Manos 1999.

Study characteristics
Methods	4‐week, double‐blind titration, placebo‐controlled protocol. Cross‐over trial with 2 interventions in 4 doses: MPH 5 mg × 2 daily MPH 10 mg × 2 daily MPH 15 mg × 2 daily placebo × 2 daily Phases Cross‐over trial with MAS (Adderall) and MPH. First phase was not blinded. (The child’s paediatrician or family physician determined whether MPH or MAS (Adderall) should be prescribed; criteria were the physician’s familiarity with the agent and whether he or she wanted the participant to receive a single dose (MAS) or a twice‐daily dose (MPH) of medication treatment for ADHD.) Second phase: a 1‐of‐3 medication dose sequence was randomly assigned. 15 mg MPH was always given after 10 mg MPH 42 of the 117 participants receiving MPH were matched, with 42 receiving MAS (Adderall) Best dose was compared with placebo. Best dose was assigned by consensus of a clinical child psychologist and a board‐certified child and adolescent psychiatrist before the medication blind was broken Manos 1999: "7 youths given MPH and 4 given Adderall [MAS] did not receive the 15 mg dose of medication. The decision to forego the 15 mg condition was based on the paediatrician’s assessment that the child was too young or underweight for this high dose and our assessment that the best dose had already been achieved at a lower dose"
Participants	Number of participants screened: 195 Number of participants included: 177. (33 boys, 9 girls) Number of participants followed up: 134 Number of withdrawals: 43 Diagnosis of ADHD: DSM‐IV (combined (55%), inattentive (45%)) Age: mean 10.1 years (SD not stated, range 5‐17) IQ: > 70 MPH‐naive: not stated Ethnicity: white (93%), African American (7%), Asian (0%), Hispanic (0%), others (0%) Country: USA Setting: outpatient clinic Comorbidity: no significant comorbid disorders. Although no formal comorbidity data are available, it appears that psychiatric comorbidity was modest in this cohort Comedication: not stated Sociodemographics: predominantly well educated Manos 1999 and Faraone 2002 (secondary reference under Manos 1999): 42 were participants matched to the MAS (Adderall) group in order of diagnostic category, age and sex. Only these 42 of 117 receiving MPH were compared with the MAS (Adderall) group   Findling 2001a (secondary reference under Manos 1999): 195 youths entered the trial. Data for a best dose were provided for 177 participants: 111 in the MPH group, 66 in the MAS group Diagnosis of ADHD: inattentive (47%), combined (53%). Inattentive subtype is over‐represented in the older age group Age group: 4‐8 years (mean 6.35) 69 (57 boys); 8‐11 years (mean 9.47) 56 (45 boys); 11‐17.59 years (mean 13.64) 52 (41 boys) Other sociodemographics: no significant differences in baseline demographics were noted between groups   Findling 2001b (secondary reference under Manos 1999): Number of participants included: 195 Number of participants completed: 137: MPH 82, MAS (Adderall) 55 Diagnosis of ADHD: DSM‐IV (combined (57%), inattentive (43%)) Age: mean 10 years (SD not stated, range 4‐17) IQ: > 70 Sex: 66 boys, 16 girls Ethnicity: white (84%), African American (6%), other (10%) Country: USA Comorbidity: without significant comorbid disorders Comedication: possible, but not recorded Sociodemographics: predominantly well educated. No differences in sex, ethnicity or ADHD subtype were found between MPH and MAS (Adderall) groups. No participants had a history of hypertension, hypotension or clinically significant cardiovascular disease Inclusion criteria "All children diagnosed with ADHD met full DSM‐IV diagnostic criteria for this disorder. The criteria are (1) presence of at least six symptoms for inattention and/or at least six symptoms for hyperactivity/impulsivity; (2) symptoms significantly interfering with functioning at home and at school as noted during structured or semi structured clinical interviews with the Computerized Diagnostic Interview for Children (CDISC); (3) symptom severity on broad‐band [i.e. Conners’ Abbreviated Symptoms Questionnaire (Conners, 1969)] and narrow‐band [e.g. ADHD‐RS (DuPaul, 1991)] rating scales at threshold or above (i.e. rated 2 or 3); (4) multiple raters (e.g. parents, teachers) agreed to the presence of the symptoms; and (5) empirical comparison with norms indicating at least a 1/5 SD cutoff on at least rating scale. It should be noted that in identifying the presence of symptoms, behaviours across informants were not pooled observations. Behaviours were considered significant only if two informants agreed to the presence of the symptom on rating scales or in interviews" (Findling 2001a, secondary reference under Manos 1999) Exclusion criteria No patients were excluded from the trial per se
Interventions	Participants were randomly assigned to different orders of 5 mg, 10 mg or 15 mg MPH and placebo Mean MPH dosage: best dose 9.1 mg‐10.4 mg Administration schedule: morning (at 8.00 am) and noon Duration of each medication condition: 1 week Washout before trial initiation: none Titration period: none Treatment compliance: 11 terminated because of AEs
Outcomes	ADHD symptoms Findling 2001a (secondary reference under Manos 1999): compared treatment for children and adolescents and weight‐adjusted dosing of MPH. Measurement instruments include the following ADHD‐RS Abbreviated Symptoms Questionnaire (Conners) Composite Rating and School Situations Questionnaire Revised, parent and teacher. Composite Rating, also observer‐rated. Rating every 7th day of each week’s dose and baseline. Best dose evaluated and compared with placebo and MAS (Adderall) Best dose based only on Abbreviated Symptoms Questionnaire ‐ Teacher. Does not separate MPH and MAS in tables Non‐serious AEs Side Effects Behavior Monitoring Scale by parents every week (symptoms were considered problematic if parents rated them as ≥ 5) BP and pulse every week Findling 2001b (secondary reference under Manos 1999) BP and pulse
Notes	Sample calculation: not stated Ethics approval: not stated Key conclusions of trial authors Manos 1999: both MPH and MAS have been shown to be effective treatments for children with ADHD Faraone 2002 (secondary reference under Manos 1999): the present report extends this prior work by applying drug–placebo response curve methods to the data reported by Manos 1999. Results show that the efficacy of MAS and MPH in improving functioning is seen throughout the full range of improvement scores. Both drugs prevent worsening and, for most patients, lead to improvements that are well into the normal range Findling 2001a (secondary reference under Manos 1999): data suggest that psychostimulants are equally effective in treating children and adolescents with ADHD. Adolescents with ADHD may not necessarily require more medication than younger children to achieve a similar therapeutic response Findling 2001b (secondary reference under Manos 1999): short‐term cardiovascular effects of both MAS and MPH were modest. No participants experienced any clinically significant change in these cardiovascular measures during the course of this brief trial Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; 15 youths in the MAS sample had been tried on MPH before enrolment in this medication trial. Because of lack of response or serious side effects, these children discontinued use of MPH. A total of 37% of the MAS sample subsequently was composed of children who had unsuccessfully used MPH but successfully responded to MAS Any withdrawals due to AEs: yes; Findling 2001a (11/195) (secondary reference under Manos 1999), due to multiple AEs Funding source: in part by from Shire Pharmaceutical Development Incorporated to Dr. Faraone Email correspondence with trial authors: April 2014. Emailed trial authors twice to request additional data but have received no answer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	First phase not blinded. MPH is a selected group
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	High risk	Clinician, teacher and parent were blinded only to dose, not to medication
Blinding of outcome assessment (detection bias) All outcomes	High risk	Clinician, teacher and parent were blinded only to dose, not to medication
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Only best dose compared with placebo. Findling (Abbreviated Symptoms Questionnaire) + 30 participants. Of 43 participants with < 4 weeks of data, 30 had only 3 weeks of data because physicians considered them too young or too small to receive 15 mg before initiating protocol Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): yes
Selective reporting (reporting bias)	Unclear risk	No protocol identified