Advancing the Clinical Trial Framework for Autism Spectrum Disorders and Knowledge of Cytokines as a Potential Biomarker

Abstract

Introduction: Autism Spectrum Disorder (ASD) is a multifaceted condition that can pervade all aspects of daily functioning and persist throughout the lifespan. Prevalence has been recently estimated to be as high as 1 in 68. Despite significant need, treatment options for ASDs remain limited. Applied behavioral analysis (ABA) an evidence-based education therapy for ASD, is highly dependent on early and intensive implementation with delivery of an effective program prohibitive for many due to significant cost. Despite considerable need, the US Food and Drug Administration has approved only two atypical antipsychotics for children with ASD, risperidone and aripiprazole, for irritability symptoms such as tantrums, aggression and self-injury behaviors, which are considered non-core symptoms and are not described in diagnostic criteria. It is unclear what is hampering the identification of efficacious treatments, especially those which are easy and cost-effective to administer and do not place additional, unnecessary burden on families and carers of those with ASDs. However, an understanding of the biological mechanisms driving pathophysiology is evolving and may provide direction. This thesis presents a series of studies that examine the clinical trial framework for ASD interventions, focusing on predictors of treatment response and placebo effects in existing trials, and then considers the potential role of cytokine profiles as an objective measure of response to treatment and as a biomarker of a clinically relevant subgroup of ASDs. Methods: Chapters 2 and 3 used meta-analysis to investigate if there are baseline characteristics or trial design features that moderate response to treatment with an active intervention and with placebo, and if there are potential methodological barriers to the identification of efficacious treatments. Chapters 5 and 6 explored the potential role of peripheral cytokines as an objective measure of treatment response or as a marker of a pathological state relating to a subgroup of ASD. The empirical study in Chapter 6 utilized a multiplex assay to analyse blood samples from a well characterized cohort of 144 children with an ASD diagnosis, in order to investigate the relationship between the severity of ASD, associated clinical traits and cytokine profiles. Results: The results of the meta-analyses identified moderators of response to active intervention and to placebo and that the limited reporting of clinical, functional and demographic characteristics at baseline maybe be impeding a thorough assessment of moderators of response, interpretation and replication of trial outcomes and contributing to heterogeneous clinical trial populations. The multiplex assay study indicated that peripheral cytokine profiles may serve as an objective measure of either a pathological state of a subgroup of ASDs or as a potential objective measure of treatment response. Furthermore, a relationship with severity and a significant interaction with gender suggested a different immune profile for females compared to males. Conclusions: The identification of objective measures of treatment response could facilitate the demonstration of efficacy in clinical trials and assist in the identification of homogeneous clinical trial populations. The role of subjectivity in determining trial outcomes, both in the type of measurement tools used and the rater of the outcome, highlight the importance of incorporating objective measures of response and the importance of alternative methods to define trial populations. Further characterization of the impact of biological mechanisms, such as immune system abnormalities, is essential, with the role of gender requiring additional clarification.