and the mean change;

however, this study was not statistically designed or powered to

assess such relationships among doses. The mean (SD) increases in

SBP (mm Hg) at end point by actual LDX doses (30, 50, and 70 mg/

day) were similar: 3.1 (9.15), 2.1 (11.49), and 2.0 (10.31), re-

spectively. For DBP (mm Hg), the mean (SD) changes from

baseline at end point were comparable: 2.0 (7.73), 3.1 (7.70), and

2.2 (9.27) for the 30, 50, and 70 mg/day actual LDX doses,

respectively. When the LDX doses were considered in the same

order, the increases in mean (SD) pulse rate (bpm) at end point were

5.7 (11.92), 4.2 (12.21), and 8.5 (13.37).

In the safety population, 33 (12.5%) participants met SBP outlier

criteria of ‡120 mm Hg with an increase from baseline of ‡10 mm

Hg, and 4 (1.5%) had an SBP measure of ‡140 mm Hg at study end

point. For DBP, 20 (7.5%) participants met outlier criteria of

‡80 mm Hg with an increase of ‡10 mm Hg, and there were no

participants with a value of ‡90 mm Hg at study end point/ET.

There were 11 (4.2%) participants who met pulse outlier criteria at

end point/ET of ‡100 bpm with an increase from baseline of

‡15 bpm, and none had a pulse rate of ‡120 bpm on two consec-

utive visits.

There were no ECG findings at end point that were deemed

clinically significant by the investigator. At study end point

(n = 257), the mean (SD) change from baseline (n = 265; antecedent

study) in heart rate was 5.2 (12.24) bpm, with a final value of 75.3

Table 2. TEAEs with an Incidence ‡5% in the Safety Population (n = 265)

TEAEs by actual LDX dose

30 mg/d 50 mg/d 70 mg/d LDX overallPreferred terminology(MedDRA v11.1) n (%) (n = 265) (n = 237) (n = 150) (n = 265)

Any TEAE 109 (41.1) 135 (57.0) 119 (79.3) 230 (86.8)Decreased appetite 23 (8.7) 21 (8.9) 19 (12.7) 56 (21.1)Dizziness 5 (1.9) 4 (1.7) 5 (3.3) 14 (5.3)Dry mouth 4 (1.5) 6 (2.5) 5 (3.3) 14 (5.3)Headache 16 (6.0) 23 (9.7) 21 (14.0) 55 (20.8)Influenza 6 (2.3) 5 (2.1) 7 (4.7) 18 (6.8)Insomnia 10 (3.8) 14 (5.9) 13 (8.7) 32 (12.1)Irritability 6 (2.3) 12 (5.1) 17 (11.3) 33 (12.5)Nasopharyngitis 5 (1.9) 8 (3.4) 8 (5.3) 19 (7.2)Upper respiratory tract infection 13 (4.9) 26 (11.0) 23 (15.3) 58 (21.9)Weight decreased 12 (4.5) 15 (6.3) 18 (12.0) 43 (16.2)

LDX, lisdexamfetamine dimesylate; MedDRA, Medical Dictionary for Regulatory Activities; TEAEs, treatment-emergent adverse events.

Table 3. Summary of Vital Signs in the Safety

Population (n = 265)

Overall n = 265

Vital sign VisitObserved,mean (SD)

Change frombaseline,

mean (SD)

Systolic bloodpressure, mm Hg

Baselinea 112.8 (10.22) –Week 12 114.4 (10.31) 1.2 (9.54)Week 24 114.1 (10.27) 1.4 (10.25)Week 36 115.5 (10.49) 2.8 (10.16)Week 52 116.2 (10.77) 3.4 (10.44)Endpoint/ET 115.1 (10.59) 2.3 (10.53)

Diastolic bloodpressure, mm Hg

Baselinea 67.4 (7.25) –Week 12 69.6 (7.62) 2.1 (9.26)Week 24 69.2 (7.91) 1.8 (9.28)Week 36 70.2 (7.29) 2.6 (9.10)Week 52 71.1 (6.84) 3.4 (8.89)Endpoint/ET 69.9 (6.82) 2.5 (8.37)

Pulse rate, bpm Baselinea 73.0 (10.34) –Week 12 78.7 (11.28) 5.8 (12.47)Week 24 79.5 (11.26) 6.8 (12.97)Week 36 79.8 (12.29) 7.5 (13.28)Week 52 80.7 (10.70) 8.1 (12.18)Endpoint/ET 79.2 (11.02) 6.3 (12.74)

aBaseline is from the antecedent 4 week study.ET, early termination; SD, standard deviation.

16 FINDLING ET AL.

(12.63). A total of 12 (4.7%) of 257 participants met heart rate

outlier criteria of ‡100 bpm. Based on the ICH clinical evaluation

guidelines suggesting that QTcF interval may be considered a

useful and relevant correction for assessing participants who re-

ceive stimulant treatment and subsequently have increases in heart

rate, the QTcF interval was used for ECG analysis (United States

Department of Health and Human Services 2005). At end point, the

mean (SD) change from baseline for the QTcF interval was 1.8

(17.19) ms. During an unscheduled posttermination visit (7 days

posttermination), one participant had a QTcF of 464 ms and an

increase from baseline of 71 ms, meeting QTcF outlier criteria of

‡ 450 ms and change from baseline of ‡ 60 ms. This participant had

an AE of elevated QTcB interval (453 ms) prior to initiating

treatment in the current study. The AE was considered unrelated to

treatment, was unresolved, and led to early termination from the

study 6 days after commencing treatment with LDX 30 mg/day.

This participant had received placebo in the antecedent study.

Height and weight were converted to mean (SD) z scores based

on the CDC growth charts data by age and sex (Centers for Disease

Control and Prevention 2010). For weight at baseline, the mean

(SD) z score was 0.6 (0.88) and, at end point, was 0.3 (0.86). Also,

by absolute weight, from baseline to end point, the mean (SD)

changes in weight (kg) by dose were - 0.1 (3.91), - 0.4 (4.80), and

- 1.9 (6.08) for the 30, 50, and 70 mg/day dose groups, respectively.

At baseline, the mean (SD) z score for height was 0.2 (0.95) and, at

end point, was 0.2 (0.94). Overall mean (SD) change in height (cm)

from baseline at end point was 2.5 (2.55). Mean (SD) z score for

body mass index (BMI) was 0.6 (0.82) at baseline and was 0.2

(0.86) at end point. Changes in z scores for weight and BMI of study

participants were numerically small at study end point, and actual

values remained slightly above the mean for the age- and sex-

matched general population. The observed weight and BMI de-

creases were consistent with known effects of psychostimulants.

Analysis of shift in BMI indicated that of the 26 participants

classified as obese at baseline, 10 participants remained classified

as obese at end point. Based on CDC-published growth chart cri-

teria for classification of weight status, of the 171 participants

classified as healthy weight at baseline, 5 were underweight at end

point/ET. There were no underweight participants at baseline.

Other safety assessments included physical examinations, clin-

ical laboratory evaluation (biochemistry, hematology, and urinal-

ysis), and the C-SSRS. There were no clinically notable physical

examination findings. Moreover, the majority of participants at

both screening of the antecedent study and end point of the current

study had normal physical examination findings. Overall, changes

in mean laboratory measures were generally modest, and there

were no clinically notable trends over time. The C-SSRS was

administered to 52 participants who were still actively enrolled at

week 24. No new suicidal ideations or behaviors were reported

by study participants during this study based on semistructured

interview items that captured the occurrence, severity, and fre-

quency of suicide-related thoughts and behaviors.

Effectiveness

Mean (SD) ADHD-RS-IV (primary effectiveness measure) total

score at baseline from the antecedent 4 week study was 38.0 (7.00)

(Fig. 2). The change from baseline in mean (SD) ADHD-RS-IV

total score at end point was - 26.2 (9.75), indicating significant

improvement in ADHD symptoms with LDX treatment (p < 0.001)

FIG. 2. ADHD-RS-IV a) total and b) subscale scores at baseline,a at endpoint, and at all postbaseline weeks in the full analysis set(n = 265). aBaseline score was from the antecedent double-blind study. p < 0.001 for change from baseline at end point and at allpostbaseline weeks. ADHD-RS-IV, ADHD Rating Scale IV; SD, standard deviation.

EFFECTIVENESS/SAFETY OF LDX IN ADOLESCENTS 17

(Fig. 2). Significant decreases in ADHD-RS-IV total scores were

achieved at all postbaseline weeks with LDX treatment (p < 0.001)

(Fig. 2). There were no significant between-group differences in

mean changes from baseline to end point in ADHD-RS-IV total

scores based on original group assignments from the antecedent

study. For the ADHD-RS-IV inattention and hyperactivity/impul-

sivity subscales, the mean (SD) baseline scores were 22.6 (3.35)

and 15.4 (6.19), respectively. The mean (SD) changes in the inat-

tention and hyperactivity/impulsivity subscale scores at end point,

from baseline of the antecedent 4 week study, were - 15.1 (6.05)

and - 11.1 (5.89), respectively, and were significant at all post-

baseline visits (p < 0.001).

A majority of the overall population was improved (CGI-I

[secondary effectiveness measure] rating of 1 or 2) with LDX

treatment as indicated at week 4 (228 of 250 [91.2%] participants)

of the dose-optimization phase and at week 28 (178 of 182 [97.8%]

participants), week 52 (153 of 156 [98.1%] participants), and end

point (231 of 265 [87.2%] participants) of the maintenance phase.

Overall, the mean (SD) CGI-I score at end point was 1.6 (0.86).

Moreover, the percentages of participants rated as improved at end

point appeared to be similar regardless of treatment assignment in

the antecedent study.

The YQOL-R (secondary effectiveness measure) perceptual

transformed total score significantly increased from baseline of the

antecedent study at end point/ET, 28 weeks, and 52 weeks

(p < 0.001 for each vs. baseline) (Table 4). At end point, the change

from baseline of the antecedent 4 week study in mean YQOL-R

perceptual transformed domain scores (self, relationship, environ-

ment, and general QOL) also indicated significantly improved QOL

(p £ 0.027). The mean changes from baseline at end point in

YQOL-R perceptual transformed total scores were similar

regardless of original group assignments.

Discussion

This study suggests that continued use of LDX in doses of 30, 50,

and 70 mg/day in adolescents with ADHD appears to demonstrate a

safety profile consistent with known effects of other long-acting

psychostimulants and to provide sustained effectiveness for up to

12 months of treatment. These results also indicate that the long-

term safety profile and effectiveness in adolescents are consistent

with those of other long-term LDX studies conducted in children

and adults with ADHD (Findling et al. 2008; Weisler et al. 2009).

Administration of dose-optimized LDX was effective in the man-

agement of ADHD in an adolescent population for up to 12 months

(52 weeks) regardless of prior LDX treatment status from the ant-

ecedent 4 week double-blind study. Moreover, LDX treat-

ment demonstrated effectiveness in reducing ADHD symptoms

as assessed by the ADHD-RS-IV total and subscale scores, and

demonstrated global symptom improvement in the majority of

participants rated by the CGI-I. Overall, participants perceived

improvement in QOL at end point with LDX treatment.

There have been few long-term studies that have assessed the

safety and effectiveness of psychostimulants, especially of long-

acting formulations, in adolescents (Hoare et al. 2005; Hammer-

ness et al. 2009; Findling et al. 2010). Overall, these studies found

that the long-term safety profile of the psychostimulant tested was

consistent with findings in short-term studies in adolescents and

children with the respective compounds, and no new safety signals

were detected with long-term use.

Safety

Common TEAEs (‡10%) in the current study included de-

creased appetite (21.1%), headache (20.8%), insomnia (12.1%),

and dizziness (5.3%), and were consistent with the known effects

of amphetamine treatment (Ahmann et al. 2001; Biederman et al.

2002; Ambrosini et al. 2006). Similar to other studies conducted

with long-acting psychostimulants (Biederman et al. 2002; Child-

ress et al. 2009), most TEAEs were mild to moderate in severity.

TEAEs that led to early termination from this study were consistent

with the safety profile of other long-acting psychostimulants used

in the treatment of ADHD, regardless of patient age. Psychiatric

AEs, such as psychotic or manic symptoms, hallucinations, exac-

erbation of thought disorder, depression, and aggressive/hostile

behavior related to psychostimulant use have been reported at

putatively therapeutic doses in adolescents, as well as in patients

with ADHD across age groups (Metadate CD [package insert]

2009; Concerta [package insert] 2010; Adderall XR [package in-

sert] 2011; Ritalin LA [package insert] 2012). These TEAEs in

adolescents, as well as in children, with ADHD generally diminish

upon cessation of psychostimulant treatment or dose adjustment

(Greenhill et al. 2002).

In general, stimulants are not recommended for patients with

various cardiovascular problems {2098, 175, 271, 1277} because

sudden death at usual doses and serious cardiovascular AEs have

been reported (Daytrana prescribing information 2010; Adderall

XR prescribing information 2011; Focalin XR prescribing infor-

mation 2012; Vyvanse prescribing information 2012). The Amer-

ican Heart Association has developed guidelines to screen and

monitor children and adolescents (Gutgesell et al. 1999). These

recommendations include determination of family/patient medical

history prior to treatment, careful follow-up/physical examination

visits that should include determination of heart rate and BP,

avoiding concomitant use of psychotropic drugs and other drugs

that are metabolized by or inhibit the cytochrome P-450 enzyme

Table 4. Baseline YQOL-R Perceptual Transformed Total Scores and Change from Baseline Scores

Observed Change from baseline

Score Visit n Mean (SD) n Mean (SD)

YQOL-R perceptual transformeda total score Baselineb 264 79.8 (11.28) – –Week 28 181 84.6 (9.36) 180 4.6 (9.31)*Week 52 154 84.9 (10.04) 153 5.0 (9.52)*Endpoint/ET 238 83.9 (11.00) 237 3.9 (9.73)*

aThe YQOL-R raw score is transformed to a 0–100-point scale to assist in result interpretation; higher scores indicate improvement in QOL.bBaseline is from the antecedent 4 week study.*p < 0.001 based on a two-sided one-sample t test.ET, early termination; QOL, quality of life; SD, standard deviation; YQOL-R, Youth Quality of Life Instrument-Research Version.

18 FINDLING ET AL.

system, as well as ECG monitoring at baseline and during chronic

therapy. Results from this study were consistent with results from

trials of LDX, as well as those from trials of other long-acting

psychostimulants in both children and adults with ADHD. Speci-

fically, the modest increases in SBP, DBP, pulse rate, and heart rate

seen here were comparable with those in previous LDX studies

conducted in children and adults with ADHD (Adler et al. 2008;

Wigal et al. 2009). As reviewed by Wolraich and colleagues,

psychostimulants were reported to result in slight increases in BP

and pulse rate, but these increases were usually not considered

clinically significant (Wolraich et al. 2007). Further, in this study,

ECG findings were deemed normal or not clinically significant with

LDX treatment, consistent with other LDX studies (Wilens et al.

2006; Wigal et al. 2009).

Slight decreases in z scores for weight and BMI were observed at

end point from baseline with LDX treatment (Faraone et al. 2010).

These data on weight decrease were consistent with findings from a

study that assessed the effects of LDX treatment on growth in

children with ADHD (Faraone et al. 2010) and from other studies

assessing growth with other psychostimulant therapy (National

Institute of Mental Health 2004; Ambrosini et al. 2006; Spencer

et al. 2006) and with other LDX studies (Findling et al. 2008;

Weisler et al. 2009; Wigal et al. 2009). Although height did not

change based on z scores in the present study, growth should still

be monitored during treatment with stimulants, and if there is an

observed slowing of growth, then the treatment regimen may

need to be reevaluated.

The number of study completers (58%) in the present 52 week

trial of LDX was consistent with other adolescent ADHD studies.

In an open-label, multicenter extension study, in which the ado-

lescent participants were treated with a long-acting psychostimu-

lant, methylphenidate transdermal system, 54% of participants

completed at 6 months (Findling et al. 2010). In a similar study of

participants on 6 months of open-label treatment with mixed am-

phetamine salts extended-release formulation, 76% completed the

study.

Effectiveness

Although long-term studies of psychostimulants in adolescents

with ADHD are limited, the effectiveness of LDX in this population

was consistent with that of other studies of psychostimulants in this

age group. One large open-label study that examined the effec-

tiveness (based on ADHD-RS-IV scores and CGI-I ratings) of

mixed amphetamine salts extended release, when administered for

up to 6 months in adolescents with ADHD, indicated sustained

symptom improvement (Spencer et al. 2005). The majority of

participants (60.9%) were rated improved at end point. In the

current analysis, most participants (87.2% at end point/ET and

98.1% up to 52 weeks) were rated as improved with LDX treatment

per CGI-I ratings.

QOL studies assessing psychostimulant treatment in adolescent

populations with ADHD are limited. The YQOL-R results indi-

cated significantly improved transformed scores from baseline at

end point for all QOL perceptual domains. In the current study,

mean (SD) YQOL-R perceptual transformed total scores at baseline

were 79.8 (11.28) and at end point were 83.9 (11.00) for LDX. It

should be noted that validation of the YQOL-R was conducted in

adolescents with a variety of disabilities, inclusive of, but not

limited to, ADHD, and indicated mean total scores of 75.2 and 82.2

for the ADHD subgroup and the normative control group, respec-

tively (Patrick et al. 2002). Despite the relatively small increase

of *4 units on the YQOL-R in the current study, the perceptual

transformed scores at end point after treatment with LDX were

similar to those of the control group of the YQOL-R validation

study (Patrick et al. 2002).

In the antecedent 4 week double-blind study of LDX in

adolescents, QOL at end point was not significantly improved

when participants who were treated with LDX were compared

with those who received placebo. That result was possibly be-

cause of the short duration of the double-blind study. The current

extension study (52 weeks) indicated that QOL was improved at

28 weeks, 52 weeks, and end point/ET suggesting that a longer

duration of time may be required for participants to perceive QOL

improvement.

Limitations

One limitation is that the study lacked a placebo group to

compare treatment effects with LDX-treated participants. The

changes that occurred may be based, to some degree, on nonspecific

or environmental factors experienced by the study groups, and not

necessarily LDX therapy. Subjective bias based on the open-label

design because of lack of blinding by investigator and study

participants cannot be excluded. The baseline demographics also

indicated that the participant majority was male, white, and non-

Hispanic. The current data may not necessarily apply to minority

adolescent populations and females; drawing conclusions should be

done with caution. Exclusion in the 4 week double-blind study of

participants who failed to respond to amphetamine therapy and/or

were well controlled on current ADHD medication may over-

estimate effectiveness in the general clinical population. Partici-

pants with comorbid psychiatric disorders and/or other medical

symptoms or conditions that may have contraindicated treatment

with LDX were not enrolled in the current analysis. This limits the

ability to generalize these findings to adolescents who have a co-

morbid disorder, which may be common in individuals with ADHD

(Young 2008). When interpreting the decrease in ADHD symptom

scores (ADHD-RS-IV scores) by week, it should be noted that

mean change is based on those participants continuing in the study

and, therefore, may be skewed to greater decreases, as it is possible

that those discontinuing the study had poorer responses to treat-

ment. However, two factors suggest that this may not be a promi-

nent effect: 1) The number of participants who withdrew from the

study because of lack of effectiveness was relatively modest (5/

269); and 2) The differences were small between ADHD-RS-IV

scores that only considered data from participants who continued to

the later weeks of the study (i.e., weeks 36–52), and the end point

scores of all participants (which incorporated early termination

scores for those participants who were discontinued prior to com-

pletion). Another study limitation is that QOL at study entry was

relatively well perceived prior to treatment and results may not

represent adolescents with a lower perceived QOL.

Conclusions

This study describes the long-term safety and effectiveness of

LDX treatment in a sizable adolescent population with ADHD.

These results are consistent with those of prior long-term LDX

studies conducted in both children and adults. Overall, the long-

term use of LDX in adolescents demonstrates a safety profile

consistent with that of long-acting psychostimulant use. In addi-

tion, LDX exhibits continued effectiveness for up to 52 weeks in

improving core ADHD symptoms in adolescents with ADHD,

similar to that in both children and adult LDX studies. Specifically,

EFFECTIVENESS/SAFETY OF LDX IN ADOLESCENTS 19

dose-optimized LDX-treated participants demonstrated ADHD

symptom improvement and global impressions of clinical im-

provement relative to baseline of the antecedent 4 week study.

Moreover, adolescents with ADHD treated with LDX also showed

improved participant-perceived QOL at week 28, week 52, and end

point from baseline.

Clinical Significance

As children mature into adolescence, ADHD symptoms may

change, and functional impairments may result in negative impact on

multiple life domains. Efficacy and safety data, as they pertain to

adolescents, are important both when considering the management

of ADHD and when developing additional therapeutic options in this

understudied population. The results of this study of LDX safety and

effectiveness over 52 weeks of open-label treatment provide clini-

cians with information about a new therapeutic option for adoles-

cents with ADHD. The focus on QOL treatment outcomes offers an

additional important and clinically relevant perspective.

Acknowledgments

Under the direction of the authors, Dr. Huda Abdullah, a former

employee of SCI Communications & Information (SCI), and

Dr. Michael Pucci, an employee of SCI, provided writing assistance.

Editorial assistance in the form of proofreading, copy editing, and

fact checking was also provided by SCI. SCI was funded by Shire

Development LLC for support in writing and editing this manu-

script. Drs. Thomas Babcock, Brian Scheckner, and Bryan Dirks

from Shire Development LLC, also reviewed and edited the man-

uscript for scientific accuracy. Although the sponsor was involved

in the design, collection, analysis, interpretation, and fact checking,

the content, ultimate interpretation, and decision to submit the

manuscript for publication to Journal of Child and Adolescent

Psychopharmacology were made by the authors. The authors ac-

knowledge the contributions to this study of Sonia Pant, Study

Manager, and Diane Schneider, Medical Writer.

Disclosures

Dr. Findling receives or has received research support, acted as a

consultant, received royalties from, and/or served on a speaker’s

bureau for Abbott, Addrenex, Alexza, American Psychiatric Press,

AstraZeneca, Biovail, Bristol-Myers Squibb, Dainippon Sumitomo

Pharma, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins

University Press, Johnson & Johnson, KemPharm Lilly, Lundbeck,

Merck, National Institutes of Health, Neuropharm, Novartis, No-

ven, Organon, Otsuka, Pfizer, Physicians’ Post-Graduate Press,

Rhodes Pharmaceuticals, Roche, Sage, Sanofi-Aventis, Schering-

Plough, Seaside Therapeutics, Sepracor, Shionogi, Shire, Solvay,

Stanley Medical Research Institute, Sunovion, Supernus Pharma-

ceuticals, Transcept Pharmaceuticals, Validus, WebMD, and

Wyeth. Dr. Cutler receives or has received research support, acted

as a consultant and/or speaker, and participated in a CME Advisory

Board for Abbott, Addrenex, AstraZeneca, Bristol-Myers Squibb,

Cephalon, GlaxoSmithKline, Janssen, Jazz, Johnson & Johnson

Pharmaceutical Research & Development, LLC, Lilly, McNeil,

Memory, Merck, Neuroscience Education Institute, Novartis,

Ortho-McNeil, Otsuka, Pfizer, Sanofi (including Sanofi-Synthelabo,

Sanofi-Aventis), Sepracor, Shionogi, Shire, Solvay, Supernus, and

Targacept. Dr. Saylor receives or has received research support and

acted as a consultant for Abbott, AstraZeneca, Bristol-Myers

Squibb, Cephalon, Lilly, Johnson & Johnson, Merck, Novartis,

Otsuka, Psychogenics, Shire, and Supernus. Dr. Gasior is an em-

ployee of Shire and holds stock and/or stock options in Shire.

Mr. Hamdani is an employee of Shire and holds stock and/or stock

options in Shire. Dr. Ferreira-Cornwell is an employee of Shire and

holds stock and/or stock options in Shire. Dr. Childress receives

or has received research support and acted as a consultant and/or

speaker for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, John-

son & Johnson Pharmaceutical Research & Development, LLC, Lilly

USA, LLC, NextWave, Novartis, Ortho-McNeil Janssen Scientific

Affairs, Pfizer, Rhodes, Sepracor, Shire, Somerset, and Sunovion.

References

Adderall XR (package insert). Wayne, PA: Shire US Inc., 2011.

Adler LA, Goodman DW, Kollins SH, Weisler RH, Krishnan S,

Zhang Y, Biederman J; on behalf of the 303 Study Group. Double-

blind, placebo-controlled study of the efficacy and safety of

lisdexamfetamine dimesylate in adults with attention-deficit/

hyperactivity disorder. J Clin Psychiatry 69:1364–1373, 2008.

Ahmann PA, Theye FW, Berg R, Linquist AJ, Van Erem AJ,

Campbell LR: Placebo-controlled evaluation of amphetamine

mixture–dextroamphetamine salts and amphetamine salts (Adder-

all): Efficacy rate and side effects. Pediatrics 107:E10, 2001.

Ambrosini PJ, Sallee FR, Lopez FA, Shi L, Michaels MA: A com-

munity assessment, open-label study of the safety, tolerability, and

effectiveness of mixed amphetamine salts extended release in school-

age children with ADHD. Curr Med Res Opin 22:427–440, 2006.

American Academy of Pediatrics Subcommittee on Attention-Deficit/

Hyperactivity Disorder and Committee on Quality Improvement:

Clinical practice guideline: Treatment of the school-aged child with

attention-deficit/hyperactivity disorder. Pediatrics 108:1033–1044,

2001.

American Psychiatric Association: Attention-deficit and disruptive

behavior disorders. In: Diagnostic and Statistical Manual of Mental

Disorders DSM-IV-TR, 4th ed., Text Revision. Washington, DC:

American Psychiatric Association; 2000; pp. 85–93.

Biederman J, Lopez FA, Boellner SW, Chandler MC: A randomized,

double-blind, placebo-controlled, parallel-group study of SLI381

(Adderall XR) in children with attention-deficit/hyperactivity dis-

order. Pediatrics 110:258–266, 2002.

Centers for Disease Control and Prevention: CDC growth files per-

centile data files with LMS values. 2000. Available at www.cdc.gov/

growthcharts/percentile_data_files.htm (last accessed June 14, 2011).

Centers for Disease Control and Prevention: Increasing prevalence of

parent-reported attention-deficit/hyperactivity disorder among

children–United States, 2003 and 2007. Morb Mortal Wkly Rep

59:1439–1443, 2010.

Childress AC, Spencer T, Lopez F, Gerstner O, Thulasiraman A,

Muniz R, Post A: Efficacy and safety of dexmethylphenidate ex-

tended-release capsules administered once daily to children with

attention-deficit/hyperactivity disorder. J Child Adolesc Psycho-

pharmacol 19:351–361, 2009.

Concerta [package insert]. Titusville, NJ: McNeil Pediatrics; 2000.

Daytrana (package insert). Wayne, PA: Shire US Inc., 2010.

Dulcan M, Work Group on Quality Issues: Practice parameters for the

assessment and treatment of children, adolescents, and adults with

attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc

Psychiatry 36:85S–121S, 1997.

DuPaul GJ, Power TJ, Anastopoulos AD, Reid R: ADHD Rating

Scale-IV: Checklists, Norms, and Clinical Interpretation. New

York: Guilford Press, 1998.

Edwards TC, Huebner CE, Connell FA, Patrick DL: Adolescent

quality of life, part I: Conceptual and measurement model.

J Adolesc 25:275–286, 2002.

20 FINDLING ET AL.

Faraone SV, Spencer TJ, Kollins SH, Glatt SJ: Effects of lisdex-

amfetamine dimesylate treatment for ADHD on growth. J Am Acad

Child Adolesc Psychiatry 49:24–32, 2010.

Findling RL, Childress AC, Cutler AJ, Gasior M, Hamdani M,

Ferreira–Cornwell MC, Squires L: Efficacy and safety of lisdex-

amfetamine dimesylate in adolescents with attention-deficit/

hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 50:

395–405, 2011.

Findling RL, Childress AC, Krishnan S, McGough JJ: Long-term

effectiveness and safety of lisdexamfetamine dimesylate in school-

aged children with attention-deficit/hyperactivity disorder. CNS

Spectr 13:614–620, 2008.

Findling RL, Katic A, Rubin R, Moon E, Civil R, Li Y: A 6-month,

open-label, extension study of the tolerability and effectiveness of

the methylphenidate transdermal system in adolescents diagnosed

with attention-deficit/hyperactivity disorder. J Child Adolesc

Psychopharmacol 20:365–375, 2010.

Focalin XR (package insert). East Hanover, NJ: Novartis Pharma-

ceuticals Corporation, 2012.

Graham J, Coghill D: Adverse effects of pharmacotherapies for at-

tention-deficit hyperactivity disorder: epidemiology, prevention and

management. CNS Drugs 22:213–237, 2008.

Green M, Wong M, Atkins D: Diagnosis of Attention Deficit/

Hyperactivity Disorder. Technical Review 3. AHCPR Publication

99–0050. Rockville, MD: US Department of Health and Human

Services, Agency for Health Care Policy and Research, 1999.

Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman

J, Benson RS, Bukstein O, Kinlan J, McClellan J, Rue D, Shaw JA,

Stock S: Practice parameter for the use of stimulant medications in

the treatment of children, adolescents, and adults. J Am Acad Child

Adolesc Psychiatry 41 (2 suppl):26S–49S, 2002.

Gutgesell H, Atkins D, Barst R, Buck M, Franklin W, Humes R,

Ringel R, Shaddy R, Taubert KA: AHA Scientific Statement:

cardiovascular monitoring of children and adolescents receiving

psychotropic drugs. J Am Acad Child Adolesc Psychiatry 38:1047–

1050, 1999.

Guy W: ECDEU Assessment Manual for Psychopharmacology.

Rockville, MD: US Department of Health, Education, and Welfare;

Public Health Service, Alcohol, Drug Abuse and Mental Health

Administration, NIMH Psychopharmacology Research Branch,

1976

Hammerness P, Wilens T, Mick E, Spencer T, Doyle R, McCreary M,

Becker J, Biederman J: Cardiovascular effects of longer-term, high-

dose OROS methylphenidate in adolescents with attention deficit

hyperactivity disorder. J Pediatr 155:84–89, 2009.

Hoare P, Remschmidt H, Medori R, Ettrich C, Rothenberger A, Santosh

P, Schmit M, Spender Q, Tamhne R, Thompson M, Tinline C, Trott

GE: 12-month efficacy and safety of OROS MPH in children and

adolescents with attention-deficit/hyperactivity disorder switched

from MPH. Eur Child Adolesc Psychiatry 14:305–309, 2005.

Medical Dictionary for Regulatory Activities (MedDRA), Version

11.0. Chantilly, VA: Northrop Grumman Corporation; 2009.

Merikangas KR, He JP, Burstein M, Swanson SA, Avenevoli S, Cui

L, Benjet C, Georgiades K, Swendsen J: Lifetime prevalence of

mental disorders in U.S. adolescents: Results from the National

Comorbidity Survey Replication—Adolescent Supplement (NCS-A).

J Am Acad Child Adolesc Psychiatry 49:980–989, 2010.

Metadate CD [package insert]. Smyrna, GA: UCB, Inc.; 2009.

National Institute of Mental Health Multimodal Treatment Study of

ADHD Follow-up: Changes in effectiveness and growth after the

end of treatment. Pediatrics 113:762–769, 2004.

Patrick DL, Edwards TC, Topolski TD: Adolescent quality of life,

part II: Initial validation of a new instrument. J Adolesc 25:287–

300, 2002.

Pliszka S, AACAP Work Group on Quality Issues: Practice parameter

for the assessment and treatment of children and adolescents with

attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc

Psychiatry 46:894–921, 2007.

Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA: The

worldwide prevalence of ADHD: a systematic review and meta-

regression analysis. Am J Psychiatry 164:942–948, 2007.

Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, Fisher P,

Zelazny J, Burke A, Oquendo M, Mann J: Columbia–Suicide Se-

verity Rating Scale. 2009. Available at www.maps.org/mdma/

mt1_docs/c-ssrs1-14-09-baseline.pdf (last accessed June 14, 2011).

Ritalin LA [package insert]. East Hanover, NJ: Novartis Pharmaceu-

ticals Corporation; 2012.

Schubiner H, Katragadda S: Overview of epidemiology, clinical

features, genetics, neurobiology, and prognosis of adolescent

attention-deficit/hyperactivity disorder. Adolesc Med State Art Rev

19:209–215, vii, 2008.

Spencer TJ, Biederman J, Wilens TE: Efficacy and tolerability of

long-term, open-label, mixed amphetamine salts extended release

in adolescents with ADHD. CNS Spectr 10:14–21, 2005.

Spencer TJ, Faraone SV, Biederman J, Lerner M, Cooper KM, Zim-

merman B: Does prolonged therapy with a long-acting stimulant

suppress growth in children with ADHD? J Am Acad Child Ado-

lesc Psychiatry 45:527–537, 2006.

US Department of Health and Human Services: Guidance for Industry

E14. The clinical evaluation of QT/QTC interval prolongation and

proarrhythmic potential for non-antiarrhythmic drugs: October 12,

2005. Available at www.fda.gov/downloads/RegulatoryInformation/

Guidances/ucm129357.pdf (last accessed June 15, 2011).

Vyvanse (package insert). Wayne, PA: Shire US Inc., 2012.

Weisler R, Young J, Mattingly G, Gao J, Squires L, Adler L, on behalf

of the 304 Study Group: Long-term safety and effectiveness of

lisdexamfetamine dimesylate in adults with attention-deficit/

hyperactivity disorder. CNS Spectr 14:573–585, 2009.

Weisler RH: Safety, efficacy and extended duration of action of mixed

amphetamine salts extended-release capsules for the treatment of

ADHD. Expert Opin Pharmacother 6:1003–1018, 2005.

Wigal SB, Kollins SH, Childress AC, Squires L, for the 311 Study

Group: A 13-hour laboratory school study of lisdexamfetamine

dimesylate in school-aged children with attention-deficit/

hyperactivity disorder. Child Adolesc Psychiatry Ment Health 3:17,

2009.

Wilens TE, Zusman RM, Hammerness PG, Podolski A, Whitley J,

Spencer TJ, Gignac M, Biederman J: An open-label study of the

tolerability of mixed amphetamine salts in adults with attention-

deficit/hyperactivity disorder and treated primary essential hyper-

tension. J Clin Psychiatry 67:696–702, 2006.

Wolraich ML, McGuinn L, Doffing M: Treatment of attention deficit

hyperactivity disorder in children and adolescents: safety consid-

erations. Drug Saf 30:17–26, 2007.

Young J: Common comorbidities seen in adolescents with attention-

deficit/hyperactivity disorder. Adolesc Med State Art Rev 19:216–

28, vii, 2008.

Youth Quality of Life Instrument–Research Version (YQOL-R).

Seattle: University of Washington, 2002.

Address correspondence to:

Robert L. Findling, MD, MBA

Director, Child & Adolescent Psychiatry

Johns Hopkins Hospital/Bloomberg Children’s Center

1800 Orleans Street/Suite 12344A

Baltimore, Maryland 21287

E-mail: RFindlil@jhmi.edu

EFFECTIVENESS/SAFETY OF LDX IN ADOLESCENTS 21