533191
research-article2014
JADXXX10.1177/1087054714533191Journal of Attention DisordersRobb et al.
Article
Efficacy, Safety, and Tolerability of a Novel Methylphenidate Extended-Release Oral Suspension (MEROS) in ADHD
Journal of Attention Disorders 1–12 © 2014 SAGE Publications Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1087054714533191 jad.sagepub.com
Adelaide S. Robb1, Robert L. Findling2, Ann C. Childress3, Sally A. Berry4, Heidi W. Belden4, and Sharon B. Wigal5
Abstract Objective: To test whether an optimal dose of Quillivant XR (methylphenidate extended-release oral suspension [MEROS]) would significantly reduce symptoms of ADHD in children. Method: A randomized, double-blind, placebocontrolled, cross-over, efficacy, safety, and tolerability study of MEROS in 45 children aged 6 to 12 years (open-label doseoptimization phase, followed by double-blind cross-over period). Results: MEROS was significantly more efficacious than placebo during double-blind cross-over laboratory classroom days (Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale and Permanent Product Measure of Performance). During the open-label phase, improvements were observed in scores of ADHD Rating Scale-IV, and Clinical Global Impression-Severity and -Improvement Scales. No occurrences of suicidal ideation or behavior were recorded; the most common open-label treatment-emergent adverse events were typical of stimulant use: decreased appetite, insomnia, and abdominal pain. Conclusion: MEROS was efficacious in the treatment of children aged 6 to 12 years with ADHD, with a safety profile similar to that of other extended-release methylphenidate pharmacotherapies. (J. of Att. Dis. XXXX; XX(X) XX-XX) Keywords ADHD, methylphenidate, laboratory school, randomized-controlled trial, math test
Introduction ADHD is one of the most common neurobehavioral disorders and has a lifetime prevalence of 9.5% in children and adolescents aged 4 to 17 years (Centers for Disease Control and Prevention, 2010). The current Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association [APA], 2013) diagnostic criteria require the onset of symptoms prior to the age of 12 years with a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning. Six or more of the nine symptoms of inattention and/or six or more symptoms of hyperactivity-impulsivity must have persisted for 6 months or more to a degree that is inconsistent with developmental level, and negatively impacts social and academic/occupational activities. For older adolescents and adults aged 17 years and above, at least five symptoms of nine are required (APA, 2013). Evaluation and multimodal treatment are recommended for patients as early as age 4 years through adolescence (American Academy of Pediatrics, 2011), and into adulthood (Kessler et al., 2006). Psychosocial treatments including correct classroom placement, tutoring, and individual, group, and family therapy are important components of a treatment
plan. The other important aspect of the treatment plan is psychopharmacologic treatment, when indicated, and is the focus of this study. Stimulants are the most commonly used medications for the treatment of ADHD (National Institute of Mental Health [NIMH], National Institutes of Health [NIH], 2012). For some patients with ADHD, the ability or willingness to swallow medication easily is part of the difficulty in ensuring adherence to treatment and optimizing outcomes. In the last decade, the development of pharmacologic options for ADHD expanded dramatically. The first major advance was the development of effective long-acting stimulants, which 1
George Washington University, Washington, DC, USA Johns Hopkins University, Baltimore, MD, USA 3 Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, NV, USA 4 Pfizer Inc., New York, NY, USA 5 AVIDA Inc, Newport Beach, CA, USA 2
Corresponding Author: Adelaide S. Robb, Departments of Psychiatry and Behavioral Sciences & Pediatrics, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, NW Washington, DC 20010, USA. Email: [email protected]
Downloaded from jad.sagepub.com by guest on November 14, 2015
2
Journal of Attention Disorders
obviated the need for multiple daily doses and associated “on-off” periods throughout the school day and into homework time. The American Academy of Child and Adolescent Psychiatry advises that long-acting forms of stimulants may be used as initial treatment for ADHD; there is no need to routinely titrate to the appropriate dose on short-acting forms and then “switch” patients to a long-acting form (Pliszka et al., 2007). These agents were followed by the development of the first effective non-stimulant, atomoxetine (Strattera prescribing information, 2013), and then two long-acting alpha-2 agonists: extended-release guanfacine (Intuniv prescribing information, 2013) and modifiedrelease clonidine (Kapvay prescribing information, 2013). These drugs are all indicated for the treatment of ADHD. While long-acting stimulants are effective in attaining sustained coverage for ADHD symptoms, some formulations require children to swallow the tablet or capsule intact, whereas others allow for sprinkling on applesauce, transdermal placement, or dissolving in water. Some children struggle with swallowing pills or do not like the texture of the sprinkles, while skin sensitivity precludes transdermal applications for some others. Clinicians treating children who are unable to swallow pills frequently resort to prescribing a chewable or liquid preparation, options that were previously only available as immediate-release formulations. With the approval of Quillivant XR (methylphenidate extended-release oral suspension [MEROS]), a long-acting liquid preparation is available for those who are unwilling or unable to swallow pills or use sprinkles. This oral methylphenidate suspension, with a concentration of 25 mg per 5 mL (5 mg/mL), allows for titration in upward or downward increments that can be flexible in their magnitude, which is limited by available dosage strengths for standard pills or capsules. The mechanism of methylphenidate delivery as well as the onset and duration of efficacy of MEROS have each been previously described (Wigal, Childress, Belden, & Berry, 2013). MEROS has demonstrated onset of action in 45 min and duration of action through 12 hr postdosing. The delivery system technology of MEROS is created by the formation of drug–polymer complexes, 80% of which are coated with an extended-release coating of varying thicknesses, which allows for release of methylphenidate throughout the day. The remaining 20% of drug–polymer complexes are left uncoated and act as immediate-release methylphenidate (Wigal et al., 2013). The relative bioavailability of 60 mg of Quillivant XR compared with 60 mg of immediate-release methylphenidate oral solution (given as two 30 mg doses 6 hr apart) is 95% (Childress & Berry, 2010). This study was designed to determine the efficacy, safety, and tolerability of the long-acting liquid methylphenidate preparation, MEROS, in a group of 45 children aged 6 to 12 years with ADHD, through open-label dose optimization followed by a double-blind cross-over period of
optimal dose MEROS versus placebo. Assessments were obtained at the end of both active and placebo weeks in a laboratory classroom setting. The efficacy of MEROS measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)-combined score has been reported in detail elsewhere (Wigal et al., 2013). This article focuses on other efficacy scales utilized in the double-blind phase (Permanent Product Measure of Performance [PERMP] score) and open-label phase (ADHD Rating Scale-IV [ADHD-RS], Clinical Global Impression of Severity [CGI-S] Scale, and Clinical Global Impression of Improvement [CGI-I] Scale scores) of the study.
Method Study Design This randomized, double-blind, placebo-controlled, crossover design laboratory classroom study was conducted to investigate the efficacy, safety, and tolerability of MEROS for the treatment of ADHD. Study design consisted of screening and baseline visits, a 4 to 6 week open-label doseoptimization phase, and a 2-week double-blind phase consisting of 1 week of treatment with either MEROS or placebo, followed by 1 week of the opposite treatment, placebo/MEROS. The study was approved by the institutional review board of both the study sites: the Child Development Center at the University of California, Irvine, CA, USA, and the Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, NV, USA. Prior to study commencement, parents or guardians provided written informed consent for study participation and all participants provided written assent. During the open-label phase, all participants received a starting dose of MEROS of 20 mg, with allowable upward titration of 10 to 20 mg increments in weekly intervals until an optimal dose was achieved; the maximum daily dose was 60 mg. To reach optimal efficacy during the open-label phase, investigators were permitted to adjust the dose of MEROS upward, using clinical judgment with the assistance of clinical efficacy scales (including the ADHD-RS and CGI-S) to inform decision making for dose optimization. Downward adjustment, during this same period, was also permissible if safety or tolerability issues occurred. When dosage adjustments were made, increases were not to exceed 20 mg, but a downward adjustment greater than 20 mg could be made if clinically necessary. Participants who could not tolerate a minimum 20-mg daily dose were discontinued from the study. Once reached, the optimal dose was maintained for the remainder of the openlabel phase and was used for the double-blind treatment period. Participants were randomly assigned in a 1:1 ratio to either the MEROS/placebo or placebo/MEROS treatment sequence. The study design allowed each participant to serve as his or her own control. At the end of each week of
Downloaded from jad.sagepub.com by guest on November 14, 2015
3
Robb et al. double-blind, randomized treatment, participants took part in a laboratory classroom study day to assess treatment in this standardized setting.
Study Population Eligibility for enrollment required age between 6 and 12 years with a diagnosis of ADHD (any type). The diagnosis must have been made by a psychiatrist, psychologist, developmental pediatrician, pediatrician, or pre-approved licensed allied health professional using the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; APA, 2000), and confirmed by administration of a diagnostic interview using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS; Kaufman et al., 1997). A score of ≥3 on the CGI-S Scale (Guy, 1976), and ≥90th percentile normative values for gender and age on the ADHD-RS (DuPaul, Power, Anastopoulos, & Reid, 1998) total score, the Hyperactive/Impulsive subscale, or the Inattentive subscale at screening or at baseline were also required. To qualify, participants needed to be symptomatic to the degree that pharmacological treatment for ADHD was necessary in the opinion of the investigator. If participants were under current treatment, they must have had either a safety or tolerability issue with their current regimen, suboptimal efficacy, or a need for a long-acting liquid regimen. Clinically significant cognitive impairment defined as an estimated intelligence quotient 110 beats per minute (bpm; or a ≥25 bpm change from baseline), or >95th percentile observed value for systolic or diastolic blood pressure for participant’s age, gender, and height based on the Fourth Report on the Diagnosis, Evaluation, and Treatment of Blood Pressure in Children and Adolescents (National Heart, Lung, and Blood Institute, NIH, 2005). A clinically significant change in weight was defined as a ≥5% decrease from baseline. The Columbia Suicide Severity Rating Scale (C-SSRS) was used to assess suicidal thoughts or behaviors at baseline and all subsequent visits (Posner, Oquendo, Gould, Stanley, & Davies, 2007). C-SSRS is a brief questionnaire that allows the clinician to assess occurrence and severity of suicidal ideation and behavior.
Statistical Analyses The primary efficacy analysis was previously described by Wigal et al. (2013). The secondary efficacy analyses were conducted on the intent-to-treat (ITT) population, which consisted of all randomized participants who took at least one dose of study medication, and had at least one post-baseline efficacy assessment available for analysis. Descriptive statistics for the PERMP scores were calculated at each time point for the test laboratory classroom days, and are presented for each treatment, as well as for the paired differences between the treatments (MEROSplacebo). The time points analyzed were pre-dose, 0.75, 2, 4, 8, 10, and 12 hr post-dose, as well as the mean of the post-dose measurements, calculated as the average of the 0.75, 2, 4, 8, 10, and 12 hr post-dose PERMP scores for each participant. The least squares (LS) mean (± standard
error) PERMP scores were plotted over time for the laboratory classroom days by treatment group. Secondary efficacy variables were assessed using a linear analysis of variance (ANOVA) model with SAS software (SAS Institute, Cary, NC, USA). Descriptive statistics for the ADHD-RS, CGI-S, and CGI-I scores were presented for each visit, based on the ITT population. The CGI-S and CGI-I scores were presented as both categorical and continuous values. In addition, the change from baseline in CGI-S, CGI-I scores, and ADHD-RS scores was presented. For the ADHD-RS, the proportion of responders is presented in the ITT population, including the exact 95% confidence intervals for the binomial proportion. The safety population was defined as all randomized participants who received at least one dose of study medication.
Results Participants A total of 45 participants were enrolled and randomized (23 to the placebo/MEROS treatment sequence and 22 to the MEROS/placebo treatment sequence). The overall mean age of participants was 8.8 years and the majority of participants were male (72.7%). Thirty-five participants were White (79.5%) and 11 (25%) were Hispanic/Latino. Most participants (70.5%) had the combined presentation of ADHD, 12 (27.3%) were predominantly inattentive, and 1 (2.3%) was diagnosed with the predominantly hyperactive/ impulsive presentation of ADHD. Mean baseline ADHD-RS total scores were 39.3 (±7.6). Approximately 30% of participants had a comorbid psychiatric diagnosis that did not require medication treatment (oppositional defiant disorder [18.2%], elimination disorder [9.1%], and specific phobias [4.5%]). Six participants discontinued during the open-label phase due to withdrawal of assent/consent and AEs (2 participants each), and lack of efficacy and lost to follow-up (1 participant each). There were 3 participants with a final optimal dose of 20 mg, 30 participants with an optimized dose of 30 or 40 mg, and 11 participants with a final optimal dose of 50 or 60 mg. The mean optimal dose was approximately 40 mg.
Efficacy The primary efficacy measure of SKAMP-combined score at 4-hr post-dose was statistically significantly lower (improved) during treatment with MEROS compared with placebo (p < .0001). This finding is discussed in more detail by Wigal et al. (2013). At each time point tested in the laboratory classroom setting, both the number of problems attempted (Figure 1) and the number correct (Figure 2) on the PERMP were significantly higher during treatment with MEROS compared
Downloaded from jad.sagepub.com by guest on November 14, 2015
5
Robb et al.
Figure 1. Permanent product measure of performance (PERMP) number of problems attempted over time (least squares mean ± standard error) by treatment group. MEROS = methylphenidate for extended-release oral suspension.
Figure 2. Permanent product measure of performance (PERMP) number of problems correct over time (least squares mean ± standard error) by treatment group. MEROS = methylphenidate for extended-release oral suspension.
with placebo. The LS mean treatment difference between MEROS and placebo reached statistical significance 45 min after dosing (p < .0001, both number attempted and number correct), and the effect persisted through the test day and remained statistically significant at the last post-dose assessment at 12 hr (p = .0019, number attempted; p = .0008, number correct). For the number of problems attempted, the LS mean of the treatment difference between MEROS and placebo ranged from 45.77 at 4-hr post-dose
(p < .0001) to 14.86 at 10-hr post-dose (p = .0155). For the number of problems correct, the LS mean of the treatment difference between MEROS and placebo treatments ranged from 45.98 at 4-hr post-dose (p < .0001) to 16.78 at 10-hr post-dose (p = .0016). Participants attempted more problems and got more problems correct throughout the day when treated with an optimal dose of MEROS compared with placebo. Statistically significantly higher post-dose measurements for both problems attempted and problems
Downloaded from jad.sagepub.com by guest on November 14, 2015
6
Journal of Attention Disorders
Table 1. Summary and Analyses of Mean Post-Dose Permanent Product Measure of Performance (PERMP): Measurements of Problems Attempted and Problems Correct for All Subgroups. Problems attempted Final dose, mg 20 (n = 2) 30/40 (n = 27) 50/60 (n = 10) Age, years 6-7 (n = 7) 8-10 (n = 23) 11-12 (n = 9) Sex Male (n = 28) Female (n = 11) ADHD subtype Inattentive (n = 11) Hyperactive/impulsive (n = 1) Combined (n = 27) ADHD severity at baseline Equal/below median (n = 20) Above median (n = 19)
Problems correct
MEROS
Placebo
p value
MEROS
Placebo
p value
NA 107.8 (11.4) 110.1 (17.3)
NA 80.0 (11.4) 73.1 (17.3)
NA < .0001 .0044
NA 101.8 (10.6) 106.9 (17.7)
NA 74.9 (10.6) 66.8 (17.7)
NA < .0001 .0014
130.6 (30.5) 99.1 (10.8) 109.5 (15.3)
85.3 (30.5) 71.9 (10.8) 85.0 (15.3)
.0526 < .0001 .0050
118.4 (27.2) 95.7 (10.4) 104.2 (15.4)
77.9 (27.2) 66.3 (10.4) 80.9 (15.4)
.0483 < .0001 .0045
112.7 (11.1) 90.1 (14.4)
82.7 (11.1) 61.9 (14.4)
< .0001 .0020
106.1 (10.4) 87.0 (14.8)
77.9 (10.4) 55.6 (14.8)
< .0001 .0003
126.7 (12.5) NA 99.2 (11.3)
88.3 (12.5) NA 73.3 (11.3)
.0001 NA .0002
117.9 (11.9) NA 95.1 (11.0)
82.8 (11.9) NA 67.7 (11.0)
.0001 NA < .0001
118.7 (12.6) 97.5 (12.9)
88.8 (12.6) 65.0 (12.9)
< .0001 .0006
115.1 (11.9) 90.5 (12.3)
85.3 (11.9) 56.1 (12.3)
< .0001 .0003
Note. Results are presented as least squares mean (standard error). The mean of post-dose measurements is calculated as the average of the 0.75, 2, 4, 8, 10, and 12-hr post-dose scores for each participant. MEROS = methylphenidate for extended-release oral suspension; NA = not available (patient numbers too small to conduct statistical analysis).
Table 2. ADHD Rating Scale (ADHD-RS) Scores During Open-Label Treatment. Baseline (Visit 2)
Week 1 (Visit 3)
Week 2 (Visit 4)
Week 3 (Visit 5)
Week 4 (Visit 6)
ADHD-RS Total scores
39.3 ± 7.6
Hyperactivity/impulsivity scores
18.5 ± 5.3
Inattentiveness scores
20.8 ± 4.3
27.6 ± 10.8 (−11.7)* 13.1 ± 5.5 (−5.4)* 14.4 ± 6.2 (−6.3)*
21.2 ± 11.2 (−17.8)* 9.7 ± 6.1 (−8.6)* 11.4 ± 6.1 (−9.2)*
16.9 ± 8.9 (−22.0)* 8.2 (5.5) (−10.1)* 8.7 ± 4.4 (−11.9)*
12.6 ± 6.3 (−26.0)* 6.0 (4.2) (−12.0)* 6.6 ± 3.5 (−14.0)*
Note. Values are mean ± standard deviation and (in parentheses) change from baseline value in the intent-to-treat population. *p < .001.
correct during treatment with MEROS than placebo were seen for all subgroup analyses of PERMP, with sufficient participants to provide inferential statistics, regardless of final dose, age, gender, ADHD type, and baseline ADHD severity (Table 1). Mean ADHD-RS total scores decreased (improved) from 39.3 (±7.6) at baseline to 12.6 (±6.3) at the end of the open-label period (see Table 2 and Figure 3). Likewise, the ADHD-RS Hyperactivity-Impulsivity subscale baseline score of 18.5 (± 5.3) improved to 6.0 (± 4.2), and the Inattentiveness subscale score of 20.8 (±4.3) at baseline improved to 6.6 (±3.5) at the end of the open-label period. The mean changes during this period were 26.0, 12.0, and 14.0 for ADHD-RS total score, hyperactivity-impulsivity
score, and inattentiveness score, respectively. Thirty-four of the 39 (87.2%) evaluable participants with ADHD-RS data were considered responders (defined as at least a 50% improvement in ADHD-RS total score) at the end of the open-label phase. The responder cohort (n = 34) had a statistically significantly lower mean SKAMP-combined score at 4-hr post-dose when receiving MEROS than when receiving placebo. The LS mean of the treatment difference was −11.88 (p < .0001). At baseline, 63.3% of participants were considered moderately ill, with responses ranging from mildly ill (2.3%) to severely ill (9.1%) as rated by investigator-scored CGI-S. Twenty-five percent of participants were considered markedly ill. At the end of the open-label period, most
Downloaded from jad.sagepub.com by guest on November 14, 2015
7
Robb et al.
Figure 3. Mean ADHD Rating Scale (ADHD-RS) total scores in the open-label phase.
Figure 4. Mean Clinical Global Impression-Severity (CGI-I) scores in the open-label phase.
participants were considered borderline ill (51.3%) and responses ranged from normal (20.5%) to moderately ill (2.6%); no participants were considered either markedly ill or severely ill. CGI-S scores decreased from a mean of 4.4 at baseline to a mean of 2.1 during this phase of the trial (Figure 4), and mean CGI-I scores improved from 2.8 at baseline to 1.4 during the same period (Figure 5). At the end of the open-label period, all participants were considered either much improved (41%) or very much improved (59%), as measured by CGI-I.
Safety Forty-two participants experienced a TEAE and 39 experienced a TEAE related to study medication during the
open-label phase (Table 3). Severe TEAEs occurred in 3 participants and 2 led to study discontinuation. One withdrawal occurred due to severe affect lability after receiving the study medication for 18 days and the other from severe aggression and taking MEROS for 9 days. Both participants recovered on the same day the AE was experienced without sequelae. The third severe TEAE was initial insomnia but did not lead to study withdrawal. The duration of the severe initial insomnia was 1 night. The severity of the event was then downgraded to mild and persisted for an additional 37 days when it resolved. The most common AEs reported during the open-label phase were decreased appetite (56%), upper abdominal pain (42%), affect lability (27%), initial insomnia (22%), insomnia (18%), and headache (18%).
Downloaded from jad.sagepub.com by guest on November 14, 2015
8
Journal of Attention Disorders
Figure 5. Mean Clinical Global Impression-Improvement (CGI-I) scores in the open-label phase. Table 3. Summary of Treatment-Emergent Adverse Events During Open-Label Phase (≥5%). Total (N = 45) Adverse event Any treatment-emergent adverse event Decreased appetite Abdominal pain (upper) Affect lability Insomnia (initial) Insomnia Headache Irritability Vomiting Upper respiratory tract infection Logorrhea Fatigue Diarrhea Aggression Dizziness Cough Flushing
n (%) 42 (93.3) 25 (55.6) 19 (42.2) 12 (26.7) 10 (22.2) 8 (17.8) 8 (17.8) 6 (13.3) 5 (11.1) 5 (11.1) 4 (8.9) 4 (8.9) 3 (6.7) 3 (6.7) 3 (6.7) 3 (6.7) 3 (6.7)
During the double-blind phase, 11 (24.4%) of participants experienced a TEAE while receiving MEROS and 5 (11.1%) had a TEAE while receiving placebo. AEs considered related to study medication occurred in 6 (13.3%) participants during MEROS treatment and 3 (6.7%) participants during placebo treatment. Affect lability was the only TEAE reported in ≥5% of participants during the doubleblind phase, with 8.9% of participants reporting this during treatment with MEROS and 2.2% while taking placebo. There were no deaths or serious AEs reported during the study.
A majority of participants had normal findings at screening on hematology and chemistry parameters and per physical exam. All participants were deemed medically suitable for participation in the study. A physical exam was also conducted at the final study visit and no unexpected studyrelated findings were noted. Evaluation of vital signs showed mean changes in systolic blood pressure from baseline to the final three visits of the study of 3.4 mmHg, 1.5 mmHg, and 3.5 mmHg, respectively. The mean changes in diastolic blood pressure during the same period were 6.0 mmHg, 4.9 mmHg, and 3.0 mmHg, respectively. The mean increases in pulse from baseline to the final three visits of the trial were 9.3 bpm, 6.9 bpm, and 9.2 bpm, respectively. There were 9 participants with post-baseline pulse values greater than 110 bpm and 10 participants with an increase from baseline ≥25 bpm. There was 1 participant with a post-baseline systolic blood pressure greater than the 95th percentile, and none with a diastolic blood pressure postbaseline value of >95th percentile. Changes in height, weight, and BMI were small and not considered clinically significant. The mean change in BMI from baseline to the end of the study was 0.13 kg/m2. There were no participants with any occurrences of suicidal ideation or behavior during the study.
Discussion This study is the first randomized, double-blind, placebocontrolled cross-over design to evaluate the efficacy, safety, and tolerability of a long-acting liquid formulation of methylphenidate (MEROS) in children aged 6 to 12 years. While the primary efficacy has been reported in a separate manuscript (Wigal et al., 2013), this article details the secondary efficacy outcomes including ADHD-RS, CGI-S and CGI-I, and PERMP scores.
Downloaded from jad.sagepub.com by guest on November 14, 2015
9
Robb et al. The laboratory classroom protocol is a well-studied measure that allows precise determination of onset and duration of efficacy of ADHD medications (Wigal & Wigal, 2006), and which has been used to study many other long-acting methylphenidate products (McGough et al., 2006; Pelham et al., 2001, 2011; Quinn et al., 2004), including MEROS (Wigal et al., 2013). Each child in this cross-over trial served as his or her own control, and ratings (using validated subjective scales, such as the SKAMP in the context of group activities between teams of students and individualized seatwork, and objective measures such as the PERMP math test) were recorded on optimal drug dose and placebo. This design allows more information to be gleaned from a smaller total subject population. It also allows comparisons to be made in each individual, both on and off medication, and the relative impairment observed in each case. The secondary outcomes of this study range from very specific functional measures, such as PERMP and ADHD-RS, to more global measures (CGI-I and CGI-S Scales). The PERMP provides an indirect measure of functionality in an academic setting. The child attempts to solve a series of math problems in a 10-min period and is scored on number of problems attempted (speed of calculation) and number correct (accuracy). This test is relevant for children with ADHD who frequently struggle with initiating and/or finishing their work (e.g., homework) and who may make multiple mistakes if rushing to finish. The PERMP math test utilized in the double-blind phase provides an objective measure of the effects of stimulant treatment in children with ADHD. These results demonstrated that children with ADHD attempted more math problems and completed more math problems correctly when treated with an individually optimized dose of MEROS compared with placebo treatment. The results of this trial show improvement in symptoms of ADHD from baseline to the end of the study, as evidenced by improvement in rating scale scores during both the open-label and double-blind portions of the trial. Participants showed a significant improvement in ADHD symptoms on the ADHD-RS utilized in the open-label phase of the study, as well as improvement in global functioning as measured by the CGI-I and CGI-S rating scales. The double-blind measures corroborated these findings by demonstrating improvement in attention and behavior under optimally dosed MEROS compared with placebo treatment, measured by the SKAMP-combined score. Following administration of MEROS, this significant effect began at the first post-dose time point included in the study (45 min) and continued through 12 hr, the last time point included in the study after dosing (Wigal et al., 2013). One of the secondary outcome measures in the trial, the ADHD-RS, yields a total/composite score, as well as subscores for both inattention and hyperactive/impulsive
symptoms individually. This universal rating scale has been used in studies of other stimulants to demonstrate efficacy in the treatment of ADHD (Coghill et al., 2013; Wigal et al., 2011) and is frequently employed to show change between baseline and end of study in the active treatment group. The participants in this study of MEROS had a pre-treatment baseline ADHD-RS total score mean of 39.3 (±7.6), with a mean reduction of 26.0 points total (12.0 for hyperactive/impulsive and 14.0 for inattentive symptoms) by the end of the open-label period. Therefore, this new formulation of methylphenidate was effective in treating both inattentive and hyperactive/impulsive symptoms of ADHD in the present study. In many of the early ADHD trials, a “responder” was defined as 30% reduction in ADHD-RS and CGI-I of 1 or 2 (much or very much improved). In this trial, the bar for response was raised to a 50% reduction in ADHD-RS during the open-label period. Despite the higher criteria required for responders in this trial, the response rate was 87.2% (34 of the 39 children who completed the trial). These results validate this long-acting liquid methylphenidate as another effective extended-release formulation for the treatment of ADHD. The CGI-I and CGI-S Scales are frequently used in clinical trials of psychiatric medications to give a clinician-rated assessment of disease severity at entry into a trial, and again at the end of a study. At the onset of this trial, most of the children were considered moderately to markedly ill. At the end of the 6 week, open-label titration phase, mean CGI-S scores had improved and were within the classification of borderline to mildly ill. All of the children (100%) were much or very much improved on the CGI-I by the end of the same period. The TEAEs in both the open-label and double-blind segments of the trial were anticipated, and in line with the use of stimulants in the school-age population (Quillivant XR prescribing information, 2013). These include the more common TEAEs of abdominal pain, loss of appetite, initial and any insomnia. Affect lability, a relatively common TEAE in this trial, was also the only TEAE with an incidence ≥5% in the double-blind phase. Three severe TEAEs were noted in the study, and one case each of aggression and affect lability led to study discontinuation; there were no serious TEAEs and no cases of suicidal ideation or behavior noted during this study. Alterations in vital signs were noted in both pulse and blood pressure, but were not clinically significant and did not lead to discontinuation. Although this trial does not report on a new class of medication for ADHD, it does describe a novel delivery system and onset and duration of action for a well-known active agent. Despite the availability of other formulations that provide long-acting alternatives, a group of children and older adolescents exist who cannot or will not swallow pills, and will not tolerate sprinkles or a transdermal patch.
Downloaded from jad.sagepub.com by guest on November 14, 2015
10
Journal of Attention Disorders
Previously, these patients may have opted for a liquid or chewable formulation only available in short-acting formulations, and were therefore potentially burdened with the limitations of multiple daily dosing. With the advent of MEROS, there is an effective long-acting oral liquid preparation for those who cannot tolerate other options, but still require full-day symptom coverage.
Limitations Although this trial demonstrates efficacy of the first longacting liquid methylphenidate, results were obtained from a small number of participants. The protocol excluded many common psychiatric and medical comorbidities, including severe oppositional defiant disorder, therefore, results may not generalize to the overall population of patients with ADHD. Participants who could not do basic timed math were also excluded, which may have prevented younger children who had more severe symptoms from participating in the study; no teenagers or adults were studied. In addition, the period of drug treatment was brief (6-8 weeks), as such, no conclusions regarding long-term safety and efficacy of MEROS can be drawn. In this trial, 87% of participants had a 50% or greater reduction of ADHD symptoms on the investigator-rated ADHD-RS. These values are higher than previously reported in double-blind placebo-controlled trials of participants with ADHD. In these studies, the non-response to a single stimulant has been reported to be 25% to 35% (Pliszka et al., 2007). Several factors may have influenced the higher rate of response with MEROS. This study included an open-label design during dose optimization and excluded many comorbid diagnoses. The small number of sites and raters conducting the study may have decreased variability in the ratings, making it difficult to compare MEROS results with those of larger trials.
Conclusion In this trial, MEROS was shown to be safe and effective for the treatment of ADHD (Wigal et al., 2013). MEROS also demonstrated efficacy on other measures of the trial, including the ADHD-RS, which captures the 18 symptoms of inattention and hyperactivity/impulsivity, and the PERMP, an evaluation of ability to adequately perform math in the classroom. Additional studies of MEROS in younger and developmentally delayed children with ADHD are needed to determine if these or other populations could benefit from the flexible delivery of a long-acting liquid formulation of methylphenidate. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this
article: Adelaide S. Robb has been an Advisory Board member for Bristol-Myers Squibb, Eli Lilly and Company, Lundbeck, Otsuka, and Pfizer Inc.; served on a Speakers Bureau for Takeda, Otsuka, and Pfizer Inc.; received research support from BristolMyers Squibb, Forest Laboratories Inc., GlaxoSmithKline, Janssen Pharmaceuticals, Inc., Lundbeck, Merck/ScheringPlough Pharmaceuticals, National Institute of Child Health and Human Development (NICHD), Otsuka, and Pfizer Inc.; received travel support from American Academy of Child and Adolescent Psychiatry (AACAP) and Pfizer Inc.; and owns stocks in Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Inc., and Pfizer Inc. Robert L. Findling receives or has received research support, acted as a consultant, and/or served on a speaker’s bureau for Alexza Pharmaceuticals, American Academy of Child & Adolescent Psychiatry, American Physician Institute, American Psychiatric Press, AstraZeneca, Bracket, Bristol-Myers Squibb, Clinsys, Cognition Group, Coronado Biosciences, Dana Foundation, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson & Johnson, KemPharm, Lilly, Lundbeck, Merck, NIH, Novartis, Noven, Otsuka, Oxford University Press, Pfizer, Physicians Postgraduate Press, Rhodes Pharmaceuticals, Roche, Sage, Seaside Pharmaceuticals, Shire, Stanley Medical Research Institute, Sunovion, Supernus Pharmaceuticals, Transcept Pharmaceuticals, Validus, and WebMD. Ann C. Childress has been a consultant to Novartis, Shionogi, NextWave Pharmaceuticals, Shire Pharmaceuticals, and Pfizer Inc.; a speaker for Novartis, Shionogi, GlaxoSmithKline, and Shire Pharmaceuticals; and received research support from Novartis, Shionogi, NextWave Pharmaceuticals, Shire Pharmaceuticals, Abbott Laboratories, Forest Laboratories, Johnson & Johnson Pharmaceutical Research & Development, LLC, Lilly USA, Ortho-McNeil Janssen Scientific Affairs, Otsuka Pharmaceutical Company Ltd, Pfizer Inc., Rhodes Pharmaceuticals LP, Sepracor Inc., Somerset Pharmaceuticals, Neos, and Theravance. Sharon B. Wigal receives or has received research support, acted as a consultant, been an Advisory Board member, and/or served on a Speakers Bureau for Addrenex Pharmaceuticals, Eli Lilly and Company, Forest Pharmaceuticals, McNeil Consumer & Specialty Pharmaceuticals, NextWave Pharmaceuticals, NIMH, Noven, NuTec Pharma Ltd., Otsuka, Inc., Pfizer Inc., Purdue, Quintiles, Rho, Rhodes Pharmaceuticals, Shionogi Inc., Shire US Inc., Sunovion, Taisho Pharmaceutical Co., and Tris Pharma, Inc. Sally A. Berry and Heidi W. Belden were employed by NextWave Pharmaceuticals, which was acquired by Pfizer Inc. Both are now consultants to Pfizer Inc., and as such, were paid contractors to Pfizer Inc. in the development of this manuscript. Adelaide S. Robb, Robert L. Findling, Ann C. Childress, and Sharon B. Wigal have declared no potential conflicts of interests with respect to the authorship and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was sponsored by NextWave Pharmaceuticals, a wholly owned subsidiary of Pfizer Inc. Writing and editorial support for this manuscript was provided by Anne Jakobsen, MSc, of Engage Scientific and funded by Pfizer Inc.
Downloaded from jad.sagepub.com by guest on November 14, 2015
11
Robb et al. References American Academy of Pediatrics. (2011). ADHD: Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics, 128, 1007-1020. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC: Author. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. Centers for Disease Control and Prevention. (2010). Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children—United States, 2003 and 2007. Morbidity and Mortality Weekly Report, 59, 1439-1443. Childress, A. C., & Berry, S. A. (2010). The single-dose pharmacokinetics of NWP06, a novel extended-release methylphenidate oral suspension. Postgraduate Medicine, 122, 35-41. Coghill, A., Banaschewski, T., Lecendreux, M., Soutullo, C., Johnson, M., & Zuddas, A., . . . Squires, L. (2013). European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder. European Neuropsychopharmacology, 23, 1208-1218. DuPaul, G. J., Power, T. J., Anastopoulos, A. D., & Reid, R. (1998). ADHD rating scales-IV: Checklists, norms and clinical interpretation. New York, NY: Guilford. Guy, W. (1976). Clinical global impressions. In ECDEU assessment manual for psychopharmacology (pp. 218-222). Rockville, MD: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch. Intuniv prescribing information. (2013). Wayne, PA: Shire US. Kapvay prescribing information. (2013). Florham Park, NJ: Shionogi. Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., . . .Ryan, N. (1997). Schedule for affective disorders and schizophrenia for school-age children–present and lifetime version (K-SADS- PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 980-988. Kessler, R. C., Adler, L., Barkley, R., Biederman, J., Conners, C. K., Demler, O., . . .Zaslavsky, A. M. (2006). The prevalence and correlates of adult ADHD in the United States: Results from the National Comorbidity Survey Replication. American Journal of Psychiatry, 163, 716-723. McGough, J. J., Wigal, S. B., Abikoff, H., Turnbow, J. M., Posner, K., & Moon, E. (2006). A randomized, double-blind, placebocontrolled, laboratory classroom assessment of methylphenidate transdermal system in children with ADHD. Journal of Attention Disorders, 9, 476-485. National Heart, Lung, and Blood Institute, National Institutes of Health. (2005). The fourth report on the diagnosis, evaluation, and treatment of blood pressure in children and adolescents (NIH Publication No. 05-5267). Retrieved from http:// www.nhlbi.nih.gov/health/prof/heart/hbp/hbp_ped.pdf National Institute of Mental Health, National Institutes of Health. (2012). Attention deficit hyperactivity disorder. Retrieved
from http://www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml Pelham, W. E., Gnagy, E. M., Burrows-Maclean, L., Williams, A., Fabiano, G. A., Morrisey, S. M., . . .Morse, G. D. (2001). Once-a-day Concerta methylphenidate versus three-timesdaily methylphenidate in laboratory and natural settings. Pediatrics, 107, E105. Pelham, W. E., Waxmonsky, J. G., Schentag, J., Ballow, C. H., Panahon, C. J., Gnagy, E. M., . . .González, M. A. (2011). Efficacy of a methylphenidate transdermal system versus t.i.d. methylphenidate in a laboratory setting. Journal of Attention Disorders, 15, 28-35. Pliszka, S. R., Bernet, W., Bukstein, O., Walter, H. J., Arnold, V., Beitchman, J., . . .Stock, S. (2007). The American Academy of Child and Adolescent Psychiatry (AACAP) Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/ hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 894-921. Posner, K., Oquendo, M. A., Gould, M., Stanley, B., & Davies, M. (2007). Columbia Classification Algorithm of Suicide Assessment (C-CASA): Classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants. American Journal of Psychiatry, 164, 1035-1043. Quillivant XR prescribing information. (2013). New York, NY: Pfizer. Quinn, D., Wigal, S., Swanson, J., Hirsch, S., Ottolini, Y., Dariani, M., . . .Cooper, T. (2004). Comparative pharmacodynamics and plasma concentrations of d-threo-methylphenidate hydrochloride after single doses of d-threo-methylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in a double-blind, placebo-controlled, crossover laboratory school study in children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 43, 1422-1429. Strattera prescribing information. (2013). Indianapolis, IN: Eli Lilly. Wigal, S. B., Childress, A. C., Belden, H. W., & Berry, S. A. (2013). NWP06, an extended-release oral suspension of methylphenidate, improved attention-deficit/hyperactivity disorder symptoms compared to placebo in a laboratory classroom study. Journal of Child and Adolescent Psychopharmacology, 23, 1-8. Wigal, S. B., & Wigal, T. L. (2006). The laboratory school protocol: Its origin, use, and new applications. Journal of Attention Disorders, 10, 92-111. Wigal, S. B., Wigal, T., Schuck, S., Brams, M., Williamson, D., Armstrong, R. B., & Starr, H. L. (2011). Academic, behavioral, and cognitive effects of OROS methylphenidate on older children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 21, 121-131.
Author Biographies Adelaide S. Robb, MD, is a professor of psychiatry and pediatrics at the George Washington University School of Medicine. She is the director of psychiatry research at Children’s National Medical Center and has published articles on ADHD, anxiety, mood, and psychotic disorders.
Downloaded from jad.sagepub.com by guest on November 14, 2015
12
Journal of Attention Disorders
Robert L. Findling, MD, MBA, is a professor of psychiatry at Johns Hopkins University. He is the director of Child & Adolescent Psychiatry at Johns Hopkins University and is the vice president of psychiatric services and research at the Kennedy Krieger Institute.
Sally A. Berry, MD, PhD, was the chief medical officer at NextWave Pharmaceuticals and is now a consultant to Pfizer Inc.
Ann C. Childress, MD, is a clinical assistant professor of family medicine at the University of Nevada School of Medicine and president of the Center for Psychiatry and Behavioral Medicine, Inc.
Sharon B. Wigal, PhD, was a professor of pediatrics at the University of California, Irvine when she conducted the reasearch. She is currently the president and director of Clinical Services at AVIDA Inc.
Heidi W. Belden, PharmD, was employed as medical director by NextWave Pharmaceuticals and is now a consultant to Pfizer Inc.
Downloaded from jad.sagepub.com by guest on November 14, 2015
research-article2014
JADXXX10.1177/1087054714533191Journal of Attention DisordersRobb et al.
Article
Efficacy, Safety, and Tolerability of a Novel Methylphenidate Extended-Release Oral Suspension (MEROS) in ADHD
Journal of Attention Disorders 1–12 © 2014 SAGE Publications Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1087054714533191 jad.sagepub.com
Adelaide S. Robb1, Robert L. Findling2, Ann C. Childress3, Sally A. Berry4, Heidi W. Belden4, and Sharon B. Wigal5
Abstract Objective: To test whether an optimal dose of Quillivant XR (methylphenidate extended-release oral suspension [MEROS]) would significantly reduce symptoms of ADHD in children. Method: A randomized, double-blind, placebocontrolled, cross-over, efficacy, safety, and tolerability study of MEROS in 45 children aged 6 to 12 years (open-label doseoptimization phase, followed by double-blind cross-over period). Results: MEROS was significantly more efficacious than placebo during double-blind cross-over laboratory classroom days (Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale and Permanent Product Measure of Performance). During the open-label phase, improvements were observed in scores of ADHD Rating Scale-IV, and Clinical Global Impression-Severity and -Improvement Scales. No occurrences of suicidal ideation or behavior were recorded; the most common open-label treatment-emergent adverse events were typical of stimulant use: decreased appetite, insomnia, and abdominal pain. Conclusion: MEROS was efficacious in the treatment of children aged 6 to 12 years with ADHD, with a safety profile similar to that of other extended-release methylphenidate pharmacotherapies. (J. of Att. Dis. XXXX; XX(X) XX-XX) Keywords ADHD, methylphenidate, laboratory school, randomized-controlled trial, math test
Introduction ADHD is one of the most common neurobehavioral disorders and has a lifetime prevalence of 9.5% in children and adolescents aged 4 to 17 years (Centers for Disease Control and Prevention, 2010). The current Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association [APA], 2013) diagnostic criteria require the onset of symptoms prior to the age of 12 years with a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning. Six or more of the nine symptoms of inattention and/or six or more symptoms of hyperactivity-impulsivity must have persisted for 6 months or more to a degree that is inconsistent with developmental level, and negatively impacts social and academic/occupational activities. For older adolescents and adults aged 17 years and above, at least five symptoms of nine are required (APA, 2013). Evaluation and multimodal treatment are recommended for patients as early as age 4 years through adolescence (American Academy of Pediatrics, 2011), and into adulthood (Kessler et al., 2006). Psychosocial treatments including correct classroom placement, tutoring, and individual, group, and family therapy are important components of a treatment
plan. The other important aspect of the treatment plan is psychopharmacologic treatment, when indicated, and is the focus of this study. Stimulants are the most commonly used medications for the treatment of ADHD (National Institute of Mental Health [NIMH], National Institutes of Health [NIH], 2012). For some patients with ADHD, the ability or willingness to swallow medication easily is part of the difficulty in ensuring adherence to treatment and optimizing outcomes. In the last decade, the development of pharmacologic options for ADHD expanded dramatically. The first major advance was the development of effective long-acting stimulants, which 1
George Washington University, Washington, DC, USA Johns Hopkins University, Baltimore, MD, USA 3 Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, NV, USA 4 Pfizer Inc., New York, NY, USA 5 AVIDA Inc, Newport Beach, CA, USA 2
Corresponding Author: Adelaide S. Robb, Departments of Psychiatry and Behavioral Sciences & Pediatrics, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, NW Washington, DC 20010, USA. Email: [email protected]
Downloaded from jad.sagepub.com by guest on November 14, 2015
2
Journal of Attention Disorders
obviated the need for multiple daily doses and associated “on-off” periods throughout the school day and into homework time. The American Academy of Child and Adolescent Psychiatry advises that long-acting forms of stimulants may be used as initial treatment for ADHD; there is no need to routinely titrate to the appropriate dose on short-acting forms and then “switch” patients to a long-acting form (Pliszka et al., 2007). These agents were followed by the development of the first effective non-stimulant, atomoxetine (Strattera prescribing information, 2013), and then two long-acting alpha-2 agonists: extended-release guanfacine (Intuniv prescribing information, 2013) and modifiedrelease clonidine (Kapvay prescribing information, 2013). These drugs are all indicated for the treatment of ADHD. While long-acting stimulants are effective in attaining sustained coverage for ADHD symptoms, some formulations require children to swallow the tablet or capsule intact, whereas others allow for sprinkling on applesauce, transdermal placement, or dissolving in water. Some children struggle with swallowing pills or do not like the texture of the sprinkles, while skin sensitivity precludes transdermal applications for some others. Clinicians treating children who are unable to swallow pills frequently resort to prescribing a chewable or liquid preparation, options that were previously only available as immediate-release formulations. With the approval of Quillivant XR (methylphenidate extended-release oral suspension [MEROS]), a long-acting liquid preparation is available for those who are unwilling or unable to swallow pills or use sprinkles. This oral methylphenidate suspension, with a concentration of 25 mg per 5 mL (5 mg/mL), allows for titration in upward or downward increments that can be flexible in their magnitude, which is limited by available dosage strengths for standard pills or capsules. The mechanism of methylphenidate delivery as well as the onset and duration of efficacy of MEROS have each been previously described (Wigal, Childress, Belden, & Berry, 2013). MEROS has demonstrated onset of action in 45 min and duration of action through 12 hr postdosing. The delivery system technology of MEROS is created by the formation of drug–polymer complexes, 80% of which are coated with an extended-release coating of varying thicknesses, which allows for release of methylphenidate throughout the day. The remaining 20% of drug–polymer complexes are left uncoated and act as immediate-release methylphenidate (Wigal et al., 2013). The relative bioavailability of 60 mg of Quillivant XR compared with 60 mg of immediate-release methylphenidate oral solution (given as two 30 mg doses 6 hr apart) is 95% (Childress & Berry, 2010). This study was designed to determine the efficacy, safety, and tolerability of the long-acting liquid methylphenidate preparation, MEROS, in a group of 45 children aged 6 to 12 years with ADHD, through open-label dose optimization followed by a double-blind cross-over period of
optimal dose MEROS versus placebo. Assessments were obtained at the end of both active and placebo weeks in a laboratory classroom setting. The efficacy of MEROS measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)-combined score has been reported in detail elsewhere (Wigal et al., 2013). This article focuses on other efficacy scales utilized in the double-blind phase (Permanent Product Measure of Performance [PERMP] score) and open-label phase (ADHD Rating Scale-IV [ADHD-RS], Clinical Global Impression of Severity [CGI-S] Scale, and Clinical Global Impression of Improvement [CGI-I] Scale scores) of the study.
Method Study Design This randomized, double-blind, placebo-controlled, crossover design laboratory classroom study was conducted to investigate the efficacy, safety, and tolerability of MEROS for the treatment of ADHD. Study design consisted of screening and baseline visits, a 4 to 6 week open-label doseoptimization phase, and a 2-week double-blind phase consisting of 1 week of treatment with either MEROS or placebo, followed by 1 week of the opposite treatment, placebo/MEROS. The study was approved by the institutional review board of both the study sites: the Child Development Center at the University of California, Irvine, CA, USA, and the Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, NV, USA. Prior to study commencement, parents or guardians provided written informed consent for study participation and all participants provided written assent. During the open-label phase, all participants received a starting dose of MEROS of 20 mg, with allowable upward titration of 10 to 20 mg increments in weekly intervals until an optimal dose was achieved; the maximum daily dose was 60 mg. To reach optimal efficacy during the open-label phase, investigators were permitted to adjust the dose of MEROS upward, using clinical judgment with the assistance of clinical efficacy scales (including the ADHD-RS and CGI-S) to inform decision making for dose optimization. Downward adjustment, during this same period, was also permissible if safety or tolerability issues occurred. When dosage adjustments were made, increases were not to exceed 20 mg, but a downward adjustment greater than 20 mg could be made if clinically necessary. Participants who could not tolerate a minimum 20-mg daily dose were discontinued from the study. Once reached, the optimal dose was maintained for the remainder of the openlabel phase and was used for the double-blind treatment period. Participants were randomly assigned in a 1:1 ratio to either the MEROS/placebo or placebo/MEROS treatment sequence. The study design allowed each participant to serve as his or her own control. At the end of each week of
Downloaded from jad.sagepub.com by guest on November 14, 2015
3
Robb et al. double-blind, randomized treatment, participants took part in a laboratory classroom study day to assess treatment in this standardized setting.
Study Population Eligibility for enrollment required age between 6 and 12 years with a diagnosis of ADHD (any type). The diagnosis must have been made by a psychiatrist, psychologist, developmental pediatrician, pediatrician, or pre-approved licensed allied health professional using the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; APA, 2000), and confirmed by administration of a diagnostic interview using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS; Kaufman et al., 1997). A score of ≥3 on the CGI-S Scale (Guy, 1976), and ≥90th percentile normative values for gender and age on the ADHD-RS (DuPaul, Power, Anastopoulos, & Reid, 1998) total score, the Hyperactive/Impulsive subscale, or the Inattentive subscale at screening or at baseline were also required. To qualify, participants needed to be symptomatic to the degree that pharmacological treatment for ADHD was necessary in the opinion of the investigator. If participants were under current treatment, they must have had either a safety or tolerability issue with their current regimen, suboptimal efficacy, or a need for a long-acting liquid regimen. Clinically significant cognitive impairment defined as an estimated intelligence quotient 110 beats per minute (bpm; or a ≥25 bpm change from baseline), or >95th percentile observed value for systolic or diastolic blood pressure for participant’s age, gender, and height based on the Fourth Report on the Diagnosis, Evaluation, and Treatment of Blood Pressure in Children and Adolescents (National Heart, Lung, and Blood Institute, NIH, 2005). A clinically significant change in weight was defined as a ≥5% decrease from baseline. The Columbia Suicide Severity Rating Scale (C-SSRS) was used to assess suicidal thoughts or behaviors at baseline and all subsequent visits (Posner, Oquendo, Gould, Stanley, & Davies, 2007). C-SSRS is a brief questionnaire that allows the clinician to assess occurrence and severity of suicidal ideation and behavior.
Statistical Analyses The primary efficacy analysis was previously described by Wigal et al. (2013). The secondary efficacy analyses were conducted on the intent-to-treat (ITT) population, which consisted of all randomized participants who took at least one dose of study medication, and had at least one post-baseline efficacy assessment available for analysis. Descriptive statistics for the PERMP scores were calculated at each time point for the test laboratory classroom days, and are presented for each treatment, as well as for the paired differences between the treatments (MEROSplacebo). The time points analyzed were pre-dose, 0.75, 2, 4, 8, 10, and 12 hr post-dose, as well as the mean of the post-dose measurements, calculated as the average of the 0.75, 2, 4, 8, 10, and 12 hr post-dose PERMP scores for each participant. The least squares (LS) mean (± standard
error) PERMP scores were plotted over time for the laboratory classroom days by treatment group. Secondary efficacy variables were assessed using a linear analysis of variance (ANOVA) model with SAS software (SAS Institute, Cary, NC, USA). Descriptive statistics for the ADHD-RS, CGI-S, and CGI-I scores were presented for each visit, based on the ITT population. The CGI-S and CGI-I scores were presented as both categorical and continuous values. In addition, the change from baseline in CGI-S, CGI-I scores, and ADHD-RS scores was presented. For the ADHD-RS, the proportion of responders is presented in the ITT population, including the exact 95% confidence intervals for the binomial proportion. The safety population was defined as all randomized participants who received at least one dose of study medication.
Results Participants A total of 45 participants were enrolled and randomized (23 to the placebo/MEROS treatment sequence and 22 to the MEROS/placebo treatment sequence). The overall mean age of participants was 8.8 years and the majority of participants were male (72.7%). Thirty-five participants were White (79.5%) and 11 (25%) were Hispanic/Latino. Most participants (70.5%) had the combined presentation of ADHD, 12 (27.3%) were predominantly inattentive, and 1 (2.3%) was diagnosed with the predominantly hyperactive/ impulsive presentation of ADHD. Mean baseline ADHD-RS total scores were 39.3 (±7.6). Approximately 30% of participants had a comorbid psychiatric diagnosis that did not require medication treatment (oppositional defiant disorder [18.2%], elimination disorder [9.1%], and specific phobias [4.5%]). Six participants discontinued during the open-label phase due to withdrawal of assent/consent and AEs (2 participants each), and lack of efficacy and lost to follow-up (1 participant each). There were 3 participants with a final optimal dose of 20 mg, 30 participants with an optimized dose of 30 or 40 mg, and 11 participants with a final optimal dose of 50 or 60 mg. The mean optimal dose was approximately 40 mg.
Efficacy The primary efficacy measure of SKAMP-combined score at 4-hr post-dose was statistically significantly lower (improved) during treatment with MEROS compared with placebo (p < .0001). This finding is discussed in more detail by Wigal et al. (2013). At each time point tested in the laboratory classroom setting, both the number of problems attempted (Figure 1) and the number correct (Figure 2) on the PERMP were significantly higher during treatment with MEROS compared
Downloaded from jad.sagepub.com by guest on November 14, 2015
5
Robb et al.
Figure 1. Permanent product measure of performance (PERMP) number of problems attempted over time (least squares mean ± standard error) by treatment group. MEROS = methylphenidate for extended-release oral suspension.
Figure 2. Permanent product measure of performance (PERMP) number of problems correct over time (least squares mean ± standard error) by treatment group. MEROS = methylphenidate for extended-release oral suspension.
with placebo. The LS mean treatment difference between MEROS and placebo reached statistical significance 45 min after dosing (p < .0001, both number attempted and number correct), and the effect persisted through the test day and remained statistically significant at the last post-dose assessment at 12 hr (p = .0019, number attempted; p = .0008, number correct). For the number of problems attempted, the LS mean of the treatment difference between MEROS and placebo ranged from 45.77 at 4-hr post-dose
(p < .0001) to 14.86 at 10-hr post-dose (p = .0155). For the number of problems correct, the LS mean of the treatment difference between MEROS and placebo treatments ranged from 45.98 at 4-hr post-dose (p < .0001) to 16.78 at 10-hr post-dose (p = .0016). Participants attempted more problems and got more problems correct throughout the day when treated with an optimal dose of MEROS compared with placebo. Statistically significantly higher post-dose measurements for both problems attempted and problems
Downloaded from jad.sagepub.com by guest on November 14, 2015
6
Journal of Attention Disorders
Table 1. Summary and Analyses of Mean Post-Dose Permanent Product Measure of Performance (PERMP): Measurements of Problems Attempted and Problems Correct for All Subgroups. Problems attempted Final dose, mg 20 (n = 2) 30/40 (n = 27) 50/60 (n = 10) Age, years 6-7 (n = 7) 8-10 (n = 23) 11-12 (n = 9) Sex Male (n = 28) Female (n = 11) ADHD subtype Inattentive (n = 11) Hyperactive/impulsive (n = 1) Combined (n = 27) ADHD severity at baseline Equal/below median (n = 20) Above median (n = 19)
Problems correct
MEROS
Placebo
p value
MEROS
Placebo
p value
NA 107.8 (11.4) 110.1 (17.3)
NA 80.0 (11.4) 73.1 (17.3)
NA < .0001 .0044
NA 101.8 (10.6) 106.9 (17.7)
NA 74.9 (10.6) 66.8 (17.7)
NA < .0001 .0014
130.6 (30.5) 99.1 (10.8) 109.5 (15.3)
85.3 (30.5) 71.9 (10.8) 85.0 (15.3)
.0526 < .0001 .0050
118.4 (27.2) 95.7 (10.4) 104.2 (15.4)
77.9 (27.2) 66.3 (10.4) 80.9 (15.4)
.0483 < .0001 .0045
112.7 (11.1) 90.1 (14.4)
82.7 (11.1) 61.9 (14.4)
< .0001 .0020
106.1 (10.4) 87.0 (14.8)
77.9 (10.4) 55.6 (14.8)
< .0001 .0003
126.7 (12.5) NA 99.2 (11.3)
88.3 (12.5) NA 73.3 (11.3)
.0001 NA .0002
117.9 (11.9) NA 95.1 (11.0)
82.8 (11.9) NA 67.7 (11.0)
.0001 NA < .0001
118.7 (12.6) 97.5 (12.9)
88.8 (12.6) 65.0 (12.9)
< .0001 .0006
115.1 (11.9) 90.5 (12.3)
85.3 (11.9) 56.1 (12.3)
< .0001 .0003
Note. Results are presented as least squares mean (standard error). The mean of post-dose measurements is calculated as the average of the 0.75, 2, 4, 8, 10, and 12-hr post-dose scores for each participant. MEROS = methylphenidate for extended-release oral suspension; NA = not available (patient numbers too small to conduct statistical analysis).
Table 2. ADHD Rating Scale (ADHD-RS) Scores During Open-Label Treatment. Baseline (Visit 2)
Week 1 (Visit 3)
Week 2 (Visit 4)
Week 3 (Visit 5)
Week 4 (Visit 6)
ADHD-RS Total scores
39.3 ± 7.6
Hyperactivity/impulsivity scores
18.5 ± 5.3
Inattentiveness scores
20.8 ± 4.3
27.6 ± 10.8 (−11.7)* 13.1 ± 5.5 (−5.4)* 14.4 ± 6.2 (−6.3)*
21.2 ± 11.2 (−17.8)* 9.7 ± 6.1 (−8.6)* 11.4 ± 6.1 (−9.2)*
16.9 ± 8.9 (−22.0)* 8.2 (5.5) (−10.1)* 8.7 ± 4.4 (−11.9)*
12.6 ± 6.3 (−26.0)* 6.0 (4.2) (−12.0)* 6.6 ± 3.5 (−14.0)*
Note. Values are mean ± standard deviation and (in parentheses) change from baseline value in the intent-to-treat population. *p < .001.
correct during treatment with MEROS than placebo were seen for all subgroup analyses of PERMP, with sufficient participants to provide inferential statistics, regardless of final dose, age, gender, ADHD type, and baseline ADHD severity (Table 1). Mean ADHD-RS total scores decreased (improved) from 39.3 (±7.6) at baseline to 12.6 (±6.3) at the end of the open-label period (see Table 2 and Figure 3). Likewise, the ADHD-RS Hyperactivity-Impulsivity subscale baseline score of 18.5 (± 5.3) improved to 6.0 (± 4.2), and the Inattentiveness subscale score of 20.8 (±4.3) at baseline improved to 6.6 (±3.5) at the end of the open-label period. The mean changes during this period were 26.0, 12.0, and 14.0 for ADHD-RS total score, hyperactivity-impulsivity
score, and inattentiveness score, respectively. Thirty-four of the 39 (87.2%) evaluable participants with ADHD-RS data were considered responders (defined as at least a 50% improvement in ADHD-RS total score) at the end of the open-label phase. The responder cohort (n = 34) had a statistically significantly lower mean SKAMP-combined score at 4-hr post-dose when receiving MEROS than when receiving placebo. The LS mean of the treatment difference was −11.88 (p < .0001). At baseline, 63.3% of participants were considered moderately ill, with responses ranging from mildly ill (2.3%) to severely ill (9.1%) as rated by investigator-scored CGI-S. Twenty-five percent of participants were considered markedly ill. At the end of the open-label period, most
Downloaded from jad.sagepub.com by guest on November 14, 2015
7
Robb et al.
Figure 3. Mean ADHD Rating Scale (ADHD-RS) total scores in the open-label phase.
Figure 4. Mean Clinical Global Impression-Severity (CGI-I) scores in the open-label phase.
participants were considered borderline ill (51.3%) and responses ranged from normal (20.5%) to moderately ill (2.6%); no participants were considered either markedly ill or severely ill. CGI-S scores decreased from a mean of 4.4 at baseline to a mean of 2.1 during this phase of the trial (Figure 4), and mean CGI-I scores improved from 2.8 at baseline to 1.4 during the same period (Figure 5). At the end of the open-label period, all participants were considered either much improved (41%) or very much improved (59%), as measured by CGI-I.
Safety Forty-two participants experienced a TEAE and 39 experienced a TEAE related to study medication during the
open-label phase (Table 3). Severe TEAEs occurred in 3 participants and 2 led to study discontinuation. One withdrawal occurred due to severe affect lability after receiving the study medication for 18 days and the other from severe aggression and taking MEROS for 9 days. Both participants recovered on the same day the AE was experienced without sequelae. The third severe TEAE was initial insomnia but did not lead to study withdrawal. The duration of the severe initial insomnia was 1 night. The severity of the event was then downgraded to mild and persisted for an additional 37 days when it resolved. The most common AEs reported during the open-label phase were decreased appetite (56%), upper abdominal pain (42%), affect lability (27%), initial insomnia (22%), insomnia (18%), and headache (18%).
Downloaded from jad.sagepub.com by guest on November 14, 2015
8
Journal of Attention Disorders
Figure 5. Mean Clinical Global Impression-Improvement (CGI-I) scores in the open-label phase. Table 3. Summary of Treatment-Emergent Adverse Events During Open-Label Phase (≥5%). Total (N = 45) Adverse event Any treatment-emergent adverse event Decreased appetite Abdominal pain (upper) Affect lability Insomnia (initial) Insomnia Headache Irritability Vomiting Upper respiratory tract infection Logorrhea Fatigue Diarrhea Aggression Dizziness Cough Flushing
n (%) 42 (93.3) 25 (55.6) 19 (42.2) 12 (26.7) 10 (22.2) 8 (17.8) 8 (17.8) 6 (13.3) 5 (11.1) 5 (11.1) 4 (8.9) 4 (8.9) 3 (6.7) 3 (6.7) 3 (6.7) 3 (6.7) 3 (6.7)
During the double-blind phase, 11 (24.4%) of participants experienced a TEAE while receiving MEROS and 5 (11.1%) had a TEAE while receiving placebo. AEs considered related to study medication occurred in 6 (13.3%) participants during MEROS treatment and 3 (6.7%) participants during placebo treatment. Affect lability was the only TEAE reported in ≥5% of participants during the doubleblind phase, with 8.9% of participants reporting this during treatment with MEROS and 2.2% while taking placebo. There were no deaths or serious AEs reported during the study.
A majority of participants had normal findings at screening on hematology and chemistry parameters and per physical exam. All participants were deemed medically suitable for participation in the study. A physical exam was also conducted at the final study visit and no unexpected studyrelated findings were noted. Evaluation of vital signs showed mean changes in systolic blood pressure from baseline to the final three visits of the study of 3.4 mmHg, 1.5 mmHg, and 3.5 mmHg, respectively. The mean changes in diastolic blood pressure during the same period were 6.0 mmHg, 4.9 mmHg, and 3.0 mmHg, respectively. The mean increases in pulse from baseline to the final three visits of the trial were 9.3 bpm, 6.9 bpm, and 9.2 bpm, respectively. There were 9 participants with post-baseline pulse values greater than 110 bpm and 10 participants with an increase from baseline ≥25 bpm. There was 1 participant with a post-baseline systolic blood pressure greater than the 95th percentile, and none with a diastolic blood pressure postbaseline value of >95th percentile. Changes in height, weight, and BMI were small and not considered clinically significant. The mean change in BMI from baseline to the end of the study was 0.13 kg/m2. There were no participants with any occurrences of suicidal ideation or behavior during the study.
Discussion This study is the first randomized, double-blind, placebocontrolled cross-over design to evaluate the efficacy, safety, and tolerability of a long-acting liquid formulation of methylphenidate (MEROS) in children aged 6 to 12 years. While the primary efficacy has been reported in a separate manuscript (Wigal et al., 2013), this article details the secondary efficacy outcomes including ADHD-RS, CGI-S and CGI-I, and PERMP scores.
Downloaded from jad.sagepub.com by guest on November 14, 2015
9
Robb et al. The laboratory classroom protocol is a well-studied measure that allows precise determination of onset and duration of efficacy of ADHD medications (Wigal & Wigal, 2006), and which has been used to study many other long-acting methylphenidate products (McGough et al., 2006; Pelham et al., 2001, 2011; Quinn et al., 2004), including MEROS (Wigal et al., 2013). Each child in this cross-over trial served as his or her own control, and ratings (using validated subjective scales, such as the SKAMP in the context of group activities between teams of students and individualized seatwork, and objective measures such as the PERMP math test) were recorded on optimal drug dose and placebo. This design allows more information to be gleaned from a smaller total subject population. It also allows comparisons to be made in each individual, both on and off medication, and the relative impairment observed in each case. The secondary outcomes of this study range from very specific functional measures, such as PERMP and ADHD-RS, to more global measures (CGI-I and CGI-S Scales). The PERMP provides an indirect measure of functionality in an academic setting. The child attempts to solve a series of math problems in a 10-min period and is scored on number of problems attempted (speed of calculation) and number correct (accuracy). This test is relevant for children with ADHD who frequently struggle with initiating and/or finishing their work (e.g., homework) and who may make multiple mistakes if rushing to finish. The PERMP math test utilized in the double-blind phase provides an objective measure of the effects of stimulant treatment in children with ADHD. These results demonstrated that children with ADHD attempted more math problems and completed more math problems correctly when treated with an individually optimized dose of MEROS compared with placebo treatment. The results of this trial show improvement in symptoms of ADHD from baseline to the end of the study, as evidenced by improvement in rating scale scores during both the open-label and double-blind portions of the trial. Participants showed a significant improvement in ADHD symptoms on the ADHD-RS utilized in the open-label phase of the study, as well as improvement in global functioning as measured by the CGI-I and CGI-S rating scales. The double-blind measures corroborated these findings by demonstrating improvement in attention and behavior under optimally dosed MEROS compared with placebo treatment, measured by the SKAMP-combined score. Following administration of MEROS, this significant effect began at the first post-dose time point included in the study (45 min) and continued through 12 hr, the last time point included in the study after dosing (Wigal et al., 2013). One of the secondary outcome measures in the trial, the ADHD-RS, yields a total/composite score, as well as subscores for both inattention and hyperactive/impulsive
symptoms individually. This universal rating scale has been used in studies of other stimulants to demonstrate efficacy in the treatment of ADHD (Coghill et al., 2013; Wigal et al., 2011) and is frequently employed to show change between baseline and end of study in the active treatment group. The participants in this study of MEROS had a pre-treatment baseline ADHD-RS total score mean of 39.3 (±7.6), with a mean reduction of 26.0 points total (12.0 for hyperactive/impulsive and 14.0 for inattentive symptoms) by the end of the open-label period. Therefore, this new formulation of methylphenidate was effective in treating both inattentive and hyperactive/impulsive symptoms of ADHD in the present study. In many of the early ADHD trials, a “responder” was defined as 30% reduction in ADHD-RS and CGI-I of 1 or 2 (much or very much improved). In this trial, the bar for response was raised to a 50% reduction in ADHD-RS during the open-label period. Despite the higher criteria required for responders in this trial, the response rate was 87.2% (34 of the 39 children who completed the trial). These results validate this long-acting liquid methylphenidate as another effective extended-release formulation for the treatment of ADHD. The CGI-I and CGI-S Scales are frequently used in clinical trials of psychiatric medications to give a clinician-rated assessment of disease severity at entry into a trial, and again at the end of a study. At the onset of this trial, most of the children were considered moderately to markedly ill. At the end of the 6 week, open-label titration phase, mean CGI-S scores had improved and were within the classification of borderline to mildly ill. All of the children (100%) were much or very much improved on the CGI-I by the end of the same period. The TEAEs in both the open-label and double-blind segments of the trial were anticipated, and in line with the use of stimulants in the school-age population (Quillivant XR prescribing information, 2013). These include the more common TEAEs of abdominal pain, loss of appetite, initial and any insomnia. Affect lability, a relatively common TEAE in this trial, was also the only TEAE with an incidence ≥5% in the double-blind phase. Three severe TEAEs were noted in the study, and one case each of aggression and affect lability led to study discontinuation; there were no serious TEAEs and no cases of suicidal ideation or behavior noted during this study. Alterations in vital signs were noted in both pulse and blood pressure, but were not clinically significant and did not lead to discontinuation. Although this trial does not report on a new class of medication for ADHD, it does describe a novel delivery system and onset and duration of action for a well-known active agent. Despite the availability of other formulations that provide long-acting alternatives, a group of children and older adolescents exist who cannot or will not swallow pills, and will not tolerate sprinkles or a transdermal patch.
Downloaded from jad.sagepub.com by guest on November 14, 2015
10
Journal of Attention Disorders
Previously, these patients may have opted for a liquid or chewable formulation only available in short-acting formulations, and were therefore potentially burdened with the limitations of multiple daily dosing. With the advent of MEROS, there is an effective long-acting oral liquid preparation for those who cannot tolerate other options, but still require full-day symptom coverage.
Limitations Although this trial demonstrates efficacy of the first longacting liquid methylphenidate, results were obtained from a small number of participants. The protocol excluded many common psychiatric and medical comorbidities, including severe oppositional defiant disorder, therefore, results may not generalize to the overall population of patients with ADHD. Participants who could not do basic timed math were also excluded, which may have prevented younger children who had more severe symptoms from participating in the study; no teenagers or adults were studied. In addition, the period of drug treatment was brief (6-8 weeks), as such, no conclusions regarding long-term safety and efficacy of MEROS can be drawn. In this trial, 87% of participants had a 50% or greater reduction of ADHD symptoms on the investigator-rated ADHD-RS. These values are higher than previously reported in double-blind placebo-controlled trials of participants with ADHD. In these studies, the non-response to a single stimulant has been reported to be 25% to 35% (Pliszka et al., 2007). Several factors may have influenced the higher rate of response with MEROS. This study included an open-label design during dose optimization and excluded many comorbid diagnoses. The small number of sites and raters conducting the study may have decreased variability in the ratings, making it difficult to compare MEROS results with those of larger trials.
Conclusion In this trial, MEROS was shown to be safe and effective for the treatment of ADHD (Wigal et al., 2013). MEROS also demonstrated efficacy on other measures of the trial, including the ADHD-RS, which captures the 18 symptoms of inattention and hyperactivity/impulsivity, and the PERMP, an evaluation of ability to adequately perform math in the classroom. Additional studies of MEROS in younger and developmentally delayed children with ADHD are needed to determine if these or other populations could benefit from the flexible delivery of a long-acting liquid formulation of methylphenidate. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this
article: Adelaide S. Robb has been an Advisory Board member for Bristol-Myers Squibb, Eli Lilly and Company, Lundbeck, Otsuka, and Pfizer Inc.; served on a Speakers Bureau for Takeda, Otsuka, and Pfizer Inc.; received research support from BristolMyers Squibb, Forest Laboratories Inc., GlaxoSmithKline, Janssen Pharmaceuticals, Inc., Lundbeck, Merck/ScheringPlough Pharmaceuticals, National Institute of Child Health and Human Development (NICHD), Otsuka, and Pfizer Inc.; received travel support from American Academy of Child and Adolescent Psychiatry (AACAP) and Pfizer Inc.; and owns stocks in Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Inc., and Pfizer Inc. Robert L. Findling receives or has received research support, acted as a consultant, and/or served on a speaker’s bureau for Alexza Pharmaceuticals, American Academy of Child & Adolescent Psychiatry, American Physician Institute, American Psychiatric Press, AstraZeneca, Bracket, Bristol-Myers Squibb, Clinsys, Cognition Group, Coronado Biosciences, Dana Foundation, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson & Johnson, KemPharm, Lilly, Lundbeck, Merck, NIH, Novartis, Noven, Otsuka, Oxford University Press, Pfizer, Physicians Postgraduate Press, Rhodes Pharmaceuticals, Roche, Sage, Seaside Pharmaceuticals, Shire, Stanley Medical Research Institute, Sunovion, Supernus Pharmaceuticals, Transcept Pharmaceuticals, Validus, and WebMD. Ann C. Childress has been a consultant to Novartis, Shionogi, NextWave Pharmaceuticals, Shire Pharmaceuticals, and Pfizer Inc.; a speaker for Novartis, Shionogi, GlaxoSmithKline, and Shire Pharmaceuticals; and received research support from Novartis, Shionogi, NextWave Pharmaceuticals, Shire Pharmaceuticals, Abbott Laboratories, Forest Laboratories, Johnson & Johnson Pharmaceutical Research & Development, LLC, Lilly USA, Ortho-McNeil Janssen Scientific Affairs, Otsuka Pharmaceutical Company Ltd, Pfizer Inc., Rhodes Pharmaceuticals LP, Sepracor Inc., Somerset Pharmaceuticals, Neos, and Theravance. Sharon B. Wigal receives or has received research support, acted as a consultant, been an Advisory Board member, and/or served on a Speakers Bureau for Addrenex Pharmaceuticals, Eli Lilly and Company, Forest Pharmaceuticals, McNeil Consumer & Specialty Pharmaceuticals, NextWave Pharmaceuticals, NIMH, Noven, NuTec Pharma Ltd., Otsuka, Inc., Pfizer Inc., Purdue, Quintiles, Rho, Rhodes Pharmaceuticals, Shionogi Inc., Shire US Inc., Sunovion, Taisho Pharmaceutical Co., and Tris Pharma, Inc. Sally A. Berry and Heidi W. Belden were employed by NextWave Pharmaceuticals, which was acquired by Pfizer Inc. Both are now consultants to Pfizer Inc., and as such, were paid contractors to Pfizer Inc. in the development of this manuscript. Adelaide S. Robb, Robert L. Findling, Ann C. Childress, and Sharon B. Wigal have declared no potential conflicts of interests with respect to the authorship and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was sponsored by NextWave Pharmaceuticals, a wholly owned subsidiary of Pfizer Inc. Writing and editorial support for this manuscript was provided by Anne Jakobsen, MSc, of Engage Scientific and funded by Pfizer Inc.
Downloaded from jad.sagepub.com by guest on November 14, 2015
11
Robb et al. References American Academy of Pediatrics. (2011). ADHD: Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics, 128, 1007-1020. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC: Author. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. Centers for Disease Control and Prevention. (2010). Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children—United States, 2003 and 2007. Morbidity and Mortality Weekly Report, 59, 1439-1443. Childress, A. C., & Berry, S. A. (2010). The single-dose pharmacokinetics of NWP06, a novel extended-release methylphenidate oral suspension. Postgraduate Medicine, 122, 35-41. Coghill, A., Banaschewski, T., Lecendreux, M., Soutullo, C., Johnson, M., & Zuddas, A., . . . Squires, L. (2013). European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder. European Neuropsychopharmacology, 23, 1208-1218. DuPaul, G. J., Power, T. J., Anastopoulos, A. D., & Reid, R. (1998). ADHD rating scales-IV: Checklists, norms and clinical interpretation. New York, NY: Guilford. Guy, W. (1976). Clinical global impressions. In ECDEU assessment manual for psychopharmacology (pp. 218-222). Rockville, MD: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch. Intuniv prescribing information. (2013). Wayne, PA: Shire US. Kapvay prescribing information. (2013). Florham Park, NJ: Shionogi. Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., . . .Ryan, N. (1997). Schedule for affective disorders and schizophrenia for school-age children–present and lifetime version (K-SADS- PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 980-988. Kessler, R. C., Adler, L., Barkley, R., Biederman, J., Conners, C. K., Demler, O., . . .Zaslavsky, A. M. (2006). The prevalence and correlates of adult ADHD in the United States: Results from the National Comorbidity Survey Replication. American Journal of Psychiatry, 163, 716-723. McGough, J. J., Wigal, S. B., Abikoff, H., Turnbow, J. M., Posner, K., & Moon, E. (2006). A randomized, double-blind, placebocontrolled, laboratory classroom assessment of methylphenidate transdermal system in children with ADHD. Journal of Attention Disorders, 9, 476-485. National Heart, Lung, and Blood Institute, National Institutes of Health. (2005). The fourth report on the diagnosis, evaluation, and treatment of blood pressure in children and adolescents (NIH Publication No. 05-5267). Retrieved from http:// www.nhlbi.nih.gov/health/prof/heart/hbp/hbp_ped.pdf National Institute of Mental Health, National Institutes of Health. (2012). Attention deficit hyperactivity disorder. Retrieved
from http://www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml Pelham, W. E., Gnagy, E. M., Burrows-Maclean, L., Williams, A., Fabiano, G. A., Morrisey, S. M., . . .Morse, G. D. (2001). Once-a-day Concerta methylphenidate versus three-timesdaily methylphenidate in laboratory and natural settings. Pediatrics, 107, E105. Pelham, W. E., Waxmonsky, J. G., Schentag, J., Ballow, C. H., Panahon, C. J., Gnagy, E. M., . . .González, M. A. (2011). Efficacy of a methylphenidate transdermal system versus t.i.d. methylphenidate in a laboratory setting. Journal of Attention Disorders, 15, 28-35. Pliszka, S. R., Bernet, W., Bukstein, O., Walter, H. J., Arnold, V., Beitchman, J., . . .Stock, S. (2007). The American Academy of Child and Adolescent Psychiatry (AACAP) Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/ hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 894-921. Posner, K., Oquendo, M. A., Gould, M., Stanley, B., & Davies, M. (2007). Columbia Classification Algorithm of Suicide Assessment (C-CASA): Classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants. American Journal of Psychiatry, 164, 1035-1043. Quillivant XR prescribing information. (2013). New York, NY: Pfizer. Quinn, D., Wigal, S., Swanson, J., Hirsch, S., Ottolini, Y., Dariani, M., . . .Cooper, T. (2004). Comparative pharmacodynamics and plasma concentrations of d-threo-methylphenidate hydrochloride after single doses of d-threo-methylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in a double-blind, placebo-controlled, crossover laboratory school study in children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 43, 1422-1429. Strattera prescribing information. (2013). Indianapolis, IN: Eli Lilly. Wigal, S. B., Childress, A. C., Belden, H. W., & Berry, S. A. (2013). NWP06, an extended-release oral suspension of methylphenidate, improved attention-deficit/hyperactivity disorder symptoms compared to placebo in a laboratory classroom study. Journal of Child and Adolescent Psychopharmacology, 23, 1-8. Wigal, S. B., & Wigal, T. L. (2006). The laboratory school protocol: Its origin, use, and new applications. Journal of Attention Disorders, 10, 92-111. Wigal, S. B., Wigal, T., Schuck, S., Brams, M., Williamson, D., Armstrong, R. B., & Starr, H. L. (2011). Academic, behavioral, and cognitive effects of OROS methylphenidate on older children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 21, 121-131.
Author Biographies Adelaide S. Robb, MD, is a professor of psychiatry and pediatrics at the George Washington University School of Medicine. She is the director of psychiatry research at Children’s National Medical Center and has published articles on ADHD, anxiety, mood, and psychotic disorders.
Downloaded from jad.sagepub.com by guest on November 14, 2015
12
Journal of Attention Disorders
Robert L. Findling, MD, MBA, is a professor of psychiatry at Johns Hopkins University. He is the director of Child & Adolescent Psychiatry at Johns Hopkins University and is the vice president of psychiatric services and research at the Kennedy Krieger Institute.
Sally A. Berry, MD, PhD, was the chief medical officer at NextWave Pharmaceuticals and is now a consultant to Pfizer Inc.
Ann C. Childress, MD, is a clinical assistant professor of family medicine at the University of Nevada School of Medicine and president of the Center for Psychiatry and Behavioral Medicine, Inc.
Sharon B. Wigal, PhD, was a professor of pediatrics at the University of California, Irvine when she conducted the reasearch. She is currently the president and director of Clinical Services at AVIDA Inc.
Heidi W. Belden, PharmD, was employed as medical director by NextWave Pharmaceuticals and is now a consultant to Pfizer Inc.
Downloaded from jad.sagepub.com by guest on November 14, 2015
