November 30, 2023

expert reaction to study of pancreatic replacement therapy for maladaptive behaviours in children with autism spectrum disorder

A study published in JAMA Network Open looks at pancreatic replacement therapy for behaviours in pre-school children with autism spectrum disorder (ASD). 

Prof Dorothy Bishop, Emeritus Professor of Developmental Neuropsychology, University of Oxford, said:

“This study is based on the premise that autism may be linked with abnormal gut function, specifically a difficulty in digesting protein. Between 2015 and 2021 190 children with autism, recruited from 32 sites across the USA, were treated with a CM-AT, a high-protease proprietary enzyme manufactured by the biopharmaceutical company Curemark, who sponsored this study. The study began as a randomized double-blind controlled trial where half of the recruited children were randomly selected to have CM-AT as a dietary supplement and the remainder had a placebo. After this period, all children received the active supplement for 24 weeks.  The primary measure of interest was the irritability score on the Aberrant Behavior Checklist. The group receiving CM-AT obtained lower (better) scores by the end of the first phase of the study, but this difference did not disappear by the end of the study, when both groups had received active treatment. Instead, scores continued to decline for both groups. The authors interpret this as indicating that the treatment has treated the ‘disease’ rather than just the symptoms, but I did not find this very plausible. Scores on measures of problem behaviours will tend to decline over time as children mature, especially when, as in this case, some of the sample are aged below 5 years (i.e., below the age range for which this questionnaire is recommended).

“In general, the notion of autism as a ‘disease’ which will be treatable by a biopharmaceutical intervention is rather out of keeping with contemporary views of autism as a heterogeneous symptom complex that can be influenced by a wide range of genetic and neurobiological causes. It would have been more convincing if the study had shown that the enzyme was specifically effective in children who had evidence of inability to digest protein (as was assessed from stool samples). The statistical analysis plan that was deposited on clinicaltrials.com specified that such an analysis would be conducted, but it is not reported here.  Without such evidence of a plausible mechanism of action, I do not find these results compelling.   I also note that the study registration mentioned recruitment of children from 3 to 8 years, whereas this report focuses only on those aged 3 to 6 years. There is a related discrepancy in the mean ages reported for the sample on clinicaltrials.gov (mean age 5.7 yr, SD 1.6 yr) and that reported in this article (mean age 4.5 yr, SD 0.8 yr), although the sample sizes are the same.  It is possible I misunderstood a detail here, as there is very limited time to evaluate an embargoed article before it is released, but it would be good to have it clarified whether older children were excluded from this analysis.”

‘Pancreatic Replacement Therapy for Maladaptive Behaviors in Preschool Children With Autism Spectrum Disorder’ by Deborah Pearson et al. was published in JAMA Network Open at 16:00 UK time on Thursday 30^th November.

DOI: 10.1001/jamanetworkopen.2023.44136

Declared interests

Prof Dorothy Bishop: I have no conflicts of interest to report.