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Original Investigation |

Baseline Factors Predicting Placebo Response to Treatment in Children and Adolescents With Autism Spectrum Disorders:  A Multisite Randomized Clinical Trial

Bryan H. King, MD1,2; Kimberly Dukes, PhD3; Craig L. Donnelly, MD4; Linmarie Sikich, MD5; James T. McCracken, MD6; Lawrence Scahill, MSN, PhD7; Eric Hollander, MD8; Joel D. Bregman, MD9; Evdokia Anagnostou, MD10; Fay Robinson, MPH3; Lisa Sullivan, PhD11; Deborah Hirtz, MD12
[+] Author Affiliations
1Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle
2Department of Psychiatry and Behavioral Medicine, Seattle Children’s Hospital, Washington
3DM-STAT, Inc, Malden, Massachusetts
4Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
5Department of Psychiatry, University of North Carolina, Chapel Hill
6The Jane and Terry Semel Institute for Neuroscience and Human Behavior, UCLA (University of California, Los Angeles)
7Department of Pediatrics, Emory University, Atlanta, Georgia
8Albert Einstein College of Medicine of Yeshiva University, Bronx, New York
9Center for Autism, Philadelphia, Pennsylvania
10Department of Pediatrics, University of Toronto, Ontario, Canada
11Boston University School of Public Health, Massachusetts
12National Institute of Neurologic Disorders and Stroke, Bethesda, Maryland
JAMA Pediatr. 2013;167(11):1045-1052. doi:10.1001/jamapediatrics.2013.2698.
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Importance  The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population.

Objective  To identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders.

Design, Setting, and Participants  Randomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression–Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Children’s Yale-Brown Obsessive-Compulsive Scale.

Interventions  Twelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d).

Main Outcomes and Measures  A positive response was defined as having a score of at least much improved on the Clinical Global Impression–Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale–Revised, and the Children’s Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire.

Results  Several baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders.

Conclusions and Relevance  This analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders.

Trial Registration  clinicaltrials.gov Identifier: NCT00086645

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Figure 1.
Placebo Response in Randomized Clinical Trials of Autism and Related Disorders in Which a Dichotomous Response (eg, Responder vs Nonresponder) Was Reported

Oral IG indicates oral human immunoglobulin; ORG 2766, an adrenocorticotropic hormone (4-9) analog; and RUPP, Research Units on Pediatric Psychopharmacology Autism Network.

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Figure 2.
Relationship Between Baseline Composite Predictor Measures Dichotomized at the Median and Response to Treatment at Week 12

The arrows, the relative risk (RR), and the corresponding 95% CI pertain to the placebo group and are interpreted as the likelihood of response if the participant entered the study with a composite score below the median value of Disruptive Behavior (A), Mood/Autism (B), and Caregiver Strain (C). Response to citalopram hydrobromide was not affected by the baseline predictor composite score.

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