| Study characteristics |
| Methods |
A 6‐week parallel trial with 3 arms:
Phases: 4 (4‐week screening/washout, 4 weeks forced titration, 2‐week maintenance dosage, 1‐week follow‐up phone‐call) |
| Participants |
Number of participants screened: 778
Number of participants included: 549 (330 to relevant interventions). 547 started treatment (361 boys, 186 girls)
Number of participants followed‐up: 464
Number of withdrawals: 85 (of which 2 were before treatment start)
Diagnosis of ADHD: DSM‐IV‐TR (358 combined, 8 hyperactive‐impulsive and 181 inattentive)
Age: 14.7 (SD 1.4, range 13‐17)
IQ: not stated
MPH‐naive: not stated
Ethnicity: Hispanic/Latino (n = 101), not Hispanic/Latino (n = 446). Race: white (n = 401), black/African American (n = 110), native Hawaiian/Pacific Islander (n = 2), Asian (n = 8), American Indian or Alaska native (n = 3), other (n = 3), multiple (n = 20)
Country: USA
Setting: outpatient clinic
Comorbidity: only ODD and mild stable asthma were not exclusionary criteria
Comedication: stable use of bronchodilator inhalers is not exclusionary
Additional sociodemographics: none
Inclusion criteria
13‐17 years of age at the time of consent Weight > 79.5 lb (approx 36 kg) The parent/legal representative must be available at approximately 7:00 am (± 2 h) Female participants must have a negative serum beta‐HCG pregnancy test and a negative pregnancy test and agree to comply with any applicable contraceptive requirements of the protocol Participant has an ADHD‐RS‐IV total score ≥ 28 Participant is able to swallow a capsule Participant does not have hypertension and has a resting sitting BP ≤ 135/85 mmHg
Exclusion criteria
Participant has a current, controlled (with medications prohibited in this trial) or uncontrolled, comorbid psychiatric diagnosis with significant symptoms such as any significant comorbid Axis II disorder or significant Axis I disorder (such as PTSD, psychosis, bipolar illness, pervasive developmental disorder, severe OCD, depressive or anxiety disorder Diagnosis of CD. ODD is not exclusionary Participant is considered a suicide risk, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation. Participants with intermittent passive suicidal ideation are not necessarily excluded Participant is underweight or overweight Participant has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition. Mild, stable asthma is not exclusionary Participant has a history of seizures (other than infantile febrile seizures), a chronic or current tic disorder, or a current diagnosis and/or a known family history of Tourette's Disorder Participant has a known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place him/her at increased vulnerability to the sympathomimetic effects of a stimulant medication Participant has a known family history of sudden cardiac death or ventricular arrhythmia Participant has any clinically significant ECG or clinically significant laboratory abnormality Participant has current abnormal thyroid function, defined as abnormal thyroid stimulating hormone (TSH) and thyroxine (T4). Treatment with a stable dose of thyroid medication for at least 3 months is permitted Participant has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the investigational product Participant has a documented allergy, hypersensitivity, or intolerance to MPH or to any excipients in the reference product Participant has failed to fully respond to an adequate course(s) (dose and duration) of MPH or amphetamine therapy Participant has a history of suspected substance abuse or dependence disorder (excluding nicotine). Participants with a lifetime history of amphetamine, cocaine, or other stimulant abuse and/or dependence will be excluded. Participant has a positive urine drug result Participant has previously participated in this trial or another clinical trial involving SPD489/NRP104 Participant has glaucoma Participant is required to take or anticipates the need to take medications that have CNS effects or affect performance, such as sedating antihistamines and decongestant sympathomimetics, or are MAOIs. Stable use of bronchodilator inhalers is not exclusionary Participant is female and is pregnant or lactating Participant is well controlled on his/her current ADHD medication Participant has a pre‐existing severe gastrointestinal tract narrowing
|
| Interventions |
Participants were randomly assigned to 3 different groups of LDX, MPH or placebo
Number randomised to each group: placebo 110, LDX 219, OROS‐MPH 220
Mean medication dosage: forced dosage: LDX week 1, 30 mg/d; week 2, 40 mg/d; week 3, 50 mg/d) and then in a 20‐mg increment (week 4) to a maximum of 70 mg/d; initial OROS‐MPH dose (18 mg/d) was increased weekly in 18‐mg increments to a maximum of 72 mg/d during weeks 2 through 4
Dosage could only be increased or be kept as it was
Administration schedule: not stated
Duration (of (each) medication): 6 weeks
Washout before trial initiation: 4 weeks of screening/washout
Titration period: 4 weeks
Treatment compliance: not stated |
| Outcomes |
ADHD symptoms
Serious AEs
C‐SSRS Spontaneous reporting
Non‐serious AEs
|
| Notes |
Sample calculation: no
Ethics approval: yes. Trial protocols and related information were approved by either a central review board or institution‐specific review boards and appropriate regulatory agencies (US FDA, Therapeutic Product Directorate of Canada, Medical Products Agency of Sweden, Medical Research Council of Hungary, The Federal Institute for Drugs and Medical Devices [Bundesinstitut für Arzneimittel und Medizinprodukte] of Germany) before trial initiation.
Key conclusion of trial authors
LDX dimesylate was superior to OROS‐MPH for improving ADHD symptoms in a forced‐dose trial but not in a flexible‐dose trial. Both LDX and OROS‐MPH are highly efficacious in treating adolescents with ADHD and are generally well tolerated, demonstrating that either stimulant class can be used with confidence. This may be important in cases of inadequate response or poor tolerability to one of the stimulant classes (as has previously been reported), although the sequencing of treatment was not assessed in these studies. The overall safety and tolerability profiles of LDX and OROS‐MPH were consistent with previous reports. LDX may have a somewhat higher effect size than OROS‐MPH at US FDA‐approved doses, though with perhaps slightly numerically higher rates of AEs.
Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes
Any withdrawals due to AEs: yes, 30 (15 in LDX group)
Funding source: Shire
Email correspondence with trial authors: September and October 2021. We contacted the trial authors for information regarding risk of bias through personal email in September and October 2021, but no answer was received. |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Participants were randomised (2:2:1) using an interactive web‐response system to once‐daily LDX, OROS‐MPH, or placebo, respectively |
| Allocation concealment (selection bias) |
Unclear risk |
Not stated |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
To maintain blinding, treatments were identical in appearance; participants were also instructed to take one capsule from 2 separate bottles |
| Blinding of outcome assessment (detection bias)
All outcomes |
Unclear risk |
Not stated |
| Incomplete outcome data (attrition bias)
All outcomes |
High risk |
No imputation for ADHD‐RS‐IV, LOCF for CGI‐S.
Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): yes, participants excluded due to lack of efficacy |
| Selective reporting (reporting bias) |
Low risk |
Reported according to protocol |
