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Meta-Analysis
. 2020 Aug 26;11(1):66.
doi: 10.1186/s13229-020-00372-z.

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis

Spyridon Siafis  1 , Oğulcan Çıray  2 , Johannes Schneider-Thoma  3 , Irene Bighelli  3 , Marc Krause  3 , Alessandro Rodolico  4 , Anna Ceraso  5 , Giacomo Deste  5 , Maximilian Huhn  3   6 , David Fraguas  7   8 , Dimitris Mavridis  9   10 , Tony Charman  11 , Declan G Murphy  12 , Mara Parellada  9   10 , Celso Arango  9   10 , Stefan Leucht  3
Affiliations
Meta-Analysis

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis

Spyridon Siafis et al. Mol Autism. .

Abstract

Background: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms.

Methods: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 .

Results: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = - 0.32, 95% CI [- 0.39, - 0.25], in repetitive behaviors - 0.23[- 0.32, - 0.15] and in scales measuring overall core symptoms - 0.36 [- 0.46, - 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain.

Limitations: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers.

Conclusions: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.

Keywords: Autism spectrum disorder; Placebo; Trials.

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Conflict of interest statement

In the last 3 years, Stefan Leucht has received honoraria as a consultant/advisor and/or for lectures from LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS Lohmann, Janssen, Johnson&Johnson, TEVA, MSD, Sandoz, SanofiAventis, Angelini, Recordati, Sunovion, and Geodon Richter. David Fraguas has been a consultant and/or has received fees from Angelini, Eisai, IE4Lab, Janssen, Lundbeck, and Otsuka. He has also received grant support from Instituto de Salud Carlos III (Spanish Ministry of Science, Innovation and Universities) and from Fundación Alicia Koplowitz. Mara Parellada has received educational honoraria from Otsuka, research grants from FAK and Fundación Mutua Madrileña (FMM), Instituto de Salud Carlos III (Spanish Ministry of Science, Innovation and Universities) and European ERANET and H2020 calls, travel grants from Otsuka and Janssen. Consultant for Exeltis and Servier. Celso Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Sanofi, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. In the last 3 years, Maximilian Huhn has received speakers honoraria from Janssen. Declan Murphy has received consulting fees from Roche. The other authors have nothing to disclose.

Figures

Fig. 1
Fig. 1
PRISMA flow chart of study selection. The list of included, ongoing and excluded records is displayed in Additional file 3: eAppendix-4.
Fig. 2
Fig. 2
Placebo response in scales measuring social-communication difficulties. Squares and bars represent standardized mean changes (SMC) and 95% confidence intervals for each study. The size of the square is proportional to the weight of the study in the meta-analysis. The diamond represent the pooled SMC. Heterogeneity is quantified with a χ2 test (Q) and I2. *In Chugani 2016, standard errors might have been reported as SDs. Therefore, we calculated SDs from the reported values (no reply from the corresponding author). It should be noted that in Niederhofer 2003, an aggregated score of ABC-L/SW rated by both caregivers and teachers were reported, in Amminger 2007, ABC-L/SW was rated by clinicians of the day care center. Scale: the scale used (clinician rated scales based on observation or interviews were preferred in the primary analysis); n: the number of participants on placebo; mean: mean change from baseline to endpoint (negative values for improvement); sd: the standard deviation used for the standardization (baseline standard deviations were preferred); SMC: standardized mean changes, 95% CI: 95% confidence intervals, k = total number of studies included in the analysis
Fig. 3
Fig. 3
Placebo response in scales measuring repetitive behaviors. Squares and bars represent standardized mean changes (SMC) and 95% confidence intervals for each study. The size of the square is proportional to the weight of the study in the meta-analysis. The diamond represent the pooled SMC. Heterogeneity is quantified with a χ2 test (Q) and I2. *In Chugani 2016, standard errors might have been reported as SDs. Therefore, we calculated SDs from the reported values (no reply from the corresponding author). In Amminger 2007, ABC-S was rated by clinicians of the day care center. Scale: the scale used (clinician rated scales based on observation or interviews were preferred in the primary analysis); n: the number of participants on placebo; mean: mean change from baseline to endpoint (negative values for improvement); sd: the standard deviation used for the standardization (baseline standard deviations were preferred); SMC: standardized mean changes, 95% CI: 95% confidence intervals, k = total number of studies included in the analysis
Fig. 4
Fig. 4
Placebo response in scales measuring overall core symptoms. Squares and bars represent standardized mean changes (SMC) and 95% confidence intervals for each study. The size of the square is proportional to the weight of the study in the meta-analysis. The diamond represent the pooled SMC. Heterogeneity is quantified with a χ2 test (Q) and I2. *In Anagnostou 2012, we reversed baseline and endpoint values of SRS: in the manuscript, original baseline values were lower than endpoint in both placebo and oxytocin arms, meaning an increase of severity of symptoms during the study, which is not consistent with the reported positive effect size and the other outcomes (no reply from the corresponding author), in Saad 2015, CARS was rated by caregivers but it was unclear if also filled by clinicians (no reply from the corresponding author), as well as in RUPP 2002 and Handen 2012 the Ritvo-Freeman Life Rating Scale was rated by caregivers. Scale: the scale used (clinician rated scales based on observation or interviews were preferred in the primary analysis); n: the number of participants on placebo; mean: mean change from baseline to endpoint (negative values for improvement); sd: the standard deviation used for the standardization (baseline standard deviations were preferred); SMC: standardized mean changes, 95% CI: 95% confidence intervals, k= total number of studies included in the analysis
Fig. 5
Fig. 5
CGI-I positive placebo response. Square and bars represent the point estimate of the proportion of responders and its 95% confidence interval for each study. The size of the squares is proportional to the weight of the study. The diamonds represent the pooled proportion and its 95% confidence intervals for each subgroup and overall. Heterogeneity is quantified with a χ2 test (Q) and I2. CGI-I positive responders: number of participants with a positive response defined as at least much improvement in the CGI-I (if not reported, it was imputed using a validated method); Total: total number of participants on placebo
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