PEDIATRICS Vol. 108 No. 4 October 2001, pp. 883-892

Randomized, Controlled Trial of OROS Methylphenidate Once a Day in Children With Attention-Deficit/Hyperactivity Disorder

Mark L. Wolraich, MD^*, Laurence L. Greenhill, MD, William Pelham, PhD^§, James Swanson, PhD, Timothy Wilens, MD^¶, Donna Palumbo, PhD^#, Marc Atkins, PhD^**, Keith McBurnett, PhD, Oscar Bukstein, MD^§§, Gerald August, PhD^||, and on behalf of the Concerta Study Group

From ^* Vanderbilt University, Nashville, Tennessee;  New York State Psychiatric Institute, New York; ^§ State University of New York at Buffalo, Buffalo, New York;  University of California at Irvine, Irvine, California; ^¶ Massachusetts General Hospital, Boston, Massachusetts; ^# University of Rochester, Rochester, Minnesota; ^** University of Illinois at Chicago, Chicago, Illinois;  University of Chicago, Chicago, Illinois; ^§§ Western Psychiatric Institute and Clinic, University of Pittsburgh, Pittsburgh, Pennsylvania; and ^|| University of Minnesota, Rochester, Minnesota.

	ABSTRACT

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Objective.  A new once-a-day methylphenidate (MPH) formulation, Concerta (methylphenidate HCl) extended-release tablets (OROS MPH), has been developed. This study was conducted to determine the safety and efficacy of OROS MPH in a multicenter, randomized, clinical trial.

Methods.  Children with attention-deficit/hyperactivity disorder (ADHD; n = 282), all subtypes, ages 6 to 12 years, were randomized to placebo (n = 90), immediate-release methylphenidate (IR MPH) 3 times a day (tid; dosed every 4 hours; n = 97), or OROS MPH once a day (qd; n = 95) in a double-blind, 28-day trial. Outcomes in multiple domains were assessed, and data were analyzed using analysis of variance and Kaplan Meier product limit estimates for time to study cessation. The primary time point for analysis was the last available patient visit using last observation carried forward.

Results.  Children in the OROS and IR MPH groups showed significantly greater reductions in core ADHD symptoms than did children on placebo. This was true both at the end of week 1 and at the end of treatment on the basis of mean teacher and parent IOWA Conners ratings. IR MPH tid and OROS MPH qd did not differ significantly on any direct comparisons. Forty-eight percent of the placebo group discontinued early compared with 14% and 16% in the IR MPH and OROS MPH groups, respectively.

Conclusions.  For the treatment of core ADHD symptoms, OROS MPH dosed qd and IR MPH dosed tid were superior to placebo and were not significantly different from each other.attention-deficit/hyperactivity disorder, methylphenidate, OROS, Concerta.

Methylphenidate (MPH) was the most widely dispensed stimulant medication used for treating attention-deficit/hyperactivity disorder (ADHD) in 1999.¹ ADHD is characterized by developmentally inappropriate inattention, hyperactivity, and impulsiveness and affects an estimated 3% to 5% of the school-age population.² Because MPH has a short half-life (2-4 hours), the standard immediate-release (IR) formulation typically must be administered 2 or 3 times a day to maintain therapeutic efficacy.³ This often causes difficulties for children who must be given a controlled substance midday at school and for school officials who must handle controlled medications. A sustained-release (SR) MPH preparation, Ritalin-SR, is available; however, its duration of action is reported to be 8 hours.⁴

A study in children with ADHD revealed that a slightly increasing plasma MPH concentration across the day provided efficacy equivalent to IR MPH dosed 3 times a day (tid).⁵ ALZA Corporation has developed a once-a-day, osmotic, controlled-release, oral dosage form of MPH, Concerta (methylphenidate HCl) extended-release tablets (OROS MPH), that provides this slightly increasing plasma concentration. OROS MPH was designed to maintain efficacy through 12 hours with once-daily dosing (qd) and to have a safety profile and efficacy comparable to IR MPH given tid at 4-hour intervals.⁶ OROS MPH eliminates the need for both in-school and after-school dosing. The purpose of this study was to determine the safety and efficacy of OROS MPH qd compared with IR MPH tid and placebo in the community setting.

	METHODS

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Patients

Boys and girls, ages 6 to 12 years, with a clinical diagnosis of any subtype of ADHD were recruited primarily through a centralized recruitment service using radio and newspaper advertisements. Patients who were taking MPH or had taken it in the past had to have been on a total daily MPH dose (IR or IR/SR combination) of at least 10 mg but not more than 60 mg. Patients were excluded from participation if they had an acute or serious chronic disease, were hypersensitive to methylphenidate, were having significant adverse experiences from methylphenidate, or were taking a medication that would interfere with the safe administration of methylphenidate. Patients with glaucoma, Tourette's syndrome, an ongoing seizure disorder, or a psychotic disorder also were excluded, as were girls who had reached menarche.

More than 4000 parents of patients made initial contact in response to institutional review board (IRB)-approved postings and advertisements, and approximately 90% of these were excluded from participation on the basis of a brief telephone screen. Reasons for exclusion at this phase included unacceptable medical condition/medication, child's age not within the range specified in the study inclusion criteria (6-12 years), girls who had reached menarche, informational requests about ADHD without interest in study participation, and distance from the investigational site. Initially, acceptable respondents were invited to the clinics at each site for a day of screening procedures.

More than 500 patients were screened at 14 investigational sites; 405 of these enrolled into a screening study to confirm the diagnosis of ADHD. After the screening study, 210 of these patients who previously had received MPH treatment within 4 weeks of entry into this study were enrolled directly into the current study, whereas 111 who had not received MPH before this study initially were enrolled into a dose-titration study. After the dose titration study, 102 patients entered the current study. One patient in the titration study did not receive treatment, and 4 terminated prematurely (1 for tics, 2 refused medication, and 1 because of possible drug diversion). An additional 4 patients did not enroll in the randomized study (because of timing of the study [n = 3] or because the 54-mg dose was found to be ineffective [n = 1]). (Of the remaining patients enrolled in the screening study, 30 participated in a pharmacokinetic and pharmacodynamic study and later were enrolled into a separate long-term safety study, and 54 discontinued participation [52 patients did not meet the entrance criteria, 1 was unable to swallow the medication, and 1 for unknown reasons].)

An effect size of 1.0 was considered in the sample size calculation. Although a smaller number of patients would be required to demonstrate the treatment difference with such an anticipated effect size, the study was planned to enroll 300 patients to enhance the safety information available. A sample size of 300 would provide >99% power to detect a difference of 3 units between OROS MPH and placebo for the primary assessment (IOWA Conners Inattention/Overactivity [I/O] subscale; based on a Student t test with standard deviation of 3.0 and  = 0.05).

To be enrolled, the child's ADHD diagnosis had to be confirmed by the Diagnostic Interview Schedule for Children (Version 4)⁷ administered by a trained interviewer. Severity of ADHD symptoms was rated both at school by the community school teacher (teacher) and at home by the parent/caregiver (parent) using the SNAP-IV⁸ and the IOWA Conners Rating Scale.⁹ Parents rated their child's impairment using the Children's Global Assessment Scale (C-GAS).¹⁰ The study-site investigators reviewed all of these assessments before making a final diagnosis on the basis of clinical judgment. Per the study protocol, patients had to agree to take the supplied study drug as the only medication for ADHD during the 4-week study period.

Each patient's parent had to read, sign, and date an IRB-approved consent form that explained the nature, purpose, risks, and duration of the study. Each patient who was 7 years old or older and who could write his or her name read (or was read) and then signed an IRB-approved assent form or followed the IRB-approved standard practice for pediatric patients at each participating study center.

Procedure

Patients were assigned to 1 of 3 treatment dose levels (18 mg OROS MPH qd/5 mg IR MPH tid, 36 mg OROS MPH qd/10 mg IR MPH tid, 54 mg OROS MPH qd/15 mg IR MPH tid), based either on titration (as described below) or conversion from previous MPH treatment. Table 1 shows the numbers of patients assigned to each dose level according to whether they underwent dose titration or dose conversion. Within each dose level, patients were randomized equally to OROS MPH qd, IR MPH (over-encapsulated Ritalin) tid, or placebo in a 3-group parallel design. A stratified randomization was conducted centrally at ALZA Corporation.

As described elsewhere in more detail,¹¹ patients who had not received MPH for ADHD from their own practitioner in the 4 weeks before study entry first participated in an open-label, dose-ranging 1- to 4-week stepwise titration trial. Patients were titrated to an optimal dose based on investigator review of parent/teacher rating forms, presence of treatment-emergent adverse events (AEs), and clinical judgment. All patients were started on a dose of OROS MPH of 18 mg qd, and this was increased to 36 mg qd and then to 54 mg qd as necessary (ie, patients were titrated up to the higher doses only if deemed necessary by the investigators).

Patients who had taken MPH during the 4 weeks before study entry were assigned to a dose level based on their prestudy therapeutic dose and regimen. Their dose was determined by taking into account both their morning and total daily IR MPH doses. In general, IR MPH doses were converted to a total daily OROS MPH dose approximately equal to 3 times the usual morning IR MPH dose.

Dosing was conducted in a double-blind and double-dummy manner. All patients received 3 OROS systems (active or placebo) and 1 IR capsule (active or placebo) at 0730 and an additional IR capsule (active or placebo) at 1130 and at 1530. Patients were dosed daily for 28 days.

During the course of the study, patients were allowed to receive behavioral interventions as long as the interventions had been initiated before the start of the study and did not change during the study. New behavioral therapy was not allowed during the course of the study.

Study Measures

Behaviors

IOWA Conners Ratings Scale The I/O subscale of the IOWA Conners Rating Scale⁹ completed by the teacher on the Friday of week 4 (day 27) was defined as the primary efficacy measure before the study began. The IOWA Conners Rating Scale consists of 10 items divided into 2 subsets, I/O and Oppositional/Defiance (O/D). Items were scored on a 4-point scale (from 0 = not at all to 3 = very much), and the subsets were analyzed separately. Teachers and parents completed both subsets of the IOWA Conners scale on each Friday during the study to evaluate inattention and behavior in school and at home. Effect size also was determined for the primary efficacy parameter. The IOWA Conners scale has been used in treatment studies and has shown adequate discriminant validity.¹²

SNAP-IV The SNAP-IV⁸ included 18 items that reflect ADHD symptoms in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (inattention and hyperactivity/impulsivity), and 8 items that reflect oppositional defiant disorder (ODD) symptoms. At the end of the study, teachers and parents completed the 26 SNAP-IV items, which were scored using the same 4-point scale as the IOWA Conners. The SNAP-IV has been used in large, multisite pediatric psychopharmacology clinical trials, showing medication effects for children who are treated with MPH.¹³

Function The parent-scored C-GAS generates a global rating of the child's impairment. The C-GAS has been found to demonstrate concurrent and discriminant validity.¹⁰

Change/Efficacy

Clinical Global Impressions-Improvement At the end of the study, study-site investigators responded to the following question using a 7-point Likert scale (from 0 = very much worse to 6 = very much improved): Rate total improvement whether or not, in your judgment, it is due entirely to treatment. Compared with his/her condition the week before the start of the 4-week treatment, how much has he/she changed?^14,15 The rating was based on a review of teacher and parent ratings and a parent interview. The Clinical Global Impressions-Improvement has been shown to be sensitive to medication effects in a trial with children and adolescents.¹⁶

Global Assessment of Efficacy Parents and teachers completed a global assessment of efficacy at the end of the study rating the patient's behavior and attention on a 4-point scale (0 = poor; 1 = fair; 2 = good; 3 = excellent) in response to the following question: What is your opinion of the effectiveness of treatment this week?

Peer Interaction On day 27, teachers rated 6 items from the SNAP-IV Peer Interaction category using the same 4-point scale as the SNAP inattention and hyperactivity/impulsivity and ODD items. These 6 items from the SNAP and 1 item from the IOWA Conners Rating Scale were analyzed to give the Peer Interaction score.

Parent Satisfaction Questionnaire A Parent Satisfaction Questionnaire was completed at the end of treatment, based on a questionnaire used in the National Institute of Mental Health Multimodal Treatment Study of Children with ADHD (MTA).¹³ At the end of the study, parents were asked to rate their satisfaction with the study medication and its benefit to the patient symptom relief compared with previous medications and whether they would recommend the treatment to other patients.

Safety Assessment

AEs were collected on days 7, 14, and 28 by asking parents whether any new development in the child's health had occurred since the last clinic visit. Spontaneously reported AEs also were recorded. Reported events were assessed to determine whether any events were serious, life-threatening, or unexpected and to assign severity and relationship to study medication. In addition, parents rated the child's sleep quality for the preceding 2 weeks on days 0, 14, and 28. Sleep quality was rated as excellent, good, fair, or poor. Parents also rated the child's appetite for the previous 2 weeks on days 14 and 28. Food intake was rated as more than before, about the same amount as before, or less than before, relative to the child's usual food intake before participating in any ALZA study. Parents were questioned at screening about the history or presence of motor and/or verbal tics and on days 0, 14, and 28 about the presence of tics and any changes in their severity or specificity. When a new occurrence or a clinically significant increase in tics was observed, it was recorded as an AE. Vital signs (blood pressure and pulse rate) were recorded at screening and on days 0, 14, and 28.

Statistical Analysis

The study protocol defined the time for conducting the primary analyses as the end of week 4 (day 27). The disparate dropout rates in the placebo and active treatment groups necessitated an amendment to this time point. The primary time point for analyses became the end of study, defined as the end of week 4 for patients who completed the trial or the last available measurement for patients who dropped out early (ie, the last available patient visit, using a last observation carried forward [LOCF] approach). An analysis with all available data (without LOCF) also was conducted, and the results were consistent with those of the LOCF analysis.

Primary analyses were conducted using analysis of variance techniques. As a further measure of efficacy, treatment groups were compared in time with dropout using Kaplan Meier product limit estimates. Effect sizes were calculated by dividing the difference of the mean scores (active vs placebo) by the standard deviation of the placebo group.

	RESULTS

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Patients

Figure 1 presents the patient disposition. A total of 312 patients were enrolled at 14 centers in the United States. A site audit at 1 site (30 patients) uncovered irregularities that made it impossible to verify the results reported, so before the study data were analyzed, a decision was made to exclude the efficacy data from this site. This included 11 patients in the dose-titration group and 19 patients who previously had received MPH treatment. However, the data also were analyzed with this site included, and the nature of the results and conclusions did not change. Of the 282 patients who were enrolled at the remaining sites, 5 were not treated (3 withdrew consent, 1 of whom was in the dose-titration group, 1 did not return, and 1 did not have the diagnosis confirmed). Therefore, 277 patients were included in the efficacy analyses (90 patients from the dose-titration group and 187 patients who previously had received MPH therapy; see Table 1). Within each dose level, patients were distributed equally among the 3 treatments. The number of patients enrolled at each of the 13 remaining sites ranged from 10 to 28. 

View larger version (29K): [in this window] [in a new window]   Fig. 1.   Patient disposition.

Seventy-one patients discontinued treatment prematurely (OROS MPH, n = 15; IR MPH, n = 13; placebo, n = 43). Table 2 shows the cumulative number of dropouts by week. Fifty-nine patients discontinued for lack of efficacy, 38 from the placebo group, 11 from the OROS MPH group, and 10 from the IR MPH group. Three patients discontinued because of noncompliance, 2 for AEs/intercurrent illnesses, and 2 because of protocol violations. In addition, 1 patient discontinued for each of the following reasons: AE requiring dose reduction, lost to follow-up, did not return, could not swallow the pills, and took supplemental MPH.

Dose of Drug

The average total daily dose for patients from the 13 sites was 29.5 mg per day (0.9 ± 0.4 mg/kg/d) for IR MPH and 34.3 mg per day (1.1 ± 0.5 mg/kg/d) for OROS MPH. These doses need to be considered in the context of the approximate 90% bioavailability of OROS MPH relative to IR MPH reported by Modi et al.¹⁷ Patients remained on the predetermined OROS MPH and IR MPH doses throughout the study.

Demographic and Baseline Characteristics

As shown in Table 3, 60.6% of patients in the study were 6 to 9 years old, 82.6% were boys, and 84.4% were white. More than two thirds (67.7%) of the patients previously had received MPH treatment for ADHD before entering the study, and 73.4% of their diagnoses were the combined subtype of ADHD. Comorbidities also were present in 46.5%; ODD (41.8%) was the major comorbidity in all 3 treatment groups. No statistically significant differences were seen among treatment groups for these demographic and baseline characteristics, except for the comorbidity general anxiety disorder, present in 4 patients in the placebo group but in no patients in the other treatment groups.

Average categorical ratings for the hyperactive/impulsive and inattentive components of the Diagnostic Interview Schedule for Children and mean scores for C-GAS at baseline were similar for patients in the 3 treatment groups. Baseline values for the IOWA Conners, Peer Interaction, and the SNAP-IV are shown in Tables 4 and 5.

Outcome Measures and Efficacy

Table 4 shows the baseline, week 1, and end-of-study results for the teacher and parent IOWA Conners I/O and O/D subscales. The teacher IOWA Conners I/O scores at the end of week 1 showed statistically significant (P < .001) improvement with both OROS MPH qd (mean: 5.58 ± 3.64) and IR MPH tid (mean: 5.70 ± 3.84) over placebo (mean: 9.87 ± 4.09). The effect sizes versus placebo were 1.05 for OROS MPH and 1.02 for IR MPH. Results of the primary efficacy measure, the teacher IOWA Conners I/O subscale completed at end of study, also showed that both OROS MPH qd (mean: 5.98 ± 3.91) and IR MPH tid (mean: 6.35 ± 4.31) were significantly better (P < .001) than placebo (mean: 9.77 ± 4.02; Fig 2). No significant difference was seen between the mean IOWA Conners scores for the OROS MPH qd and IR MPH tid treatment groups at week 1 (P = .838) or at the end of the study (P = .539). Teacher and parent IOWA Conners O/D ratings, evaluating patients' oppositional defiance, also supported the findings of superior efficacy for the 2 active treatments. Analysis revealed no significant treatment by site interactions for the primary end point at the final assessment.

View larger version (35K): [in this window] [in a new window]   Fig. 2.   Teacher IOWA Conners I/O Scores.

Table 5 shows the baseline and end-of-study results for the secondary efficacy endpoints. Teacher and parent SNAP-IV scores evaluating inattention, hyperactivity/impulsivity, and ODD behaviors were significantly better (P < .001) for patients who were on the 2 active treatments than for patients who were on placebo. No significant difference in scores was seen between the OROS MPH and IR MPH groups for these measures.

For the global assessment of efficacy, teachers and parents rated the 2 active treatments significantly better than placebo (P < .001). Teachers rated treatment efficacy as good or excellent for 42.9% of patients who were taking OROS MPH, 46.9% of patients who were taking IR MPH, and 17.7% of patients who were taking placebo. Parent global assessment scores were similar (OROS MPH, 54.0%; IR MPH, 46.5%; placebo, 20.3%).

Results of the clinical global impression, completed by the investigator at each site, also showed significant benefits (P < .001) for both active treatments compared with placebo. Ratings of very much improved or much improved were obtained by 46.7% of patients who were taking OROS MPH qd, 47.2% of patients who were taking IR MPH tid, and 16.7% of patients who were taking placebo.

Logistic regression analysis of responses to the Parent Satisfaction Questionnaire completed at the end of treatment showed that parents were significantly more satisfied with the active treatments than with placebo (P < .001). In particular, when asked how pleased they were with the medication for their child's ADHD symptoms, 62.6% and 64.0% of parents responded pleased, very pleased, or extremely pleased for the OROS MPH and IR MPH treatments, respectively, compared with 21.0% for placebo. No significant differences were observed in this measure for the OROS MPH and IR MPH treatments.

AEs

From all sites, patients who received at least 1 dose of study medication (n = 306) were included in the analysis of safety. No serious AEs were reported during the study. Fewer than half of the 306 patients (126 [41.2%]) reported any AEs, and the majority of the events reported were mild. A similar percentage of patients reported at least 1 AE on OROS MPH qd (42.3%) and on IR MPH tid (46.2%). Fewer patients (34.7%) reported at least 1 AE on placebo. One patient from each treatment group discontinued the study early because of the following AEs: depression on OROS MPH, considered by the investigator possibly to be related to treatment; emotional lability on IR MPH tid, considered probably to be related to treatment; and twitching (tics) on placebo, also considered by the investigator probably to be related to treatment. (Relationship to treatment was assigned before the blind was broken.)

The most commonly reported AEs were headache and upper respiratory tract infection, followed by abdominal pain, cough, pharyngitis, vomiting, and otitis media. Of these, only headache and abdominal pain, both known to occur with MPH, were considered to be related to study medication in the majority of patients who reported these AEs. For patients on OROS MPH, IR MPH, and placebo, headache occurred in 14.4%, 5.8%, and 10.2% of patients and abdominal pain occurred in 6.7%, 5.8%, and 1.0%, respectively. Other AEs known to occur with MPH and considered related to study drug included appetite suppression (OROS treatment) and insomnia (OROS, IR, and placebo treatments). No clinically significant changes in vital signs occurred in any of the treatment groups.

Sleep

At day 0, most patients were assessed as having good or excellent sleep quality: 70.5%, 72.8%, and 76.6% of patients in the OROS MPH, IR MPH, and placebo groups, respectively. As rated on days 14 and 28, the majority of patients (65%) in each treatment group continued to have good or excellent sleep quality. No statistically significant differences were observed in the way the individual sleep quality categories (excellent, good, fair, or poor) distributed among the 3 treatment groups.

Appetite

Parents rated food intake as usual amount or more than usual amount in >75% of patients. At day 14, the percentage of patients who were eating less than usual during the previous 2 weeks was significantly higher (P < .001) for the 2 active treatments compared with placebo (22.5%, 18.8%, and 12.0% for the OROS MPH, IR MPH, and placebo treatments, respectively). Similar results were seen on day 28. Values for patients who were receiving OROS MPH and IR MPH treatments were not significantly different.

Tics

Thirteen patients were reported on a parent questionnaire to have had tics during the study. Nine of these 13 patients had a history of tics prestudy. For this study, a new onset of tics or a clinically significant increase in tics was considered to be an AE. Five patients had tics that were reported as AEs: 4 patients on placebo and 1 on IR MPH. No patient on OROS MPH had tics that were reported as an AE.

	DISCUSSION

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The results of this study show that OROS MPH administered once a day and IR MPH administered 3 times a day were significantly better than placebo and not significantly different from each other for the primary efficacy measure, teacher IOWA Conners I/O subscale score, which evaluated attention and behavior at school. Furthermore, a significant improvement in attention and behavior was seen in the first week for patients who were taking OROS MPH qd or IR MPH tid compared with placebo, and this improvement was maintained throughout the 4 weeks of the study. These results were consistent across settings (home and school), raters (parents, teachers, clinical investigators), and measures (IOWA Conners, SNAP-IV, Peer Interaction, Global Assessments, Parent Satisfaction) and were statistically significant.

Determination of effect sizes for the 2 active treatments versus placebo yielded values of 1.05 for OROS MPH and 1.02 for IR MPH. These values are greater than those recently reported for the highly controlled, double-blind MTA MPH titration trial, which reported effect sizes of 0.8 and 1.0 for MPH.¹⁸ The response rate for Clinical Global Impressions (Clinical Global Impressions for the IR MPH group was not different from that of the MTA Cooperative study [55%]).¹³ Any comparisons between this study and the MTA study, however, should be viewed with caution because the 2 studies have very different study designs (this study used a placebo comparator, whereas the MTA study used a "treatment as usual" group), different age ranges (this study enrolled children 6-12 years of age, whereas the MTA study involved children 7-9 years of age who thus were more likely to have been naïve to all treatments), and different study durations (this study lasted 1 month, whereas the MTA study lasted 14 months), and drug dosage adjustment was allowed in the MTA study but not in this study.

No serious AEs were reported during this study. The majority of patients did not report any AEs, and the majority of those reported were mild. This may be attributable, in part, to the fact that 75% of patients were already receiving MPH before entering the study. The mean daily dose that patients were receiving in this study (1.1 ± 0.5 mg/kg/d for OROS MPH and 0.9 ± 0.4 mg/kg/d for IR MPH) was not meaningfully different from the average dose given in other studies. For example, the average dose given at the end of the MTA study ranged from 1.2 to 1.3 mg/kg/d.¹³ However, these are the mean doses; thus, the dose received by some individual patients was significantly higher (eg, range for OROS MPH, 0.3-2.5 mg/kg/d). The low incidence of AEs thus is unlikely to be attributable to the use of lower doses. However, one would expect a greater incidence of AEs in individual patients in whom higher doses are used, as reported in previous studies of lower and higher doses of IR MPH.^19,20 Overall, the type and incidence of AEs reported in this study were consistent with previous work with MPH.¹⁹

The results from this study are limited by the 26% attrition rate, concentrated in the placebo treatment arm. The dropout rate in the placebo group (48%) by the end of the treatment was higher than that found in either the OROS MPH group (16%) or the IR MPH group (14%). Unless adjusted for in the analysis, this attrition biases toward a Type II error (ie, accepting the hypothesis of no difference when there are real differences).

The primary reason for attrition in the placebo group was lack of efficacy, which reflects that the appropriate patient population (ie, patients requiring medication) was enrolled in the study. This may be related to the fact that 75% of study patients had been taking stimulant medication before the beginning of the study. The proportion of stimulant-naïve patients (25%) was much lower than in the MTA study, in which 66% were stimulant naïve.¹³ Families that are familiar with their child's response to stimulant medication would be more aware of whether the medication showed a lack of effect and would be quick to abandon placebo.

In comparison with the placebo group, the rate of patient discontinuation for lack of efficacy was significantly lower on both the OROS MPH and IR MPH treatments (P < .001 with log-rank and Wilcoxon tests). No significant difference was seen in the number of dropouts in the 2 active treatment groups.

The study was not designed to assess duration of treatment effect and thus is not able to demonstrate whether the duration of daily clinical effects of OROS MPH is comparable to those of IR MPH tid. However, this has been demonstrated in previous controlled crossover studies comparing OROS MPH qd with IR MPH tid and placebo.^6,21,22 Other limitations of the current study include the participation of evaluators who were not independent of the clinicians adjusting the medication and the need to exclude one of the treatment sites.

The results of this study indicate that OROS MPH dosed qd provides efficacy superior to placebo and not significantly different from IR MPH dosed tid. The convenience of once-daily dosing could provide additional benefits. Because OROS MPH will eliminate the need for dosing in school and after school, it potentially could eliminate the embarrassment that a child may feel when called to report to a school authority for medication, the bureaucracy required at school to administer a controlled substance to a child, and the potential for diversion of the drug.

	ACKNOWLEDGMENTS

This study was funded by ALZA Corporation (Mountain View, CA) on behalf of Crescendo Pharmaceuticals Corporation (Mountain View, CA). M.W., L.L.G., W.P., J.S., and T.W. are paid consultants of ALZA Corporation.

We thank the members of the Concerta Study Group and, in particular, J.S. and W.P. for their early work in this program.

The Concerta Study Group: Howard Abikoff, PhD (New York University Child Study Center); Marc Atkins, PhD (University of Illinois at Chicago); Gerald August, PhD (University of Minnesota); Joseph Biederman, MD (Harvard University); Oscar Bukstein, MD (Western Psychiatric Institute and Clinic, University of Pittsburgh); C. Keith Conners, PhD (Duke University); Laurence Greenhill, MD (New York State Psychiatric Institute); Martin Hoffman, MD (University of Buffalo School of Medicine); Marc Lerner, MD (University of California at Irvine); Keith McBurnett, PhD (University of Chicago); Donna Palumbo, PhD (University of Rochester); William Pelham, PhD (State University of New York at Buffalo); Mark Stein, PhD (Children's National Medical Center); James Swanson, PhD (University of California at Irvine); Sharon Wigal, PhD (University of California at Irvine); Timothy Wilens, MD (Massachusetts General Hospital); and Mark Wolraich, MD (Vanderbilt University).

	FOOTNOTES

Received for publication Jun 5, 2000; accepted Mar 2, 2001.

Reprint requests to (M.L.W.) Child Study Center, 1100 NE 13th St, Oklahoma City, OK 73117. E-mail: mark_wolraich{at}ouhsc.edu

	ABBREVIATIONS

MPH, methylphenidate hydrochloride; ADHD, attention-deficit/hyperactivity disorder; IR, immediate release; SR, sustained release; tid, 3 times a day; qd, once a day; IRB, institutional review board; AE, adverse event; I/O, inattention/overactivity; C-GAS, Children's Global Assessment Scale; O/D, oppositional defiance; ODD, oppositional defiant disorder; LOCF, last observation carried forward.

	REFERENCES

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