Response (minimum clinically relevant change) in ASD symptoms after an intervention according to CARS-2: consensus from an expert elicitation procedure

Abstract

The lack of consensual measures to monitor core change in Autism Spectrum Disorder (ASD) or response to interventions leads to difficulty to prove intervention efficacy on ASD core symptoms. There are no universally accepted outcome measures developed for measuring changes in core symptoms. However, the CARS (Childhood Autism Rating Scale) is one of the outcomes recommended in the EMA Guideline on the clinical development of medicinal products for the treatment of ASD. Unfortunately, there is currently no consensus on the response definition for CARS among individuals with ASD. The aim of this elicitation process was to determine an appropriate definition of a response on the CARS2 scale for interventions in patients with Autism Spectrum Disorder (ASD). An elicitation process was conducted following the Sheffield Elicitation Framework (SHELF). Five experts in the field of ASD and two experts in expert knowledge elicitation participated in an 1-day elicitation workshop. Experts in ASD were previously trained in the SHELF elicitation process and received a dossier of scientific evidence concerning the topic. The response definition was set as the mean clinically relevant improvement averaged over all patients, levels of functioning, age groups ***and clinicians. Based on the scientific evidence and expert judgment, a normal probability distribution was agreed to represent the state of knowledge of this response with expected value 4.03 and standard deviation 0.664. Considering the remaining uncertainty of the estimation and the available literature, a CARS-2 improvement of 4.5 points has been defined as a threshold to conclude to a response after an intervention. A CARS-2 improvement of 4.5 points could be used to evaluate interventions' meaningfulness in indivudals. This initial finding represents an important new benchmark and may aid decision makers in evaluating the efficacy of interventions in ASD.

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“…Further, a recent study has suggested that clinicians on an average would like to see a 4.5-point improvement to conclude to a meaningful improvement after an intervention in the context of ASD. 19 In this study, only a three-point improvement was observed after Nichi-Glucan supplementation. However, this is only a pilot study, and larger randomised, multi-centric clinical trials of longer duration for validation to attain a clinical meaningful response and to overcome the above-mentioned limitations are warranted.…”

“…An improvement on the CARS by at least 4.5 points. 19 The CARS was monitored at baseline and after 90 days between the Gr.1 (control) and Gr.2 (Nichi Glucan). The CARS score was calculated based on a cumulative score obtained on the CARS scale, wherein a score below 30 indicates absence of sufficient signs and symptoms indicative of autism, a score between 30 and 36 indicates mildto-moderately severe autism, and a score from 37 to 60 is correlated with severe autism.…”

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“…In particular, in four out of seven studies, CARS was applied. The validity of CARS has been demonstrated in a variety of studies in children of all ages [ 33 , 34 ]. Significant improvements in CARS scoring were evident in all papers included in our review [ 25 , 27 , 29 , 30 ].…”

“…CARS-2 is a widely employed and validated tool for assessing ASD symptom burden [ 33 , 34 ]. Based on our review, we believe CARS-2 could be an effective quick, and nimble instrument to monitor changes in AD core symptoms over time.…”

“…Moreover, Vineland adaptive behavior scale II (VABS II) [ 34 ] and parent-rated adaptive behavior assessment system II (ABAS II) questionnaire [ 34 , 40 ] could be feasible, reliable, and accurate measures to quantify meaningful changes in response to treatment [ 33 ] and should be administered, in our opinion, by an independent, trained rater, before KD administration, after the review of the treatment at 6 months and then once a year.…”