| Study characteristics |
| Methods |
7‐week, multi‐centre, double‐blind, parallel, dose‐optimised trial with 3 arms:
LDX dimesylate OROS‐MPH placebo
|
| Participants |
Number of participants screened: not stated
Number of participants included: 221 (181 boys, 40 girls) (To the MPH and placebo group, not the LDX group)
Number of participants followed up: MPH 74, placebo 42
Number of withdrawals: MPH 38, placebo 68
Diagnosis of ADHD: DSM‐IV‐TR (combined (MPH 86.4%, placebo 79.1%), hyperactive‐impulsive (MPH 0.9%, placebo 6.4%), inattentive (MPH 12.7%, placebo 14.5%)
Age: mean 10.9 years (range 6‐17)
IQ: normal
MPH‐naive: MPH 60 (54.1%), placebo 58 (52.7%)
Ethnicity: white (MPH 96.4%, placebo 98.2%), African American (0%), Asian (0%), Hispanic/Latino (MPH 1.8%, placebo 0%)
Countries: Germany, Sweden, Spain, Hungary, France, UK, Italy, Belgium, Poland, the Netherlands
Setting: outpatient clinic
Comorbidity: ODD (MPH 9.0%, placebo 7.3%), concomitant psychiatric diagnosis (MPH 26.1%, placebo 18.2%)
Comedication: not stated
Other sociodemographics: no significant differences in baseline demographics were noted between the 2 groups
Inclusion criteria
Boys and girls 6‐17 years of age Meeting criteria for ADHD according to DSM‐IV‐TR Baseline ADHD moderate severity with ADHD‐RS‐IV score of ≥ 28 Age‐appropriate intellectual functioning BP measurements within the 95th percentile for age, sex and height Ability to swallow a capsule Girls of childbearing potential had to have a negative urine pregnancy test at baseline and to comply with any contraceptive requirements of the protocol
Exclusion criteria
Failure to respond to previous OROS‐MPH therapy Presence of a CD (excluding ODD) Pregnancy or lactation Weight < 22.7 kg; BMI > 97th percentile for age and sex Positive urine drug test (with the exception of patient’s current ADHD therapy) Clinically significant ECG or laboratory abnormalities Suspected substance abuse or dependence disorder (excluding nicotine) within the previous 6 months History of seizures Tics or Tourette’s disorder Known structural cardiac abnormality Any other condition that might increase vulnerability to the sympathomimetic effects of a stimulant drug Patients whose current ADHD medication provided effective control of symptoms with acceptable tolerability Patient currently considered a suicide risk, with previous suicide attempt or with history of, or currently demonstrating, active suicidal ideation Patient with glaucoma Patient with documented allergy, hypersensitivity or intolerance to amphetamine or MPH Patient with documented allergy, hypersensitivity or intolerance to any excipients in test or reference products Patients with known family history of sudden cardiac death or ventricular arrhythmia Patients with pre‐existing severe gastrointestinal tract narrowing (pathological or iatrogenic) Patients unable to tolerate the trial drug were withdrawn from the trial
|
| Interventions |
Participants were randomly assigned to OROS‐MPH or placebo
Number of participants randomly assigned: MPH 112, placebo 111
Mean MPH dosage: 45.4 ± 12.7 mg/d (9.9% 18 mg, 19.8% 36 mg, 53.2% 54 mg)
Administration schedule: once/d, 7:00 am
Duration of intervention: 7 weeks
Titration period: 4‐week stepwise dose‐optimisation period after randomisation. 3‐week dose‐maintenance period followed by 1‐week washout and safety follow‐up
Treatment compliance: 2 discontinued in placebo group because of non‐compliance, 3 in MPH group |
| Outcomes |
ADHD symptoms
ADHD‐RS‐IV: total score at endpoint, investigator‐rated at baseline and weekly for 7 weeks. Endpoint was defined as the last on‐therapy, post‐randomisation treatment visit with a valid ADHD‐RS‐IV, total score
Quality of life
Health Utilities Index‐2: parent‐rated at baseline and at weeks 4 and 7. Scoring ranges from 0.00 (dead) to 1.00 (perfect health). Higher scores represent better health status Child Health and Illness Profile, Child Edition: Parent Report Form: parent‐rated at baseline and at weeks 4 and 7. Questionnaire comprises 76 items classed into 5 domains and 12 associated subdomains. Most items relate to the past 4 weeks; the remainder are not associated with a specific time period. Parents use a 5‐point response format to assess each item. Achievement is considered the primary health‐related quality of life outcome
Non‐serious AEs
Safety assessments included TEAEs, clinical laboratory evaluations, physical examinations, vital signs and ECGs, observer‐rated weekly for 8 weeks
|
| Notes |
Sample calculation: yes
Ethics approval: approved by an independent ethics committee/institutional review board and regulatory agency at each centre (as appropriate) before trial initiation
Comments from trial authors
Individuals with comorbid conditions, such as PTSD, bipolar affective disorder or severe anxiety disorder, were excluded from this trial As a result of European regulations, the maximum dose of OROS‐MPH administered in this trial was 54 mg/d. However, it is possible that the smaller than usual placebo response did, at least in part, contribute to this large treatment effect. ADHD is currently less frequently diagnosed in Europe than in North America, with evidence of underrecognition and underdiagnosis (healthcareimprovementscotland.org). Consequently, it is likely that individuals who are diagnosed are at the more severe end of the spectrum and therefore would be less likely to show a response to placebo. Consistent with this suggestion, reassessment of data from the MTA trial revealed that children who had been diagnosed with ADHD on the basis of DSM‐IV criteria, but also met the more restrictive ICD‐10 criteria for hyperkinetic disorder, showed a more robust response to medication compared with those who met DSM‐IV criteria alone
Key conclusions of trial authors
In this European 7‐week phase III trial, LDX dimesylate was more effective than placebo in improving symptoms in children and adolescents with ADHD Compared with placebo, significant improvements in both ADHD core symptoms and global functioning were observed LDX dimesylate was well tolerated, with TEAEs consistent with those reported in previous studies Robust efficacy outcomes were also observed for OROS‐MPH, which was included in this trial as a reference arm
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: yes, 2 in the MPH group and 2 in the placebo group (as well as 5 in the LDX dimesylate group)
Funding source: Shire Development LLC |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Interactive voice/web response system was used to allocate a unique randomisation number to each participant. Randomisation was stratified by country and age group (6 to 12 or 13 to 17 years of age) |
| Allocation concealment (selection bias) |
Low risk |
Interactive voice/web response system |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
Trial drugs were over‐encapsulated and appeared identical |
| Blinding of outcome assessment (detection bias)
All outcomes |
Low risk |
Masking: double‐blinded (participant, caregiver, investigator, outcomes assessor) |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
LOCF approach was used when efficacy assessments were incomplete for a participant owing to early withdrawal from the trial or for missing data. However, as the review authors cannot understand the relationship between the n of the full analysis set and the endpoint data, we assessed risk of bias as unclear
Selection bias (e.g. titration before randomisation → exclusion): no |
| Selective reporting (reporting bias) |
Low risk |
Outcomes according to protocol |
