Hardan 2019.

Study characteristics
Methods	‐week trial of memantine versus placebo
Participants	Inclusion criteria: had completed open‐label trial preceding the double‐blind trial, was classified as a 'responder' ( The responder criterion was defined as having at least a 10‐point improvement (reduction in score) in the Social Responsiveness Scale (SRS) total raw score relative to the Visit 1 total raw score in Study MEM‐MD‐91) during the open‐label trial children 6‐12 years of age diagnosis of Asperger's or ASD based on DSM‐5 criteria IQ score ⩾50 on the Kaufman BriefIntelligence Test, Version 2 (or other standardized IQ test), ABC‐I score < 17 Exclusion criteria: children with a concurrent medical condition that may confound the interpretation of study results significant risk of suicidality history of significant renal, hepatic, cardiovascular, respiratory, gastrointestinal, neurologic, endocrine, or other disorders Setting/location: paediatric outpatient settings at multiple study sites (92 sites in 15 countries) Sample size: 158 and 160 randomised to memantine and placebo groups respectively and 108 and 116 completed the trial Number of withdrawals/dropouts: 8 (placebo 1 protocol violation, 1 consent withdrawal; memantine reduced dose 1 did not meet eligibility criteria; memantine full dose 1 did not meet eligibility criteria, 3 protocol violation, 1 LTFU) Gender: placebo 88.8% were male, memantine 84.1% were male Mean age: placebo mean age 8.9 years, memantine mean age 9.2 years IQ: placebo mean IQ 93.3, memantine mean IQ 91.1 Baseline ABC‐I or other BoC: not reported Concomitant medications: "83.8% of participants were taking concomitant medications and supplements, most commonly (≥ 10.0%) melatonin (17.0%), multivitamin (15.9%), ibuprofen (11.4%), risperidone (10.6%), and paracetamol (10.3%)" History of previous medications: not reported
Interventions	Intervention (memantine): doses were based on weight; ≥ 60 kg maximum 15 mg/day, 40‐59 kg maximum 9 mg/day, 20‐39 kg maximum 6 mg/day, < 20 kg maximum 3 mg/day. These doses were reduced to 6 mg/day, 3 mg/day, 3 mg/day and 3 mg every other day, for each respective group. Comparator (placebo): matching placebo for 12 weeks
Outcomes	Primary outcomes: irritability (ABC‐I) (Aman 1985) AEs Secondary outcomes: tolerability
Notes	Study start date: May 2009 Study end date: August 2012 Funding: "Funding for these studies was provided by Forest Research Institute (Jersey City, NJ), the sponsor at the time the studies were conducted." Conflicts of interest: none declared Trial registry: NCT00872898
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Premier, Inc. provided Interactive Web Response System (IWRS) services for randomization."
Allocation concealment (selection bias)	Unclear risk	Details not provided
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind ‐ no further details provided
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind ‐ no further details provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	Low dropout; an ITT analysis was used that included all participants with at least 1 post‐baseline outcome assessment.
Selective reporting (reporting bias)	High risk	ABC‐I (change from baseline) was mentioned as an outcome in the paper, but it was not reported, only "At week 12, no clinically meaningful changes from baseline were observed between treatment groups on the additional efficacy variables, CGI‐I and CGI‐S, ABC‐C, or SRS [Social Responsiveness Scale] subscales and SRS total raw score."
Other bias	High risk	Funding for these studies was provided by Forest Research Institute (Jersey City, NJ), the sponsor at the time the studies were conducted. Writing support was funded by Allergan plc (formerly Forest Research Institute; Madison, NJ). Two of the listed study authors were employed by the sponsor.