Pancreatic Replacement Therapy for Maladaptive Behaviors in Preschool Children With Autism Spectrum Disorder.

Pearson, Deborah A.; Hendren, Robert L.; Heil, Matthew F.; McIntyre, William R.; Raines, Shane R.

This cohort study evaluates the use of pancreatic replacement therapy for maladaptive behaviors in preschool children with autism spectrum disorder. Key Points: Question: Does high-protease pancreatic replacement therapy in preschool children with autism spectrum disorder (ASD) improve long-term maladaptive behaviors? Findings: In this cohort study, 190 children aged 3 to 6 years with ASD treated with high-protease pancreatic therapy improved the maladaptive behaviors of irritability and agitation on the Aberrant Behavior Checklist both in the double-blind randomized clinical trial segment and in a long-term delayed-start analysis. No safety issues emerged. Meaning: These findings suggest improvement in maladaptive behaviors in preschool children with ASD, such as irritability or agitation, can be seen with the use of high-protease pancreatic replacement therapy. Importance: There is an urgent unmet need for a treatment addressing the core symptoms and associated maladaptive symptoms of autism spectrum disorder (ASD), especially in preschool populations. Objectives: To evaluate whether treatment of children with ASD aged 3 to 6 years treated with high-protease pancreatic therapy produces long- and short-term improvements in autism-associated maladaptive behaviors. Design, Setting, and Participants: This cohort study at 32 sites across the US used a double-blind parallel group, delayed-start design comprising a 2-week blinded placebo run-in, and a double-blind, randomized, placebo-controlled segment (12 weeks). Children were recruited into the study in 2015, with data collection continuing until 2021. The analyses were completed from June 2021 to February 2022. Interventions: All participants were randomly assigned to receive either 900 mg high-protease pancreatic replacement therapy or placebo with food 3 times a day for 12 weeks, followed by all receiving 900 mg high-protease pancreatic replacement therapy for 24 weeks. Main Outcomes and Measures: The primary outcome was the irritability/agitation subscale of the Aberrant Behavior Checklist (ABC-I). All potential participants were screened using the Social Communication Questionnaire (SCQ) with diagnosis confirmed by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) for ASD and the Autism Diagnostic Inventory–Revised (ADI-R). Outcomes were measured at the conclusion of the 12-week double-blind segment and at the conclusion of the 24-week open-label segment (total 36 weeks). Results: A total of 190 participants (150 male [79%]), aged 3 to 6 (mean [SD] age, 4.5 [0.8]) years were randomized. Mixed model for repeated measures analysis performed on ABC-I demonstrated statistically significant differences of −2.49 (95% CI, −4.66 to −0.32; Cohen d = 0.364; P =.03) at the 12-week timepoint and -3.07 (95% CI, −5.81 to −0.33; Cohen d = 0.516; P =.03) at 36-week timepoint. No convergence was noted. Our high-protease pancreatic replacement (CM-AT) was well tolerated with no emergent safety concerns or related serious adverse events noted. Conclusions and Relevance: This cohort study of preschool children sustained cumulative reduction in the maladaptive behavior of irritability in autism. This delayed-start analysis, used to demonstrate disease and condition modification, may prove to be an important tool to evaluate treatments for ASD. Trial Registration: ClinicalTrials.gov Identifier: NCT02410902 and NCT02649959

UNITED States; TREATMENT of behavior disorders in children; CONFIDENCE intervals; EFFECT sizes (Statistics); PROTEOLYTIC enzymes; CHILDREN with disabilities; TREATMENT effectiveness; RANDOMIZED controlled trials; PLACEBOS; AUTISM; BLIND experiment; QUESTIONNAIRES; DESCRIPTIVE statistics; REPEATED measures design; RESEARCH funding; PSYCHOLOGICAL adaptation; STATISTICAL sampling; DATA analysis software; LONGITUDINAL method; PATIENT safety; DISEASE complications; EVALUATION; CHILDREN

JAMA Network Open, 2023, Vol 6, Issue 11, pe2344136

2574-3805

Academic Journal

10.1001/jamanetworkopen.2023.44136