McCracken 2016.

Study characteristics
Methods	An 8‐week parallel‐trial with 3 arms: weeks 1‐4: placebo; weeks 5‐8: placebo + ER‐D‐MPH weeks 1‐4: IR‐guanfacine; weeks 5‐8: IR‐guanfacine + placebo weeks 1‐4: IR‐guanfacine; weeks 5‐8: IR‐guanfacine + ER‐d‐MPH Phases: 2
Participants	Number of participants screened: 323 Number of participants included: 212; 5 withdrew, before receiving trial drug, leaving 207 participants (142 (68%) boys, 65, (32%) girls) Number of participants followed‐up: 182 (ER‐d‐MPH = 61, IR‐guanfacine = 60, IR‐guanfacine+ER‐d‐MPH = 61) Number of withdrawals: 30 (including 5 before receiving trial drug) (ER‐d‐MPH = 9, IR‐guanfacine = 11, IR‐guanfacine+ER‐d‐MPH = 10) Diagnosis of ADHD: DSM‐IV (information available for 202 participants: 105 (51% ) combined, 5 (2%) hyperactive/impulsive, 92 (44%) inattentive) Age: mean 10.0 years (SD2.1, range 7‐14) IQ: mean 102.4 (SD 13.5) MPH‐naive: not stated Ethnicity: Hispanic (n = 44, 21.3%). Race reported: white (n = 143, 69%), African American (n = 36, 17%), Asian, Pacific Islander (n = 16, 8%), other (n = 12, 6%) Country: USA Setting: not stated Comorbidity: ODD 68 (33%) Comedication: CNS medication not allowed Additional Sociodemographics: none Inclusion criteria 7‐14 years Diagnosis of DSM‐IV ADHD by K‐SADS‐PL and confirmed by clinical interview CGI‐S score of at least 4 for ADHD Resided with primary carer for at least 6 months prior to trial entry Exclusion criteria History of autism, pervasive developmental disorder, chronic tic disorder, psychosis, or bipolar disorder Current major depression or panic disorder SBP or DBP at screening > 95th percentile or < 5th percentile for age and BMI Any medical condition that might make stimulant or alpha agonist therapy medically inadvisable Need for chronic use of other medications with CNS effects Pregnant, breastfeeding, or beyond menarche and has a positive urine pregnancy test History of structural heart defects, syncope, or fainting while exercising Clinically significant cardiac abnormality as determined by ECG at trial entry Intellectual disability as determined by clinical functional assessment and an IQ estimate of < 70 based on Wechsler Adult Intelligence Scale (WAIS) subtests
Interventions	Participants were randomly assigned to 3 different treatment sequences covering the periods baseline, weeks 1‐4, and weeks 5‐8 as follows: sequence 1: placebo (weeks 1‐4) ‐ placebo + ER‐d‐MPH (weeks 5‐8) sequence 2: IR‐guanfacine (weeks 1‐4) ‐ IR‐guanfacine + placebo (weeks 5‐8) sequence 3: IR‐guanfacine (weeks 1‐4) ‐ IR‐guanfacine + ER‐d‐MPH (weeks 5‐8) ER‐d‐MPH (sequence 1 and 3) was given to participants < 25 kg at 5 mg on week 5, 10 mg to participants > 25 kg with an increase of 5 mg/week until week 7 IR‐guanfacine (sequence 2 and 3) was initiated at 0.5 mg then increased to 1 mg and increased by 0.5 mg each week until week 3. If Clinical‐Global Impression—Improvement ratings were either 1 or 2, no dose increases were made Placebo was mirrored Number randomised to each group: 70 ER‐d‐MPH, 71 IR‐guanfacine, 71 IR‐guanfacine + ER‐d‐MPH Mean medication dosage: mean final (week 8) daily doses of: ER‐d‐MPH: 16.0 mg (± 3.9) IR‐guanfacine: 2.2 mg (± 0.7) IR‐guanfacine + ER‐d‐MPH: IR‐guanfacine 2.4 mg (± 0.6), ER‐d‐MPH 15.1 mg (± 4.8) Mean mg/kg daily doses of guanfacine were 0.06 (+ 0.03) mg/kg/d for both guanfacine groups Administration schedule: twice daily ER‐d‐MPH: once daily for placebo, once daily for ER‐d‐MPH IR‐guanfacine: twice daily for IR‐guanfacine, once daily for placebo IR‐guanfacine + ER‐d‐MPH: twice daily for IR‐guanfacine, once for ER‐d‐MPH IR‐guanfacine and IR‐guanfacine placebo; twice daily, ER‐d‐MPH and ER‐d‐MPH placebo; once daily Duration (of (each) medication): IR‐guanfacine 8 weeks, ER‐d‐MPH 4 weeks, placebo (sequence 2) 4 weeks, placebo (sequence 1) 8 weeks Washout before trial initiation: not stated Medication‐free period between interventions: no Treatment compliance: not stated
Outcomes	ADHD symptoms ADHD‐RS‐IV Serious AEs Spontaneous reporting Non‐serious AEs Assessed by a modification of the Physical Symptoms Checklist 48 Open‐ended clinician inquiry Vital signs ECG AE recordings
Notes	Sample calculation: not stated Ethics approval: yes; “All study procedures were approved by the University of California, Los Angeles (UCLA) institutional review board and were overseen by a data safety and monitoring board." Comments from trial authors “[…] We note that this differs by degree from a traditional 3‐arm longitudinal design with each arm receiving a specific treatment over the entire study period, but this is a hybrid sequential within‐/between subjects design. This design arose from the clinical and ethical need to keep trial length and placebo‐only exposure to a minimum. However, the within‐subject component also increases statistical power.” “Larger group sizes would have enabled more conclusive tests of treatment differences.” “Our study design began with guanfacine first, with the addition of a stimulant second, which may yield differences in comparison to those study designs adding guanfacine to ongoing stimulants, and, like any sequential design, may blur the timing of individual treatment effects when combined.” Key conclusion of trial authors “ The clinical implications of our results suggest that combination of DMPH and GUAN over 8 weeks is associated with substantial clinical benefits on ADHD symptoms in the short term, and is more successful at approaching contemporary goals for ADHD treatment.” “Our results also support the acceptable safety profile of COMB treatment.” Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: no Any withdrawals due to AEs: yes, IR‐guanfacine =1, Er‐d‐MPH 1, IR‐guanfacine + ER‐d‐MPH = 2 Funding source: NIMH Research Center grant P50MH077248, “Translational Research to Enhance Cognitive Control” (JTM) Email correspondence with trial authors: September 2021. We received supplemental information regarding risk of bias assessment through personal email correspondence with the trial authors in September 2021 (Storm 2021e [pers comm])
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised based on a computer‐generated program to yield a 1:1:1 allocation to the 3 different treatment sequences
Allocation concealment (selection bias)	Low risk	Dosing clinicians were blinded to group assignment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	At the time of submission of a participant found to be eligible into the centralised database, the program generated the treatment sequence assignment, which was then sent electronically to the Research Pharmacist only and was not shared with any trial staff. All staff involved in clinical assignments remained blinded, as were participants. Participants were blinded by use of uniform over‐encapsulation of drug or placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	A blinded clinician without knowledge of AEs completed the CGI‐S and ADHD‐RS‐IV at baseline and at the end of each within‐participant condition or last visit based on parent, participant and other available data.
Incomplete outcome data (attrition bias) All outcomes	High risk	Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): yes, exclusion of 1 non‐responder
Selective reporting (reporting bias)	Low risk	No indication of selective reporting. The secondary outcome Tests of Academic Performance is set in the second phase of the trial. Analysis has not yet been completed or published.