Riggs 2011.

Study characteristics
Methods	16‐week, randomised, 11‐centre, parallel‐group trial with 2 arms: OROS‐MPH placebo Participants in both medication groups received manual‐standardised, individual CBT through motivational enhancement approaches throughout the 16‐week medication trial
Participants	Number of participants screened: 1334 prescreened, 450 were consented and screened. An unknown number was included in the pre‐randomisation titration phase. Number of participants included: 303 (239 boys, 64 girls) Number of participants followed up: 303 (MPH 151, placebo 152) Number of withdrawals 76 (MPH 33, placebo 43) Diagnosis of ADHD: DSM‐IV (combined (68.6%), hyperactive‐impulsive (2.6%), inattentive (28.1%)) Age: mean 16.5 years (SD 1.3; range 13‐18) IQ: all participants were cognitively normal MPH‐naive: not stated Ethnicity: Hispanic (15.2%) Race: white (61.7%), African American (23.2%), Asian (1.3%), Native American/Alaskan (1.0%), other (12.7%) Country: USA Setting: outpatient clinic Comorbidity: major depressive disorder (12.5%), CD (32.3%), non‐nicotine substance use disorder (100%) Comedication: drug/alcohol use Other sociodemographics: none Differences between groups : No statistically significant differences in baseline demographics were noted between the 2 groups Inclusion criteria Meets DSM‐IV diagnostic criteria for ADHD Meets DSM‐IV diagnostic criteria for ≥ 1 non‐nicotine substance use disorder DSM‐IV ADHD Symptom Checklist score ≥ 22 derived from the adolescent‐completed checklist Exclusion criteria Serious medical illness or cardiac illness History of tic disorder Pregnant or breastfeeding Meets DSM‐IV criteria for current or lifetime psychotic disorder Meets DSM‐IV criteria for current or lifetime bipolar disorder Requires/or prescribed other concurrent psychotropic medication Taking any medications that may produce interactions with OROS‐MPH Opiate dependence Methamphetamine abuse, dependence or past month use Suicidal risk Enrolled in an inpatient, residential, day treatment or outpatient substance abuse programme within 28 days before signing consent Participation in other substance or mental health treatment Exploratory analyses of treatment response (ADHD‐RS) ADHD subtypes Defined according to DSM‐IV criteria (i.e. inattentive subtype with ≥ 6 inattentive symptoms and not ≥ 6 hyperactive‐impulsive symptoms) Number of participants excluded: 13 because they did not meet criteria for a subtype, 14 because they did not meet criteria for hyperactive‐impulsive subtype Number of participants included: inattentive subtype 103, combined subtype 173. Subtypes did not differ with regard to age or ethnicity but did differ with regard to sex, comorbid CD, inattentive and hyperactive‐impulsive symptoms and dependence diagnoses More strictly defined subtypes (i.e. strict inattentive subtype with ≥ 6 inattentive symptoms and ≤ 3 hyperactive‐impulsive symptoms; strict combined type with ≥ 6 inattentive symptoms and ≥ 8 hyperactive‐impulsive symptoms) Number of participants included: inattentive subtype 52, combined subtype 97 Major depressive disorder comorbidity 38 participants with major depressive disorder, 265 without major depressive disorder Number of participants randomly assigned MPH: 19 with major depressive disorder, 133 without major depressive disorder placebo: 19 with major depressive disorder, 132 without major depressive disorder No significant differences between groups were noted with regard to ADHD symptom severity, comorbid CD or substance abuse or dependence diagnoses. Differences between groups were noted with regard to age, sex, court mandate to substance treatment and days of past‐month non‐nicotine substance use Comorbid CD 299 participants included in this analysis. 4 were excluded because they did not have a non‐tobacco substance use disorder or did not meet inclusion criteria for ADHD Number of participants randomly assigned: MPH 48 with CD, placebo 49 with CD
Interventions	Participants were randomly assigned to OROS‐MPH or placebo Number randomised to each group: MPH 151, placebo 152 Mean MPH dosage at the end of treatment: 68 mg Administration schedule: single dose in the morning Duration of intervention: 16 weeks Titration period: 2 weeks post‐randomisation Treatment compliance: 79% (pill counts), 82.3% (self‐reports)
Outcomes	ADHD symptoms ADHD‐RS, clinician‐administered, adolescent informant: rated at baseline and weekly for 16 weeks ADHD‐RS, clinician‐administered, parent informant: rated at weeks 8 and 16 Serious AEs Systematically assessed by medical clinicians during weekly visits Non‐serious AEs Systematically assessed by medical clinicians during weekly visits Laboratory assessments ascertained at baseline and at 16 weeks included liver function testing, complete blood count with differential and urinalysis Massachusetts General Hospital Abuse and Diversion Questionnaire, self‐administered and completed monthly Massachusetts General Hospital Liking Scale completed at trial weeks 4, 8, 12 and 16. Relevant subscales: feeling high, feeling depressed, craving medication, craving substances
Notes	Sample calculation: yes; sample size of 300 participants was calculated for ADHD‐RS Ethics approval: yes; Institutional Review Boards approved the protocol before participant enrolment Comments from trial authors One participant did not meet diagnostic criteria for ADHD, and 1 did not have a score ≥ 22 on the ADHD‐RS, but both were included in analyses 2 participants did not meet diagnostic criteria for a non‐tobacco substance use disorder but were included in analyses Results of this study add to the growing suspicion that CBT (for substance use disorder) may contribute to ADHD treatment response and warrants further investigation Limitations: this study was not powered to address safety, and no current consensus exists regarding the most valid outcome measures for ADHD in adolescents with or without substance use disorder Key conclusions of trial authors OROS‐MPH did not show greater efficacy than placebo for ADHD or greater reduction in substance use among adolescents concurrently receiving individual CBT for co‐occurring substance use disorders OROS‐MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures With good monitoring, and in the context of substance abuse treatment, OROS‐MPH can be used safely in adolescents with a substance use disorder despite non‐abstinence Higher baseline use of alcohol and cannabis was associated with increased risk of experiencing a treatment‐related AE with OROS‐MPH, but baseline use did not increase the risk of serious AEs or of any particular category of AEs For adolescent misuse/diversion of OROS‐MPH, results suggest that OROS‐MPH was not misused/diverted to a greater extent than placebo and was not impacted by baseline substance use severity Despite baseline differences, both inattentive and combined subtypes responded equally to treatment, suggesting limited relevance for subtype designation in treatment planning ADHD symptom severity (based on DSM‐IV ADHD‐RS) followed a slightly different course of improvement, although with no differences between the group with comorbid major depressive disorder and the group without major depressive disorder in baseline or 16‐week symptom severity, or in 16‐week reduction: presence of major depressive disorder was not associated with ADHD treatment response in this sample Interaction effects showed that OROS‐MPH improved substance use disorder outcomes among adolescents with comorbid CD compared with placebo Although severe substance use disorder may require more intensive psychosocial treatment, OROS‐MPH may improve substance treatment outcomes among adolescents with comorbid attention and conduct problems Inclusion of MPH responders only/exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: unclear. Participants underwent a 2‐week titration period prior to randomisation. It is not reported if any participants withdrew during the titration period due to AEs or lack of efficacy. Any withdrawals due to AEs: reasons for withdrawals not stated Funding source: OROS‐MPH and matching placebo were supplied to the Clinical Trials Network contract pharmacy (EMINENT Services Corporation) by McNeil Consumer and Specialty Pharmaceuticals (distributor for Concerta), at no cost. Comment from review authors Data are influenced by drug abuse, especially data on AEs, but no statistically significant differences between OROS‐MPH and placebo in self‐reported medication abuse were noted. Email correspondence with trial authors: December 2013. We obtained supplemental information (IQ, allocation concealment and detailed description of 1 of the serious AEs)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly assigned to OROS‐MPH or matching placebo in a 1:1 ratio, stratified by site and completed by computer at a centralised location
Allocation concealment (selection bias)	Low risk	Product was supplied in pre‐randomly assigned kits containing individual bottles. Kits and bottles were labelled with the protocol number and treatment/randomisation number. Labeling protected the trial, ensuring that it remained blinded, and indicated that the medication was investigational
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Sites were provided blinded medication bottles for each randomly assigned participant Masking: double‐blinded (participant, caregiver, investigator, outcomes assessor)
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	Low risk	Primary analyses were ITT, including all randomly assigned trial participants Completers (N = 227) were not different from non‐completers (N = 76) in baseline demographic or clinical characteristics, and the proportion of completers did not differ by treatment assignment Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias)	Low risk	No indication of selective reporting.