[Summary text]
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention
Control
Included criteria: Between the ages of 6 and 17 yearsFulfilling DSM-IV and ADI-R criteria with a rating of at least moderate (four or greater) on the CGI were included in the study.free of psychotropic medications for at least 4 weeks prior to starting the study drug with the exception of stable dose (at least 3 months) of anticonvulsants for seizures or clonidine or chloral hydrate given only at bedtime for sleep
Excluded criteria: Subjects who were responding well toprior pharmacological treatment were ex-cluded. Exclusion criteria also included psy-chotic disorders and a history of anyclinically significant medical illness (with theexception of a stable seizure disorder)
Intervention Characteristics
Intervention
Control
Funktionsniveau, klinikerbedømt, CGI-S, lower better
Ikke-alvorlige bivirkninger, totalt
Vægt, kg
Vægt, antal personer
Sponsorship source: Lilly Research Laboratories
Authors name: Eric Hollander
Institution: Seaver and NY Autism Center of Excellence, Mount Sinai School of Medicine,
Address: One Gustave L. Levy Place, Box 1230, New York, New York
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention
Control
Overall
Included criteria: Children and adolescents aged 6–17 years with a diagnosis of autistic disorder (not ASD) defined by the DSM-IV-TR criteria, and with behavioral problems such as irritability, agitation, self-injurious behavior, or a combination of these symptoms, and with a Clinical Global Impression-Severity of Illness scale (CGI- S) score of ≥4 and an Aberrant Behavior Checklist Japa- nese Version (ABC-J) score of ≥18 at screening and baseline.
Excluded criteria: Patients who had complications or histories of schizophrenia, other psychosis, and mood disorders including bipolar disorder and major depression according to the DSM-IV-TR criteria.Diagnosis of Rett disorder, childhood disintegrative disorder, Asperger’s disorder, or pervasive development disorder not otherwise specified according to the DSM-IV-TR, or a diagnosis of fragile X syndrome.Treatment resistance to antipsychotic medication, significant risk of committing suicide, or a profound intellectual disability. Patients who had previously used aripiprazole, who received any investigational drug within 30 days before providing informed consent, or who received any concomitant drug or therapy specified as prohibited in the study protocol
Pretreatment:
Intervention Characteristics
Intervention
Control
Alvorlige bivirkninger-totalt
Funktionsniveau, klinikerbedømt, CGI-S, lower better
Ikke-alvorlige bivirkninger, totalt
Antal personer med Vægtøgning
Irritabilitet, ABC-J irritability subscale, higher better because change score
Sponsorship source: Otsuka Pharmaceutical Co, Ltd (Tokyo, Japan)
Country: Japan
Setting:
Comments:
Authors name: Hironobu Ichikawa
Institution: Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan
Email: Tadori.Yoshihiro@otsuka.jp
Address:
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention
Control
Intervention 2
Overall
Included criteria: Children 5 to 17 years (inclusive), weighing at least 20 kg, with a diagnosis of autistic disorder (using Diag- nostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria).Parent-rated scores of at least 18 for Aberrant Behavior Checklist-IrritabilityScores of at least 4 (moderately ill) for Clinical Global Impressions-Severity (CGI-S) scaleRequired to have a mental age of more than 18 monthsPatients with a history of seizures were required to be seizure-free for at least 6 consecutive months or on a stable dosage of antiepileptic drugsPatients were prohibited from taking psychotropic medications for at least 1 week (4 weeks for fluoxetine, and 8 weeks for depot medications) before baseline. Normal fasting glucose and creatinine, and liver function test levels less than 1.5 times the upper limit of normal.
Excluded criteria: Previous or current DSM-IV diagnosis of psychotic disorder or Pervasive Developmental Disorders other than autism, determined by history and clinical interview. Neurologic disorders, moderate or severe extrapyramidal symptoms or tardive dyskinesia, and lack of response to risperidone treatment in the past. Girls who were pregnant or breast feeding
Intervention Characteristics
Intervention
Control
Intervention 2
Antal personer med agressioner
Alvorlige bivirkninger-totalt
Funktionsniveau, klinikerbedømt, CGI-Severity, higher better because change score
Ikke-alvorlige bivirkninger, totalt
Antal personer med Vægtøgning
Irritabilitet, ABC-J irritability subscale, higher better because change score
Sponsorship source: Johnson & Johnson Pharmaceutical Research & Development, LLC
Country: USA
Setting:
Comments:
Authors name: Justine M. Kent
Institution: Janssen Research & Development, LLC
Email: jkent@its.jnj.com
Address: 1125 Trenton-Harbourton Road, PO Box 200,Titusville, NJ 08560, USA
Study design:
Study grouping:
Baseline Characteristics
Intervention
Control
Intervention 2
Included criteria: 6 to 17 years of age; Met DSM-IV-TR criteria for autistic disorder;Demonstrated behaviors such as irritability, agitation, self-injurious behavior, or a combination of these symptoms;CGI-S score of 4 or higher and ABC-I subscale score of 18 or higher at screening and baseline;All of the subjects were required to weigh 15 kg or greater.
Excluded criteria: Current diagnosis of bipolar disorder, psychosis, schizophrenia or major depression, fragile X syndrome, or diagnosis of another disorder on the autism spectrum including PDDY not otherwise specified, Asperger’s disorder, Rett disorder, or childhood disintegrative disorder;History of neuroleptic malignant syndrome;Significant risk for committing suicide;Seizure in the past year; History of severe head trauma or stroke; History or current evidence of any unstable medical conditions; Abnormal laboratory test result, considered clinically significant vital sign result, or electrocardiogram (ECG) finding considered clinically significant;Known allergy or hypersensitivity to aripiprazole
Intervention Characteristics
Intervention
Control
Intervention 2
Intervention 3
Alvorlige bivirkninger-totalt
Funktionsniveau, klinikerbedømt, CGI-Severity, higher better because change score
Ikke-alvorlige bivirkninger, totalt
Vægt, kg
Antal personer med vægtøgning
Irritabilitet, ABC-J irritability subscale, higher better because change score
Sponsorship source: Bristol-Myers Squibb (Princeton, NJ) and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan)
Country: USA
Authors name: RONALD N. MARCUS
Institution: Bristol-Myers Squibb
Email: randall.owen@bms.com
Address: 5 Research Parkway, Wallingford, CT, 06492
Secondary publications of Marcus 2009 (reporting on quality of life and caregiver strain):
Owen, R.; Sikich, L.; Marcus, R. N.; Corey-Lisle, P.; Manos, G.; McQuade, R. D.; Carson, W. H.; Findling, R. L.
Aripiprazole in the treatment of irritability in children and adolescents with autistic disorderPediatrics 2009;124(6):1533-1540United States 2009.
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention
Control
Included criteria: All children met the criteria for autistic disorder described in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, with tantrums, aggression, self-injurious behavior, or a combination of these problems;Age of 5 to 17 years, a weight of at least 15 kg, and a mental age of at least 18 months.
Excluded criteria: Serious medical disorders and of other psychiatric disorders requiring medication.Children receiving a psychotropic drug that was deemed effective for the treatment of aggression, tantrums, or self-injurious behavior
Intervention Characteristics
Intervention
Control
Alvorlige bivirkninger-totalt
Funktionsniveau, klinikerbedømt, CGI-improvement, much eller very-much improved (score of 1 or 2)
Ikke-alvorlige bivirkninger, totalt
Vægt, kg
Irritabilitet, ABC-J irritability subscale,lower better
Country: USA
Authors name: James T. McCracken
Institution: University of California, Los Angeles
Secondary analyses of MacCracken 2002 (posthoc analyses of subgroups with no further outcomes):
Vo, L. C.; Snyder, C.; McCracken, C.; McDougle, C. J.; McCracken, J. T.; Aman, M. G.; Tierney, E.; Arnold, L. E.; Levi, D.; Kelleman, M.; Carroll, D.; Morrissey, J.; Vitiello, B.; Scahill, L.
No Apparent Cardiac Conduction Effects of Acute Treatment with Risperidone in Children with Autism Spectrum DisorderJournal of child and adolescent psychopharmacology 2016;26(10):900-908United States 2016
&
Anderson, G. M.; Scahill, L.; McCracken, J. T.; McDougle, C. J.; Aman, M. G.; Tierney, E.; Arnold, L. E.; Martin, A.; Katsovich, L.; Posey, D. J.; Shah, B.; Vitiello, B.
Effects of short- and long-term risperidone treatment on prolactin levels in children with autismBiological psychiatry 2007;61(4):545-550United States 2007
Study design: RCT
Study grouping: Parrallel
Baseline Characteristics
Intervention
Control
Included criteria: Physically healthy male and female outpatients who were aged 5 to 12 years;Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I diagnosis of PDD1 and a total scoreof 30 or more on the Childhood Autism Rating Scale (CARS), with or without mental retardation.
Excluded criteria: Schizophrenia, other psychotic disorders, clinically relevant nonneurologic disease, clinically significant laboratory abnormalities, or a seizure;Receiving >1 anticonvulsant or had a seizure in the last 3 months;history of hypersensitivity to neuroleptics, tardive dyskinesia, neuroleptic malignant syndrome, drugor alcohol abuse, or human immunodeficiency virus infection;Used risperidone in the last 3 months, been previously unresponsive or intolerant to risperidone, or using a prohibited medication
Intervention Characteristics
Intervention
Control
Funktionsniveau, klinikerbedømt, CGI-improvement, much eller very-much improved (score of 1 or 2)
Ikke-alvorlige bivirkninger, totalt
Antal personer med vægtøgning
Irritabilitet, ABC-J irritability subscale, higher better because change score
Sponsorship source: Janssen-Ortho Inc, Canada, and Johnson & Johnson Pharmaceutical Research and Development
Country: Canada
Authors name: Sarah Shea
Institution: IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada
Email: sarah.shea@iwk.nshealth.ca
Address: 5850 University Ave, Developmental Clinic, 8th Fl, Halifax, Nova Scotia, Canada B3J 3G9
Secondary publlications of Shea 2004 (reporting posthoc subgroup analyses with no further outcomes):
Pandina, G. J.; Bossie, C. A.; Youssef, E.; Zhu, Y.; Dunbar, F.Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trialJournal of Autism and Developmental Disorders 2007;37(2):367-373United States 2007
Wrong intervention
Wrong comparator
Wrong patient population
Wrong comparator
Wrong patient population
Wrong study design
Wrong comparator
Wrong study design
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Judgement Comment: Insufficient information on sequence generation
Quote: "with ASD in Japan. Methods <b>This multicenter, randomized, double-blind, placebo- controlled phase 3 study was conducted at 50 sites</b> in Japan between June 2012"
Quote: "Patients who met inclusion crite- ria at baseline were randomized to receive aripiprazole or placebo (1:1)."
Quote: "Clinicians were required to input infor- mation regarding eligible patients on the Interactive Web Response System (IWRS), and then the registration center assigned a trial drug code to each patient."
Judgement Comment: Insufficient information on sequence generation
Quote: "During the double-blind phase, eligible patients were randomized (1:1:1 ratio) to one of two fixed-dose, weight- based, regimens of risperidone or to placebo. The ran- domization was conducted by using randomly permuted blocks, and was stratified by center and baseline weight (20 to \45 kg or C45 kg)."
Quote: "The subjects meeting criteria for inclusion at baseline were then randomized to receive aripiprazole (5, 10, or 15 mg/day) or placebo in a 1:1:1:1 ratio."
Judgement Comment: Insufficient information on sequence generation
Quote: "The first phase of the study was an eight-week, double-blind, ran- domized, placebo-controlled trial of risperidone"
Judgement Comment: Insufficient information on sequence generation
Quote: "eligible subjects were ran- domized (1:1) to receive either risperidone or placebo in a double- blind manner."
Judgement Comment: Insufficient information on sequence generation
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Judgement Comment: Insufficient information on allocation concealment
Quote: "The investigators and subjects were blinded to the trial drug randomization code."
Judgement Comment: "Clinicians were required to input information regarding eligible patients on the Interactive Web Response System (IWRS), and then the registration center assigned a trial drug code to each patient." Likely adequate concealment.
Quote: " <b>drugs supplied were identical in appearance and packed in identical child-resistant containers. Patients, parents or primary caregivers, and the site personnel were all blinded to treatment assignment. Study</b> Medication Risperidone and its matching"
Judgement Comment: Insufficient information on allocation concealment
Judgement Comment: Insufficient information on allocation concealment
Judgement Comment: Insufficient information on allocation concealment
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Quote: "Olanzapine and placebo were distributed in identical forms."
Judgement Comment: Both participants and personnel was blind to group allocation
Quote: "The investigators and subjects were blinded to the trial drug randomization code. Aripiprazole"
Judgement Comment: Double-blinded
Judgement Comment: Double-blinded
Judgement Comment: Double-blinded. Both participants and personnel were blind to treatment groups
Judgement Comment: Double-blinded. Both participants and personnel were blind to treatment group.
Detection bias due to knowledge of the allocated interventions by outcome assessors
Quote: "Patients were evaluated weekly for the first 4 weeks and biweekly for the next 4 weeks in a double-blind fashion by the treating psychiatrist."
Judgement Comment: The treating clinician who was blind to group allocation was also the outcome assessor
Judgement Comment: Likely investigators were blinded: "The investigators and subjects were blinded to the trial drug randomization code."
Judgement Comment: Double-blinded
Judgement Comment: Double-blinded.For caregiver reported outcomes, the assessor is blind to treatment group. It is unclear if outcome assessor for clinician rated outcomes are the same is treatment personnel
Quote: "Each child was seen weekly by two clinicians who were unaware of the treatment assignment: a primary clinician, who reviewed side effects and adjusted the dose of medication, and a clinical evaluator, who assessed the response to treatment. The primary outcome measures were the score at eight weeks on the Irritability subscale of the Aberrant Behavior Checklist, based on the parent’s or pri- mary caretaker’s rating, and the rating on the Clinical Global Im- pressions — Improvement (CGI-I) scale, as determined by the clin- ical evaluator."
Quote: "The ABC and N-CBRF subscales were completed by the parent or caregiver under the guidance of the investigator;"
Judgement Comment: Double-blinded
Attrition bias due to amount, nature or handling of incomplete outcome data
Quote: "we used mixed regression analysis to assess differences in the improvement ratings be- tween the treatment and control groups. This analysis did not eliminate subjects, but instead estimated effects using the data available for each subject."
Quote: "A total of 43 data points (out of a possible 55) were available."
Quote: "One child dropped out right after randomization due to parental disagreement regarding study participation. Two others dropped out during the study because their parents were noncompliant with their follow- up appointments."
Quote: "This analysis did not eliminate subjects, but instead estimated effects using the data available for each subject. The reasons for missing data were children who discontinued the study be- fore 8 weeks and missed treatment visits."
Judgement Comment: Likely appropriate ITT analysis.
Judgement Comment: Low attrition rates in both groups, thus three patients discontinued from placebo group. Appropriate ITT analysis.
Quote: "Efficacy analyses included all patients who had received at least 1 dose of study medication and had both baseline and postbaseline efficacy measurements (intent-to-treat [ITT] population)."
Quote: "Overall, 80 % of the randomized patients (n = 77 of 96) completed the 6-week double-blind phase. Most frequent reasons for early withdrawal during the study were insuf- ficient response (7 %) and patient choice (5 %). A higher percentage of patients in the placebo group than in either risperidone group discontinued due to insufficient response (Fig. 1)."
Judgement Comment: Low attrition in all groups and not for reasons that affect outcomes. ITT analyses were also performed
Quote: "Of the subjects included in the randomized sample, two subjects were excluded from the safety sample; one subject treated with placebo no longer met study criteria, and one subject treated with aripiprazole 5 mg/day with- drew consent, both before receiving study medication. An additional three subjects were excluded from the effi- cacy sample; one"
Quote: "follow-up, one subject treated with placebo withdrew con- sent, and one subject treated with aripiprazole 15 mg/day discontinued because of elevated potassium levels, all before completing a postbaseline efficacy evaluation."
Quote: "Analyses were performed on both the last observation carried forward (LOCF; primary data set) and the observed case data. Two additional sensitivity analyses, using two different methods of addressing missing data on the primary scale (a likelihood-based repeated-measures approach and a pattern-mixture model), corroborated the LOCF analysis results."
Judgement Comment: 83-87% completed in intervention groups, 73% completed in control group.
Quote: "Data were analyzed according to the intention-to-treat principle."
Quote: "57 children declined par- ticipation. <b>The remaining 101 children (82 boys and 19 girls) were enrolled and randomly assigned to re- ceive risperidone (49 children) or placebo (52). We subsequently identified four children who did not meet the entry criteria because their Irritability sub- scale had fallen below the threshold of 18 at base line. An analysis of the Irritability data that excluded these four children had results that were virtually identical to those with the full sample. Thus, the intention-to- treat analysis included all 101 children.</b> The children ranged in age"
Quote: "Therefore, 79 subjects (40 in the risperidone group, 39 in the placebo group) were included in the ITT population, the primary safety assessment population. In addition, because 1 subject in each group had no postbaseline efficacy data recorded, 77 subjects (39 in the risperidone group, 38 in the placebo group) were included in the ITT-efficacy population, the primary efficacy assess- ment population."
Reporting bias due to selective outcome reporting
Judgement Comment: There were no reference to study protocol, but appears to report on outcomes of interest
Quote: "The study was registered at ClinicalTrials.gov (identifier: NCT01617447)."
Quote: "The primary endpoint was the mean change in the caregiver-rated ABC-J irritability subscale score [14] from baseline to week 8."
Judgement Comment: Only ABC-J) Irritability Subscale Score pre-specified (of any outcomes) in protocol, but as primary outcome. No secondary outcomes pre-specified.
Judgement Comment: Protocol available, NCT00576732 (clinicaltrials.gov), an no noticed protocol violation
Quote: "http://clinicaltrials.gov. Unique identifier: NCT00337571."
Judgement Comment: PedsQL and CGSQ was not stated in protocol
Quote: "http://clinicaltrials.gov. Unique identifier: NCT00337571."
Judgement Comment: PedsQL and CGSQ was not stated in protocol
Judgement Comment: No protocol however, thorough reporting of relevant and expected outcomes
Judgement Comment: No protocol however, relevant and expected outcomes reported.
Bias due to problems not covered elsewhere in the table
Quote: "Dr. Hollander serves on the advisory board of Abbott, Wyeth, Solvay, Somaxon Pharma- ceuticals and receives research grants from Lilly, Abbott, Pfizer, UCB-Pharma, and Ortho- McNeil Pharmaceuticals."
Judgement Comment: First author are very financially involved in pharma companies
Quote: "Mr. Ono, Ms. Usuki and Dr. Tadori are employ- ees of Otsuka Pharmaceutical Co., Ltd."
Judgement Comment: Otsuka Pharmaceuticals has funded the research
Quote: "Conflict of Interest Dr. Aman was an investigator for this study and has received research support or been a consultant for Janssen Research & Development, LLC, Bristol-Myers Squibb, Pfizer, Forest Research, and Hoffman La Roche. Drs. Ness, Singh, Hough and Kent and Mr. Karcher are employees of Janssen Research & Development,"
Quote: "LLC. Drs. Ning and Kushner were employed by Janssen Research & Development, LLC during the design and conduct of this study. Dr. Ning is currently employed by Purdue Pharma and Dr. Kushner is at CFG Health Systems, L.L.C."
Judgement Comment: There might be some economic conflict of interest by some authors
Quote: "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 Phar- maceutical Development and Commercializaion."
Judgement Comment: Unclear role of conflicts of interest
Quote: "Supported by contracts from the National Institute of Mental Health (N01MH70009, to Dr. Scahill; N01MH70010, to Dr. McCracken; N01MH70001, to Dr. McDougle; and N01MH80011, to Dr. Aman), Gen- eral Clinical Research Center grants from the National Institutes of Health (M01 RR00750, to Indiana University; M01 RR00052, to Johns Hopkins University; M01 RR00034, to Ohio State University; and M01 RR06022, to Yale University), and a grant from the Korczak Foundation (to Dr. Sca- hill). Study medications were donated by Janssen Pharmaceutica."
Judgement Comment: No reasons to suspect other sources of bias.
Quote: "This trial was supported by Janssen-Ortho Inc, Canada, and Johnson & Johnson Pharmaceutical Research and Development."
Judgement Comment: No reasons to suspect other sources of bias, despite limited reporting of funding and conflicts of interest by authors.