| Study characteristics |
| Methods |
Multi‐centre, double‐blind, double‐dummy, placebo‐controlled, cross‐over trial in an analogue classroom setting comparing 3 treatment conditions
ER‐MPH (Metadate CD) ER‐MPH (Concerta) placebo
Each treatment intervention lasted a week |
| Participants |
Number of participants screened: 214
Number of participants included: 184 (131 boys, 48 girls)
Number of participants followed up: 157/184 ITT
Number of withdrawals: 27
Diagnosis of ADHD: DSM‐IV (combined (82.2%), hyperactive‐impulsive (4.8%), inattentive (13.0 %))
Age: mean 9.6 years (range 6‐12)
IQ: > 80
MPH‐naive: none
Ethnicity: white (70%), African American (11.5%), Asian (1.7%), Hispanic (12.5%), other (5.3%)
Country: USA
Setting: outpatient clinic
Comorbidity: approximately 25% had a comorbid condition; anxiety and ODD were most frequent. Girls had a greater rate of comorbid anxiety disorder (from Sonuga‐Barke 2007). Anxiety: 20.8 girls, 5.9 boys. ODD: 12.5 girls, 8.8 boys. Insomnia: 2.1 girls, 5.1 boys
Comedication: not stated
Other sociodemographics: none
Inclusion criteria
Children (6‐12 years old) who had clinical diagnoses of a DSM‐IV subtype of ADHD (inattentive type, hyperactive‐impulsive type or combined type) were recruited Treatment with MPH in doses of 10 mg/d to 60 mg/d (5 mg‐20 mg per administration, 1 to 3 times/d) Children were deemed otherwise healthy by means of a medical history, physical examination, vital signs measurement (BP, heart rate, respiration and temperature) and clinical laboratory assessments (haematology and urinalysis) In addition, children had to demonstrate the ability to swallow placebo trial treatment capsules whole and without difficulty Receiving an approved form of MPH with demonstrated clinical improvement during this treatment
Exclusion criteria
Intelligence quotient < 80 or inability to follow or understand trial instructions Pregnancy History of seizure or tic disorder Family history of seizure or Gilles de La Tourette’s syndrome Congenital cardiac abnormality History of cardiac disease including myocardial infarction within 3 months of trial entry Glaucoma Hyperthyroidism History of substance abuse or carer with history of substance abuse Concurrent chronic or acute illness or other condition that might confound trial rating measures Documented allergy or intolerance to MPH Use of an investigational drug within 30 days of trial entry Use of concomitant medication that could interfere with assessment of efficacy and safety of trial treatments
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| Interventions |
Participants were randomly assigned to 1 of 6 possible drug condition orders of ER‐MPH (Metadate CD), ER‐MPH (Concerta), and placebo
Dose: children treated with low doses (20 mg/d ) of MPH were randomly assigned to receive ER‐MPH (Metadate CD) 20 mg, ER‐MPH (Concerta) 18 mg, or placebo; those treated with medium doses (20 to 40 mg/d ) were randomly assigned to receive ER‐MPH (Metadate CD) 40 mg, ER‐MPH (Concerta) 36 mg, or placebo; children treated with high doses (40 mg/d ) were randomly assigned to receive ER‐MPH (Metadate CD) 60 mg, ER‐MPH (Concerta) 54 mg, or placebo
Administration schedule: once daily in the morning
Duration of each medication condition: 7 days
Washout before trial initiation: no
Medication‐free period between interventions: not stated
Titration period: none
Treatment compliance: regarding the medicine, not stated. 157 received all 3 levels of treatment and participated in all 7 classroom sessions |
| Outcomes |
ADHD symptoms
SKAMP: tested on day 7 in the laboratory school by 2 trained observers. Time points for the test (after ingestion of medication/placebo): h = 0, h = 1.5, h = 3.0, h = 4.5, h = 6, h = 7, h = 12.0 SNAP: parent‐rated, administered twice during each treatment week on days 3 and 6
Non‐serious AEs
AEs reported by participant or parent (guardian). Reported AEs were characterised (by the investigator at each site) as mild, moderate or severe Barkley Side Effects Rating Scale: rated symptoms during past week and completed weekly by parent (guardian) on day 6 Heart rate: measured before doses were taken and at the following time points after ingestion: h = 1.5, h = 3.0, h = 4.5, h = 6, h = 7, h = 12.0 BP: measured before doses were taken and at the following time points after ingestion: h = 1.5, h = 3.0, h = 4.5, h = 6, h = 7, h = 12.0
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| Notes |
Sample calculation: yes
Ethics approval: yes
Comments from trial authors
"In ANOVA of measures of BP and heart rate, only 2 statistically significant differences related to treatment emerged: SBP at h 7.5, and pulse rate at h 1.5" "Site differences in this trial deserve some comment because this is a common finding in multi‐site studies. Site difference was most prominent for subjective outcome measures on the SKAMP Rating Scale, which depends on the training of observers (difficult to equate across sites) and the context of the classroom (controlled but still may vary across sites because of class size, physical space and other factors that may not be standardised)" "Regarding analysis of sex (Sonuga‐Barke 2007): despite the relatively large number of females in the sample, power was insufficient to include dose level as a factor in the analysis" "Given the manner in which sex effects appeared to vary across the day, present results may be consistent with pharmacokinetic or pharmacodynamic explanations, or a combination of the 2. Early and late sex‐related differences in clinical effect may be independent of one another or linked. Several possible explanations seem worth testing. The superior MPH response shown by females in the early part of the day may result from greater sensitivity to MPH or from higher MPH plasma concentrations due to increased rates or efficiency of absorption of IR‐components. The steeper decline in MPH response shown by females may be a consequence of earlier but normative clearance of MPH following more rapid absorption, or may be indicative of more rapid clearance in females than in males"
Limitations
"Laboratory setting lacks many features of the natural environment of the home and school. Thus, it is not certain whether the patterns reported here would be observed in school settings in which an ADHD student would be in a classroom in which most students not affected by this disorder" "Trial was designed to contrast total absorbed daily doses that were approximately equal, although this resulted in differences in initial bolus doses of the 2 active treatments (Metadate CD and Concerta). In this trial, doses were not evaluated that were equal to the initial bolus doses of IR‐MPH, which would provide another test of the PK/PD model" "Effects of both Metadate CD and Concerta in the low‐dose subgroup were smaller than in the high‐dose subgroup, but we do not know whether a higher dose in the low‐dose subgroup would have increased the ES. Lack of tailoring to achieve rigorous experimental control may be another limitation of this trial" "This trial included only patients who already were being treated successfully with MPH. This means that severe and marked AEs are unlikely to be seen in this trial, and it is possible that lack of effect on side effects rating scale factors other than sleep/appetite may occur more readily in medication‐naive patients. Furthermore, it is important to recognise that this was a secondary analysis of a trial powered to show non‐equivalence between the 2 MPH formulations in terms of efficacy, not in terms of AEs" Sonuga‐Barke 2009 (secondary reference under Swanson 2004b): "this trial included only patients who already were being treated successfully with MPH. This means that severe and marked AEs are unlikely to be seen in this trial" "Trial was also underpowered for detecting rare events that could be severe. Measures of AEs were derived only from parent ratings, not from direct observations of behaviour" "Significant side effects not measured by the Barkley Side Effects Rating Scale may have occurred"
Key conclusions of trial authors
"Once‐daily doses of Metadate CD and Concerta produced statistically significantly different PD effects on surrogate measures of behaviour and performance among children with attention deficit hyperactivity disorder in the laboratory school setting" "As predicted by the PK/PD [pharmacokinetic/pharmacodynamic] model, superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration"
Sex differences
"Dose titration of once‐daily formulations of MPH ideally should be based on systematic evidence of response at different periods across the day" "Responses of female patients may require additional assessments later in the day to determine optimal dose"
Comment from review authors
Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes
Any withdrawals due to AEs: 3 trial participants discontinued because of AEs that were judged to be unrelated to medications (gastroenteritis: Concerta (n = 1); fever: placebo (n = 1); sunburn: placebo (n = 1))
Funding: Celltech Pharmaceuticals Incorporated
Email correspondence with trial authors: June 2014. We emailed trial authors to obtain supplemental data. Unfortunately, data in the correct format are no longer accessible. |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Unclear risk |
Randomised |
| Allocation concealment (selection bias) |
Unclear risk |
Randomised |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
Double‐blind, double‐dummy. Treatments were packaged according to a double‐dummy design. Each treatment pack contained a 1‐week supply of trial treatment, with each day’s supply consisting of 1 large capsule to accommodate the size of any dose level of Concerta (containing Concerta or placebo) and, depending on dose level, between 1 and 3 smaller Metadate CD‐sized capsules (containing Metadate CD or placebo) |
| Blinding of outcome assessment (detection bias)
All outcomes |
Unclear risk |
Not stated |
| Incomplete outcome data (attrition bias)
All outcomes |
Low risk |
Data from participants finishing the whole trial (n = 157) and from the ITT population (n = 184)
Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no |
| Selective reporting (reporting bias) |
Unclear risk |
No protocol identified |
