Methods

Phase 1: single‐blind, aripiprazole, flexibly dosed, to aripiprazole (2 to 15 mg/d) for 13 to 26 weeks. Chldren and adolescents with a stable response (> 25% decrease in ABC‐I subscale score and rating of "much improved" or "very much improved" on CGI‐I subscale score for 12 weeks randomised into phase 2)

Phase 2: 1:1 randomisation to titrated dose of aripiprazole (2 to 15 mg/d) or placebo for 16 weeks in this double‐blind, randomised, placebo‐controlled, parallel‐group study

Participants

Sample size: 85 children/adolescents entered phase 2 (double‐blind randomisation), from 157 in phase 1 (single‐blind stabilisation)

Particpants randomised in phase 2

Sample size: 85 (intervention 41, placebo 44)

Sex: 17 girls (intervention 11, placebo 6), 68 boys (intervention 30, placebo 38)

Mean age: overall 10.4 (SD 2.8); intervention 10.1 (SD 2.80); placebo 10.8 (SD 2.77)

Race: 59 white (intervention 31, placebo 28), 19 black/African American (intervention 8, placebo 11), 3 Asian (0 intervention, 3 placebo), 1 American Indian/Alaskan Native (0 intervention, 1 placebo), 3 other (2 intervention, 1 placebo)

Inclusion criteria (both phases)

• Boys or girls

• Aged 6 to 17 years inclusive with current DSM‐IV‐TR diagnosis of autistic disorder and displays behaviours such as tantrums, aggression, self injurious behavior or a combination of these problems. Diagnosis of autistic disorder will be confirmed by ADI‐R

• Children/adolescent or designated guardian/caregiver is able to comprehend and satisfactorily comply with protocol requirements, in the opinion of the investigator

• Demonstrates behaviours such as tantrums, aggression or self injury or a combination of these problems

• ABC‐I subscale score ≥ 18 AND CGI‐S subscale score ≥ 4 at screening and baseline visits

• Mental age ≥ 24 months

Inclusion criteria (phase 2)

• Patients whose symptoms of irritability demonstrated a stable response to aripiprazole therapy for 12 consecutive weeks in phase 1. Response was defined as ≥ 25% decrease from baseline in caregiver‐rated ABC‐I and rating of 1 or 2 (“very much improved” or “much improved”) on the clinician‐rated CGI‐I

Interventions

Aripiprazole 2, 5, 10 or 15 mg/d or placebo

Outcomes

Primary outcome

• Percentage of children and adolescents relapsing by week 16, defined by 1 of 4 criteria:

  • ABC‐I score increase > 25% compared with end of phase 1 score and CGI‐I rating of "much worse" or "very much worse" relative to end of phase 1 for 2 consecutive visits

  • ABC‐I and CGI‐I scores as per above definition at 1 visit plus 'lost to follow‐up' at next visit

  • ABC‐I and CGI‐I scores as per above definition at 1 visit plus initiation of a prohibited drug to treat worsening symptoms of irritability associated with autistic disorder at the next visit

  • Child or adolescent discontinued because of hospitalisation for worsening symptoms of irritability associated with autistic disorder or because of lack of efficacy based on investigator assessment

Secondary outcomes

• Adjusted mean change from baseline to week 16 on ABC‐I subscale score (LOCF)

• Change from baseline in mean CGI‐I scale score at week 16

• Number of children and adolescents with death as outcome, serious adverse events and adverse events leading to discontinuation during phase 1

Notes

Study dates: March 2011 to June 2012

Study location: United States

Funding: Bristol‐Myers Squibb

Conflicts of interest

• Dr. Findling receives or has received research support from, acted as a consultant to, received royalties from and/or served on a speaker’s bureau for Abbott, Addrenex, Alexza, American Psychiatric Press, AstraZeneca, Biovail, Bracket, Bristol‐Myers Squibb, Dainippon Sumitomo Pharma, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson & Johnson, KemPharm, Lilly, Lundbeck, Merck, National Institutes of Health, Neuropharm, Novartis, Noven, Organon, Otsuka, Pfizer, Physicians Postgraduate Press, Rhodes Pharmaceuticals, Roche, Sage, Sanofi‐Aventis, Schering‐Plough, Seaside Therapeutics, Sepracore, Shionogi, Shire, Solvay, Stanley Medical Research Institute, Sunovion, Supernus, Transcept, Validus, WebMD and Wyeth

• Dr. Mankoski was an employee of Bristol‐Myers Squibb at the time the research was conducted and currently is a stock shareholder in Bristol‐Myers Squibb

• Dr. McQuade is an employee of Otsuka and holds stock in Bristol‐Myers Squibb

• Dr. Amatniek is an employee of and stock shareholder in Bristol‐ Myers Squibb and is a stock shareholder in Johnson & Johnson and Forest

• Drs. Marcus, Sheehan and McCartney and Mr. Eudicone are employees of Bristol‐Myers Squibb

• Mss. Timko and Lears are employees of and stock shareholders in Bristol‐Myers Squibb

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation was not described in the manuscript

Allocation concealment (selection bias)

Low risk

Randomisation was performed via a centralised call‐in system

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded aripiprazole or matching placebo was taken once daily

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Double‐blinded aripiprazole or matching placebo was taken once daily

Incomplete outcome data (attrition bias)
All outcomes

High risk

Not all raw data were provided

Selective reporting (reporting bias)

Low risk

All outcomes in protocol were reported in the study

Other bias

Low risk

From the report, it does not appear that any other sources of bias are present

Methods

Randomised 1:1:1:1 to aripiprazole (5, 10 or 15 mg/d) or placebo in this 8‐week double‐blind, randomised, placebo‐controlled, parallel‐group study

Participants

Sample size: 218 children and adolescents (intervention 166 (54 = 15 mg, 59 = 10 mg, 53 = 5 mg), placebo 52)

Sex: 23 girls (intervention 19 (4 = 15 mg, 9 = 10 mg, 6 = 5 mg), placebo 4), 195 boys (intervention 147 (50 = 15 mg, 50 = 10 mg, 47 = 5 mg), placebo 48)

Age: 166 between 6 and 12 years of age (intervention 131 (42 = 15 mg, 45 = 10 mg, 44 = 5 mg), placebo 35), 52 between 13 and 17 years of age (intervention 35 (12 = 15 mg, 14 = 10 mg, 9 = 5 mg), placebo 17)

Race: 155 white (intervention = 120 (42 = 15 mg, 41 = 10 mg, 37 = 5 mg), placebo = 35), 50 black (intervention = 37 (9 = 15 mg, 13 = 10 mg, 15 = 5 mg), placebo = 13), 46 Asian (intervention = 43 (0 = 15 mg, 42 = 10 mg, 1 = 5 mg), placebo = 3), 7 other (intervention = 6 (3 = 15 mg, 1 = 10 mg, 2 = 5 mg), placebo = 1)

Inclusion criteria

• Boys or girls

• Aged 6 to 17 years inclusive at the time of randomisation

• Meets current DSM‐IV‐TR diagnostic criteria for ASD and demonstrates serious behavioural problems; diagnosis confirmed by ADI‐R

• CGI scale score > 4 AND ABC‐I subscale score > 18 at screening and baseline

• Mental age ≥ 18 months

Interventions

Aripiprazole (5, 10 or 15 mg/day) versus placebo

Outcomes

Primary outcome

• Mean change (week 8 to baseline) in ABC‐I subscale score

Secondary outcomes

• Mean CGI‐I score

• Number of children and adolescents with response at week 8 (response defined as ≥ 25% reduction from baseline to endpoint in ABC‐I subscale score and CGI‐I score of 1 or 2 at endpoint)

• Mean change (week 8 to baseline) in CY‐BOCS (compulsion scale only)

• Mean change (week 8 to baseline) in other ABC subscale scores

• Mean change (week 8 to baseline) in CGI‐S

• Summary of safety, deaths, adverse events, serious adverse events, treatment‐emergent adverse events and adverse events leading to discontinuation

• Change from baseline in body weight

Notes

Study dates: June 2006 to June 2008

Study location: United States

Funding: Bristol‐Myers Squibb and Otsuka Pharmaceutical

Conflicts of interest

• Dr. Aman has received research support from and served as a consultant to Bristol‐Myers Squibb, Johnson & Johnson and Forest

• Dr. Marcus is an employee of Bristol‐Myers Squibb

• Dr. Owen is an employee of Bristol‐Myers Squibb

• Dr. Kamen is an employee of Bristol‐ Myers Squibb

• Dr. Manos is an employee of Bristol‐Myers Squibb

• Dr. McQuade is an employee of Otsuka Pharmaceutical Development and Commercializaion

• Dr. Carson is an employee of Otsuka Pharmaceutical Development and Commercializaion

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Although a double‐blind placebo‐controlled trial was described, the study did not describe how randomisation occurred

Allocation concealment (selection bias)

Unclear risk

Although a double‐blind placebo‐controlled trial was described, the study did not describe the method of concealment of allocation of intervention type

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Although a double‐blind trial was described, the study did not describe assurance of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Although a double‐blind trial was described, the study did not describe assurance of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Sufficient information was provided to address incomplete outcome data and how LOCF analysis of such data was performed. Excluded children and adolescents and reasons for exclusion were reported fully

Selective reporting (reporting bias)

Low risk

Study protocol is available; its pre‐specified, primary outcomes have been reported online to reduce the likelihood of selective reporting

Other bias

Low risk

From the report, it seems clear that no other risks of bias are present

Methods

Randomised 1:1 to flexibly dosed aripiprazole (target dose 5, 10 or 15 mg/d) or placebo in this 8‐week, double‐blind, randomised, placebo‐controlled, parallel‐group study

Participants

Sample size: 98 children/adolescents (intervention 47, placebo 51)

Sex: 12 girls (intervention 7, placebo 5), 86 boys (intervention 40, placebo 46)

Age: 83 between 6 and 12 years of age (intervention 46, placebo 37), 15 between 13 and 17 years of age (intervention 10, placebo 5)

Race: 73 white (intervention 41, placebo 32), 18 black (intervention 11, placebo 7), 2 Asian (2 intervention, 0 placebo), 5 other (intervention 2, placebo 3)

Inclusion criteria

• Boys or girls

• Aged 6 to 17 years inclusive at the time of randomisation

• Meets current DSM‐IV‐TR diagnostic criteria for ASD and demonstrates serious behavioural problems; diagnosis confirmed by ADI‐R. CGI score > 4 AND ABC‐I subscale score > 18 at screening and baseline

• Mental age ≥ 18 months

Interventions

Aripiprazole (5, 10 or 15 mg/d) versus placebo

Outcomes

Primary outcome

• Mean change (week 8 to baseline) in ABC‐I subscale score

Secondary outcomes

• Mean CGI‐I score

• Number of children/adolescents with response at week 8 (response defined as ≥ 25% reduction from baseline to endpoint in ABC‐I subscale score and CGI‐I score of 1 or 2 at endpoint)

• Mean change (week 8 to baseline) in CY‐BOCS (compulsion scale only)

• Mean change (week 8 to baseline) in other ABC subscale scores

• Mean change (week 8 to baseline) in CGI‐S (CGI‐S)

• Summary of safety, deaths, adverse events, serious adverse events, treatment‐emergent adverse events and adverse events leading to discontinuation

• Change from baseline in body weight

Notes

Study dates: June 2006 to April 2008

Study location: United States

Funding: Bristol‐Myers Squibb and Otsuka Pharmaceutical

Conflicts of interest

• Dr. Sikich receives or has received research support from Bristol‐Myers Squibb, Curemark, Neuropharm, Seaside Pharmaceuticals, Janssen, Lilly, Pfizer and Otsuka, and has also given continuing medical education lectures supported by Bristol‐Myers Squibb

• Drs. McQuade and Carson are employees of Otsuka Pharmaceutical Development and Commercialization, Inc

• Dr. Findling receives or has received research support from or acted as a consultant and/or served on a speaker’s bureau for Abbott, Addrenex, AstraZeneca, Bristol‐ Myers Squibb, Forest, GlaxoSmithKline, Johnson & Johnson, KemPharm, Lilly, Lundbeck, Neuropharm, Novartis, Organon, Otsuka, Pfizer, Sanofi‐Aventis, Sepracore, Shire, Solvay, Supernus Pharmaceuticals, Validus and Wyeth

• Drs. Owen, Corey‐Lisle, Manos and Marcus are employees of Bristol‐Myers Squibb

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer‐generated randomisation schedule using permuted block design was used for randomisation

Allocation concealment (selection bias)

Low risk

A call‐in interactive voice response system was readily available for participating intervention sites when children and adolescents were ready to be randomly assigned

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Medication bottle numbers were assigned to children and adolescents, thus reducing the risk that blinding could have been broken

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Investigators and caregivers were blinded to the intervention; dosage increases were made incrementally

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Sufficient information was provided to address incomplete outcome data and the way LOCF analysis of such data was performed. Excluded children and adolescents and reasons for exclusion were reported fully. 3 randomised children were excluded from the analysis ‐ 1 child randomised to placebo was lost to follow‐up before entering the double‐blind intervention phase, 1 child randomised to placebo withdrew consent and 1 child randomised to aripiprazole discontinued on day 2 of the study before completing a post‐baseline efficacy evaluation. We do not think exclusion of these 3 children would alter study results, even if extreme results were obtained in all 3 cases

Selective reporting (reporting bias)

Low risk

Study protocol is available; its pre‐specified primary outcomes have been reported online to reduce the likelihood of selective reporting

Other bias

Low risk

From the report, it seems clear that no other risks of bias are present