Laboratory Classroom Setting Research Articles

5.1 D-Amphetamine Transdermal System (d-ATS) in the Treatment of Children and Adolescents With ADHD: Secondary Endpoint Results From a Phase 2 Trial

Amphetamines are a first-line treatment for ADHD. The dextroamphetamine transdermal system (d-ATS) was developed as an alternative to oral amphetamine formulations. A randomized controlled trial of d-ATS in children and adolescents with ADHD was conducted, and its primary and key secondary endpoints were met. Here, we report the secondary endpoints of the study, further assessing the efficacy and safety of d-ATS. This study comprised a 5-week, open-label dose-optimization period (DOP) followed by a 2-week, randomized, crossover double-blind treatment period (DBP). All eligible subjects received d-ATS 5 mg/9 hours (hr) and were evaluated weekly for possible dose increase to 10 mg/9 hr, 15 mg/9 hr, and 20 mg/9 hr (DOP). Once reached, the optimal dose was maintained for the DOP and utilized for the DBP. The secondary objectives for this study included an assessment of efficacy via Permanent Product Measure of Performance-Attempted and -Correct (PERMP-A, PERMP-C), ADHD Rating Scale-IV (ADHD-RS-IV), Conners’ Parent Rating Scale–Revised: Short Form (CPRS–R:S), and Clinical Global Impression (CGI) scores in a laboratory classroom setting. A mixed-model repeated-measures (MMRM) approach was used to analyze efficacy. Safety assessments included treatment-emergent adverse events (TEAEs) and dermal safety. In total, 110 subjects were enrolled in the DOP, and 106 subjects were randomized in the DBP. Subjects receiving d-ATS demonstrated significant improvement vs placebo in PERMP-A and -C scores in the DBP consistently from 2 to 12 hours postdose (p < 0.001 for all timepoints). ADHD-RS-IV total scores improved during the DOP and improved further during the DBP, with a least-squares (LS) mean (95% CI) difference for d-ATS vs placebo of –13.1 (–16.2 to –10.0; p < 0.001). Significant differences between placebo and d-ATS in the DBP were also observed for the CPRS-R:S and CGI scales (p < 0.001). Most TEAEs were mild or moderate, with 3 TEAEs (abdominal pain, irritated mood, and appetite loss) leading to study discontinuation in the DOP and none in the DBP. No patients discontinued due to dermal reactions across both phases. d-ATS was effective in the treatment of ADHD in children and adolescents, meeting its primary endpoint (reported elsewhere) and all secondary endpoints. d-ATS was safe and well tolerated, with minimal dermal reactions.

Efficacy and Safety of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: To determine the efficacy and safety of amphetamine extended-release oral suspension (AMPH EROS) in the treatment of attention-deficit/hyperactivity disorder (ADHD) in a dose-optimized, randomized, double-blind, parallel-group study.Methods: Boys and girls aged 6 to 12 years diagnosed with ADHD were enrolled. During a 5-week, open-label, dose-optimization phase, patients began treatment with 2.5 or 5 mg/day of AMPH EROS; doses were titrated until an optimal dose (maximum 20 mg/day) was reached. During the double-blind phase, patients were randomized to receive treatment with either their optimized dose (10–20 mg/day) of AMPH EROS or placebo for 1 week. Efficacy was assessed in a laboratory classroom setting on the final day of double-blind treatment using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP) test. Safety was assessed measuring adverse events (AEs) and vital signs.Results: The study was completed by 99 patients. The primary efficacy endpoint (change from predose SKAMP-Combined score at 4 hours postdose) and secondary endpoints (change from predose SKAMP-Combined scores at 1, 2, 6, 8, 10, 12, and 13 hours postdose) were statistically significantly improved with AMPH EROS treatment versus placebo at all time points. Onset of treatment effect was present by 1 hour postdosing, the first time point measured, and duration of efficacy lasted 13 hours postdosing. PERMP data mirrored the SKAMP-Combined score data. AEs (>5%) reported during dose optimization were decreased appetite, insomnia, affect lability, upper abdominal pain, mood swings, and headache.Conclusion: AMPH EROS was effective in reducing symptoms of ADHD and had a rapid onset and extended duration of effect. Reported AEs were consistent with those of other extended-release amphetamine products.

6.15 Dasotraline Efficacy Throughout the Day in Children With Attention-Deficit/Hyperactivity Disorder (ADHD): Results of a Phase Three, Randomized, Double-Blind, Placebo-Controlled Study in a Laboratory Classroom Setting

6.15 Dasotraline Efficacy Throughout the Day in Children With Attention-Deficit/Hyperactivity Disorder (ADHD): Results of a Phase Three, Randomized, Double-Blind, Placebo-Controlled Study in a Laboratory Classroom Setting

Med Check

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessMed CheckNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:20 Jul 2017https://doi.org/10.1176/appi.pn.2017.7a21FDA Approves Two-Month Aripiprazole Injectable The Food and Drug Administration (FDA) has approved a two-month formulation of Aristada (aripiprazole lauroxil), a long-acting injectable antipsychotic for the treatment of schizophrenia. Aristada is currently approved in both once monthly (at 441 mg, 662 mg, or 882 mg) and once every six weeks (at 882 mg) injections. The new two-month injection will be dosed at 1,064 mg.“As the first and only long-acting atypical antipsychotic approved in three dosing durations and with the ability to initiate treatment at any dose or duration, Aristada provides a range of options to help clinicians tailor treatment to the individual needs of their patients,” said Elliot Ehrich, M.D., executive vice president for research and development of Aristada manufacturer Alkermes, in a press release.The efficacy of the longer-form injectable was demonstrated in a randomized, open-label trial of 140 individuals with stable schizophrenia. The study showed that patients who received the 1,064 mg dose every two months had similar safety and pharmacokinetic profiles as those receiving 441 mg of aripiprazole monthly or 882 mg every six weeks. Endo Pharmaceuticals Pulls Opana From Market at FDA’s RequestOn July 6, Endo Pharmaceuticals agreed to voluntarily remove its opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market. The removal followed a formal withdrawal request by the FDA in June. “This is the first time the agency has taken steps to remove a currently marketed opioid pain medication from sale due to the public health consequences of abuse,” the agency stated in a press release. The agency based its decision on postmarketing data that revealed that Opana ER was being abused via injection following the product’s reformulation. (Opana ER was reformulated to make the drug resistant to manipulation for abuse by snorting or injecting.) Injection abuse of the medication has been associated with a serious outbreak of HIV and hepatitis C, as well as cases of the blood disorder thrombotic microangiopathy, according to the agency. In March, a joint FDA advisory committee voted 18-8 that the benefits of reformulated Opana ER no longer outweighed its risks. Endo iterated in a statement that despite the voluntary withdrawal, it remains confident in data demonstrating Opana’s safety, efficacy, and favorable risk-benefit profile when used as intended. FDA Approves First XR Orally Disintegrating Methylphenidate TabletThe FDA in June approved Cotempla XR-ODT, the first extended-release, orally disintegrating methylphenidate tablet for the treatment of attention-deficit/hyperactivity disorder (ADHD) in pediatric patients aged 6 to 17. The approval of Cotempla XR-ODT was based in part on the results of a phase 3 clinical trial of children in a laboratory classroom setting, according to Neos Therapeutics Inc., the manufacturer of the medication. The study found that children who took Cotempla XR-ODT experienced significantly improved ADHD symptoms compared with placebo; effects were evident after one hour and lasted through 12 hours. The adverse-event profile for Cotempla XR-ODT was consistent with the established safety profile for other extended-release methylphenidate products.Cotempla XR-ODT will be commercially available beginning this fall, according to Neos. ■ ISSUES NewArchived

Efficacy, Safety, and Tolerability of an Extended-Release Orally Disintegrating Methylphenidate Tablet in Children 6-12 Years of Age with Attention-Deficit/Hyperactivity Disorder in the Laboratory Classroom Setting.

Objective: Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) represent a new technology for MPH delivery. ODTs disintegrate in the mouth without water and provide a pharmacokinetic profile that is consistent with once-daily dosing. This study sought to determine the efficacy, safety, and tolerability of this novel MPH XR-ODT formulation in school-age children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting.Methods: Children aged 6–12 years with ADHD (n = 87) were enrolled in this randomized, multicenter, double-blind, placebo-controlled, parallel, laboratory classroom study. The MPH XR-ODT dose was titrated to an optimized dose during a 4-week open-label period and maintained on that dose for 1 week. Participants (n = 85) were then randomized to receive their optimized dose of MPH XR-ODT or placebo once daily for 1 week (double blind), culminating in a laboratory classroom testing day. Efficacy was evaluated using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Attention, Deportment, and Combined scores along with Permanent Product Measure of Performance (PERMP; Attempted and Correct) assessments. Onset and duration of drug action were also evaluated as key secondary endpoints. Safety assessments included adverse events (AEs), physical examinations, electrocardiograms (ECGs), and the Columbia Suicide Severity Rating Scale (C-SSRS).Results: The average SKAMP-Combined score on the classroom study day was significantly better for the MPH XR-ODT group (n = 43) than for the placebo group (n = 39; p < 0.0001). The effect was evident at 1 hour and lasted through 12 hours postdose. The average SKAMP-Attention, SKAMP-Deportment, PERMP-A, and PERMP-C scores were indicative of significantly greater ADHD symptom control for the MPH XR-ODT group. The most common AEs reported were decreased appetite, upper abdominal pain, headache, insomnia, upper respiratory tract infection, affect lability, irritability, cough, and vomiting.Conclusions: MPH XR-ODT was effective and well tolerated for the treatment of children with ADHD in a laboratory classroom setting.Clinical Trial Registry: NCT01835548 (ClinicalTrials.gov).

Incorporating Fermentation into Undergraduate Laboratory Courses

Laboratory courses in universities have a responsibility to introduce current research practices and trends in scientific research to adequately prepare students for work in the field. One such research practice gaining popularity in recent years is that of green chemistry. Since the 1960s, increasing concern over the release of toxic chemicals into the environment has led to a push for more environmentally responsible chemistry. A growing faction of chemists has begun to adopt methods to eliminate chemical waste and support green chemistry. Fermentation is an ideal technique to demonstrate environmentally sustainable chemistry in an undergraduate laboratory class. Fermentation of complex natural products, as opposed to traditional organic synthesis, is beneficial as it supports a number of principles of green chemistry; it is conducted at ambient temperature and pressure, uses inexpensive and innocuous materials, makes use of renewable resources, and does not require a fume hood. Skills implemented during fermentation can be easily taught to upper-level Chemistry and Biochemistry undergraduate students, who typically have limited exposure to complex natural products in their coursework. Such a course would be interdisciplinary in nature, incorporating fungal biology and metabolism as well as organic chemistry. Students would learn a variety of skills, including growth media selection and preparation, inoculation of fungal cultures, extraction of natural products, and purification and characterization of metabolites. Experiments of this nature would allow for discussions of several areas of research: green chemistry, natural products and their application to medicine, identification of functional groups in complex molecules by spectroscopy, and introduction to biochemistry and metabolism. Roquefortine C, a prenylated indole alkaloid readily produced by a variety of species of Penicillia, is an excellent candidate for demonstrating fermentation in a laboratory classroom setting, owing to its ease of purification from other metabolites and its unique structural features.

Training TAs in scientific teaching for the human physiology and anatomy laboratory

SCIENTIFIC TEACHING (ST) is a method developed nearly a decade ago by Handelsman and colleagues (2) in which instructional practice in undergraduate science is based on current educational research findings and established best practices. The ST approach uses a process in which all students, especially those in courses with large enrollments, are more actively engaged in learning compared with traditional lecture-based courses. Unique to ST is an active learning and inquiry-based framework that aims to ensure that the needs of students with diverse learning styles and backgrounds are addressed. Furthermore, students’ ongoing progress toward achieving the course learning goals can be assessed dynamically (e.g., via in-class responses while students are engaged in the process of learning) and at higher cognitive levels (e.g., beyond rote memorization), as demonstrated by Bloom’s taxonomy of learning domains (1). When integrated into a curriculum, ST methods have been shown to improve student knowledge retention because participation in these structured activities and group discussions has been shown to facilitate the identification of misconceptions, construction of new knowledge, and development of critical-thinking skills (9). Implementation of a variety of structured activities also appeals to a broader variety of learning styles (9). In 2010, we incorporated the ST approach into the lecture portion of our Enhanced Human Anatomy and Physiology course at the University of Connecticut. Because this approach is particularly well suited to the laboratory classroom setting where an interactive approach is much more easily implemented, in 2011 we also adopted the ST approach into the laboratory component of our course. To facilitate this process as well as to extend the impact of an individual instructor, we trained a cohort of graduate teaching assistants (TAs) to use this teaching approach in multiple sections of inquiry-based laboratory and regular laboratory settings. Despite a few articles that address student-centered TA training in chemistry laboratory courses (3, 4), there are no published reports evaluating the application of ST to graduate student TA training in physiology. What follows is an examination of the effects that training TAs in ST had on student attitudes about 1) their perceived laboratory learning experience and 2) their perceived integration of what is learned in the laboratory to their overall understanding of course content.

Teaching Receiver Operating Characteristic Analysis: An Interactive Laboratory Exercise

Despite its fundamental importance in the evaluation of diagnostic tests, receiver operating characteristic (ROC) analysis is not easily understood. The purpose of this project was to create a learning experience that resulted in an intuitive understanding of the basic principles of ROC analysis. An interactive laboratory exercise was developed for a class about radiology testing taught within a clinical epidemiology course between 2000 and 2009. The physician students in the course were clinical fellows from various medical specialties who were enrolled in a graduate degree program in clinical investigation. For the exercise, the class was divided into six groups. Each group interpreted radiographs from a set of 50 exams of the peripheral skeleton to determine the presence or absence of an acute fracture. Data from the class were pooled and given to each student. Students calculated the area under the ROC curve (AUC) corresponding to overall class performance. A binormal ROC curve was also fitted to the data from each class year. The laboratory exercise was conducted for 8 years with approximately 20-30 students per year. The mean AUC over the eight laboratory classes was 0.72 with a standard deviation of 0.08 (range, 0.60-0.85). With some simplifications in design, an observer study can be conducted in a laboratory classroom setting. Participatory data collection promotes the intuitive understanding of ROC analysis principles.

A Randomized, Double-Blind Study of 30 Versus 20 mg Dexmethylphenidate Extended-Release in Children With Attention-Deficit/Hyperactivity Disorder

The objective of this study was to evaluate the safety and efficacy of dexmethylphenidate extended-release (d-MPH-ER) 30 versus 20 mg in children with attention-deficit/hyperactivity disorder (ADHD) in a 12-hour laboratory classroom setting. In a randomized, double-blind, 3-period × 3-treatment, crossover study, children aged 6 to 12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-diagnosed ADHD previously stabilized on MPH (40-60 mg/d) or D-MPH (20-30 mg/day) [corrected] were randomized to receive D-MPH-ER 20 mg/day, 30 mg/day, [corrected] or placebo for 7 days each. Primary efficacy measurements were change in the average SKAMP-Combined [corrected] score from predose to 10, 11, and 12 hours postdose [Avg(10-12)] between 30 mg [corrected] and 20 mg D-MPH-ER. Safety was assessed by adverse events, (AEs), [corrected] vital sign monitoring, and ECGs. [corrected] A total of 165 children were randomized, and 162 included in the intent-to-treat analysis. Mean Avg (10-12) change from pre-dose [corrected] in SKAMP-Combined score was significantly greater for D-MPH-ER 30 mg (-4.47) compared with D-MPH-ER 20 mg (-2.02; P = 0.002). Most common adverse events (≥ 3% in any group) were decreased appetite (6.1%, 4.9%, and 0%), headache (4.3%, 4.3%, and 1.9%), abdominal pain (3.7%, 3.1%, and 3.1%), and tachycardia (1.2%, 3.1%, and 0.6%) for D-MPH-ER 30 mg, D-MPH-ER 20 mg, and placebo, respectively). Significantly greater improvement in ADHD symptoms was noted with D-MPH-ER 30 mg compared with D-MPH-ER 20 mg at hours 10 through 12. Tolerability was comparable between doses. Dexmethylphenidate extended-release 30-mg dose may provide further benefit to patients who do not maintain optimal symptom control later in the day with D-MPH-ER 20 mg.

Effects of OROS Methylphenidate on Academic, Behavioral, and Cognitive Tasks in Children 9 to 12 Years of Age With Attention-Deficit/Hyperactivity Disorder

To assess effects of OROS methylphenidate on cognitive and academic tasks in 9 to 12 year olds with attention-deficit/hyperactivity disorder (ADHD). A double-blind, within-subject, crossover design was used to compare OROS methylphenidate with placebo in a laboratory classroom setting on several cognitive and academic tasks for 68 children who met randomization criteria. Performance on the following measures was significantly better when children received individually optimized OROS methylphenidate than placebo: math fluency and accuracy measured by the Permanent Product Math Test, ADHD symptoms observed in the laboratory setting, computerized indices of attention and impulsivity as measured by the Test of Variables of Attention (TOVA), and visual-spatial working memory (Finger Windows Backwards). Study medication was well tolerated; adverse events were generally consistent with previous reports. OROS methylphenidate improves performance on measures of attention and vigilance, behavior, and working memory in a laboratory school setting in 9 to 12 year olds with ADHD.

A Double-Blind, Randomized, Placebo/Active Controlled Crossover Evaluation of the Efficacy and Safety of Ritalin®LA in Children with Attention-Deficit/Hyperactivity Disorder in a Laboratory Classroom Setting

The primary objective of this study was to demonstrate efficacy of Ritalin(®) LA 20 mg by showing superiority to placebo and noninferiority to Medikinet(®) Retard in a laboratory classroom setting. Secondary objectives included safety/tolerability and further efficacy parameters. A total of 147 children with attention-deficit/hyperactivity disorder (ADHD) diagnosed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and aged 6-14 (81% males) and known to be methylphenidate (MPH) responders were enrolled in this multicenter, double-blind, randomized, placebo/active-controlled, three-period (7 days each) crossover study. The Swanson, Kotlin, Agler, M-Flynn, and Pelham (SKAMP) scale was used for efficacy ratings. The mean of SKAMP Combined ratings performed at 10:30 a.m., at 12:00 a.m., and at 1:30 p.m. was defined as the primary parameter. In all, 146 patients completed all treatment periods. Intensity and frequency of adverse events were comparable between the two formulations. Ritalin(®) LA demonstrated superiority compared to placebo (p<0.0001). The observed difference in the SKAMP scores between Ritalin(®) LA and Medikinet(®) Retard between the hours 1.5 until 4.5 did not exceed the noninferiority margin (p=0.0003); therefore, the difference is regarded as not clinically relevant. Similar results were obtained for the secondary efficacy variables. Ritalin(®) LA is an efficacious, well-tolerated treatment option for children aged 6-14 with ADHD.

Efficacy and Safety of Extended-Release Dexmethylphenidate Compared withd,l-Methylphenidate and Placebo in the Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A 12-Hour Laboratory Classroom Study

This study compared the efficacy and safety of extended-release dexmethylphenidate (d-MPH-ER) 20 mg/day and 30 mg/day with extended-release racemic methylphenidate hydrochloride (d,l-MPH-ER) 36 mg/day and 54 mg/day, and placebo in children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. This multicenter, double-blind, crossover study included children (N = 84) 6-12 years of age, stabilized on total daily doses of 40 mg to 60 mg d,l-MPH or 20 mg/day or 30 mg/day d-MPH who were randomized to different treatment sequences. Primary efficacy was measured by the change from pre-dose in Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores at 2 hours post-dose (d-MPH-ER 20 mg/day versus d,l-MPH- ER 36 mg/day). Adverse events were monitored throughout the study period. Mean change in SKAMP-Combined score at 2 hours post-dose was significantly larger for d-MPH-ER 20 mg/day versus d,l-MPH-ER 36 mg/day (p < 0.001). Both doses of d-MPH-ER had a more rapid onset and greater morning effect relative to d,l-MPH-ER while d,l-MPH-ER had a greater effect at the end of the 12-hour day. All active treatments provided a significant benefit over placebo at most time points to 12 hours post-dosing. Both treatments were well tolerated. d-MPH-ER and d,l-MPH-ER improved ADHD symptoms and were well tolerated. While d-MPH-ER had a faster onset of action, d,l-MPH-ER retained greater effect at the end of the 12- hour classroom day.

A Randomized, Double-Blind, Crossover Study of Once-Daily Dexmethylphenidate in Children with Attention-Deficit Hyperactivity Disorder

Long-acting methylphenidate formulations provide control of attention-deficit hyperactivity disorder (ADHD) symptoms for up to 12 hours; however, not all formulations have rapid onset of therapeutic effect, which is essential for providing symptom control during morning hours. The primary objective of this randomized, double-blind, crossover study was to assess the efficacy of dexmethylphenidate extended release (ER) versus placebo by measuring the change from pre-dose to 0.5 hours post-dose on the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale. Eighty-six children (6-12 years) with ADHD diagnosed using the DSM-IV criteria were randomized to receive dexmethylphenidate ER 20 mg/day or placebo, sequentially, for 7 days, with the final dose administered in a laboratory classroom setting on day 7 of each treatment period. The primary efficacy comparison was change in the SKAMP-Combined score from pre-dose to 0.5 hours post-dose, with additional secondary assessments at 1, 2, 4, 6 and 8 hours post-dose. Secondary efficacy measures included change from pre-dose at all timepoints in the SKAMP-Attention and SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores, and change from baseline on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P). In an exploratory analysis, a daily diary card was completed by parents on the children's in-home behaviour before school. Safety was assessed by occurrence of adverse events, monitoring of vital signs and interpretation of ECGs. Significant improvements were noted at 0.5 hours and at all timepoints post-dose throughout the 8-hour laboratory classroom day for dexmethylphenidate ER vs placebo in the primary outcome measure of the SKAMP-Combined scores (p < 0.001), as well as SKAMP-Attention, SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores (p < 0.05). The changes from baseline in CADS-P scores were significantly greater with dexmethylphenidate ER than placebo (-16.382 vs -4.622; p < 0.001). Responses to all diary questions indicated significant improvement with dexmethylphenidate ER treatment versus placebo (all p < 0.001). The most common adverse events were abdominal pain (dexmethylphenidate ER 3.5%; placebo 4.7%), headache (dexmethylphenidate ER 3.5%; placebo 2.3%) and increased appetite (dexmethylphenidate ER 0%; placebo 3.5%). Compared with placebo, once-daily dexmethylphenidate ER 20 mg provided rapid and significant improvement at 0.5 hours post-dose in attention, deportment and academic performance, which was sustained for 8 hours post-dose. Overall, once-daily dexmethylphenidate ER 20 mg was well tolerated. In an analysis of parental assessment of diary responses, children appeared more organized, and morning preparation for school was smoother and less frustrating with once-daily dexmethylphenidate ER compared with placebo.

Heterogeneity in the pharmacodynamics of two long-acting methylphenidate formulations for children with attention deficit/hyperactivity disorder

To use growth mixture modelling (GMM) to identify subgroups of children with attention deficit hyperactive disorder (ADHD) who have different pharmacodynamic profiles in response to extended release methylphenidate as assessed in a laboratory classroom setting. GMM analysis was performed on data from the COMACS study (Comparison of Methylphenidates in the Analog Classroom Setting): a large (n = 184) placebo-controlled cross-over study comparing three treatment conditions in the Laboratory School Protocol (with a 1.5-h cycle of attention and deportment assessments). Two orally administered, once-daily methylphenidate (MPH) bioequivalent formulations [Metadate CD/Equasym XL (MCD-EQXL) and Concerta XL (CON)] were compared with placebo (PLA). Three classes of children with distinct severity profiles in the PLA condition were identified. For both MCD-EQXL and CON, the more severe their PLA symptoms the better, the children's response. However, the formulations produced different growth curves by class, with CON having essentially a flat profile for all three classes (i.e. no effect of PLA severity) and MCD-EQXL showing a marked decline in symptoms immediately post-dosing in the two most severe classes compared with the least severe. Comparison of daily doses matched for immediate-release (IR) components accounted for this difference. The results suggest considerable heterogeneity in the pharmacodynamics of MPH response by children with ADHD. When treatment response for near-equal, bioequivalent daily doses the two formulations was compared, marked differences were seen for children in the most severe classes with a strong curvilinear trajectory for MCD-EQXL related to the greater IR component.

Efficacy of Two Long-Acting Methylphenidate Formulations in Children with Attention- Deficit/Hyperactivity Disorder in a Laboratory Classroom Setting

The aim of this study was to compare efficacy and safety of two long-acting formulations of methylphenidate (MPH) for attention-deficit/hyperactivity disorder (ADHD) in school-age children. Children 6-12 years of age diagnosed with ADHD and stabilized on MPH (20-40 mg/day) participated in a five-way, randomized, placebo-controlled, single-blind, crossover study conducted in a laboratory classroom setting. Children alternately received single doses of extended-release MPH (ER-MPH) 20 and 40 mg, modified-release MPH (OROS-MPH) 18 and 36 mg, and placebo over 6 consecutive weeks. Efficacy was assessed using SKAMP rating subscales and written math tests. Data were examined using between-treatment comparisons of area under the curve (AUC) for change from predose values during hours 0-4, 0-8, 8-12, and 0-12. Safety was assessed. Fifty-three children completed the study. For all efficacy measures, improvements from predose were significantly greater with ER-MPH 40 mg than with OROS-MPH 36 mg in terms of AUC(0-4) (p < or = 0.005), AUC(0-8) (p < or = 0.006), and AUC(0-12) (p < or = 0.035). For most measures, ER-MPH 20 mg was equivalent to both doses of OROS-MPH in AUC(0-4), AUC(0-8), and AUC(0-12). No serious adverse events were reported. The efficacy of ER-MPH 20 mg is similar to that of OROS-MPH 18 and 36 mg during the first 8 hours postdose. Statistically greater benefits are observed with ER-MPH 40 mg than with OROS-MPH 36 mg and persist through hour 8. Active treatments show comparable efficacy from 8 to 12 hours postdose. Both doses of each MPH formulation are well tolerated.

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

Methylphenidate has four optical isomers due to two asymmetries (erythro-threo and dextro-levo). The initial commercial formulation eliminated the erythro isomer, but the dextro-levo asymmetry was racemic, with equal amounts of d and l-threo isomers (d,l-MPH). Previous work has suggested that the d-threo isomer methylphenidate (d-MPH) rather than the l-threo isomer (l-MPH) is responsible for the clinical effects in children with attention-deficit/hyperactivity disorder (ADHD). This study compared the efficacy of acute equimolar doses of d-MPH and dl-MPH in reducing ADHD symptoms over an 8-hour period in a laboratory school setting and investigated the relationship of efficacy to plasma levels of MPH. Thirty-two children with ADHD enrolled in this double-blind, placebo-controlled, crossover study, and 31 completed the study. On seven separate occasions separated by at least 6 days, the children received a single morning dose of d-MPH (2.5, 5, or 10 mg), d,l-MPH (5, 10, or 20 mg), or placebo and then were observed in a laboratory classroom setting for 8 hours. At specified intervals, blinded observers rated behavior, and the children performed a computerized math test. The plasma levels of MPH were related to the response to study medication. The safety profiles of the two formulations were compared. For both formulations, the responses to both MPH preparations were dose related, the plasma concentrations of l-MPH were negligible and of d-MPH were indistinguishable, and clinical efficacy was highly correlated with plasma concentrations of d-MPH. The efficacy of the d-isomer was equivalent to the racemic preparation in reducing ADHD symptoms and increasing academic productivity. The efficacy of MPH resides in the d-isomer. The elimination of the l-isomer does not diminish the efficacy of an acute dose of methylphenidate.

Classroom behavior and children with mental retardation: Comparison of children with and without ADHD

Thirty-four children (ages 6-12 years) with moderate to borderline mental retardation were studied in a laboratory classroom setting to determine whether children identified as having attention deficit hyperactivity disorder on the basis of Conners Questionnaires differed in classroom behavior. Half of the children scored 15 or greater on both the Parent and Teacher Conners; the remaining children scored 11 or less. All were participants in a Saturday Education Program serving children with mental retardation. Direct observation of the laboratory classroom documented significant differences between groups on measures of on-task behavior and fidgetiness, especially during situations where little direct teacher feedback or supervision was available. Saturday Education Program staff, while blind as to group designation, rated the two groups as differing significantly on all scales of two standardized behavior problem checklists. Checklists by parents and teachers appear to be valid measures of classroom behavior of children with moderate to borderline mental retardation.

Tripartite behavioral intervention to reduce stereotypic and disruptive behaviors in young multihandicapped children

A comprehensive, tripartite intervention to reduce maladaptive stereotypic and disruptive behaviors exhibited by three young multihandicapped children was carried out. First, preferred stimuli were systematically identified for each child by scoring approach responses to each of 18 stimulus items. Highly preferred stimuli were used as positive reinforcers in DRO behavior management programs. Second, behavioral interventions were applied and evaluated in multiple-baseline designs within a laboratory classroom setting. Momentary DRO plus immobilization time-out and momentary DRO combined with overcorrection were found to be effective in reducing disruptive and/or stereo-typic behaviors. Third, efficacy of treatments was demonstrated in the regular classroom environment using A-B-A-B experimental designs. In two cases, behavioral programs were gradually faded to facilitate application by classroom staff. Concurrent effects of treatment, trainer compliance, and cost effectiveness were monitored throughout the study. Gains were maintained across five-month follow-up period.