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

Siafis, Spyridon; Çıray, Oğulcan; Schneider-Thoma, Johannes; Bighelli, Irene; Krause, Marc; Rodolico, Alessandro; Ceraso, Anna; Deste, Giacomo; Huhn, Maximilian; Fraguas, David; Mavridis, Dimitris; Charman, Tony; Murphy, Declan G.; Parellada, Mara; Arango, Celso; Leucht, Stefan

doi:10.1186/s13229-020-00372-z

Molecular Autism

Table 1 Univariable meta-regression analyses

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

Covariate		Social-communication difficulties				Repetitive behaviors and restricted interests				Overall core symptoms
Covariate		k, n	β [95% CI]	p	R² (%)	k, n	β [95% CI]	p	R² (%)	k, n	β [95% CI]	p	R² (%)
Intervention	Route (ref. not oral)	52, 1497	0 [− 0.205, 0.206]	0.998	0	52, 1492	− 0.166 [− 0.391, 0.059]	0.148	8.13	45, 1063	− 0.042 [− 0.301, 0.217]	0.749	0
	Experimental intervention (ref. dietary supplement)	52, 1497	− 0.082 [− 0.229, 0.064]	0.268	2.61	52, 1492	− 0.081 − 0.262, 0.1]	0.382	0	45, 1063	− 0.023 [− 0.228, 0.181]	0.822	0
	Dose schedule (ref. fixed)**	51, 1491	− 0.095 [− 0.229, 0.038]	0.163	2.57	51, 1486	− 0.195 [− 0.351, − 0.038]	0.015	27.03	44, 1057	− 0.044 [− 0.276, 0.189]	0.713	0
Study design	Publication year	52, 1497	0.016 [0.003, 0.03]	0.017	31.53	52, 1492	− 0.006 [− 0.022, 0.009]	0.416	0	45, 1063	− 0.004 [− 0.021, 0.013]	0.607	0
	Country (ref. outside US/mixed)	52, 1497	− 0.002 [− 0.139, 0.135]	0.973	0	52, 1492	− 0.024 [− 0.194, 0.145]	0.778	0	45, 1063	− 0.054 [− 0.257, 0.148]	0.598	0.03
	Sponsorship (ref. no)	50, 1469	0.078 [− 0.054, 0.21]	0.246	2.89	51, 1470	0.002 [− 0.172, 0.175]	0.984	0	43, 996	0.057 [− 0.152, 0.266]	0.590	0
	No. sites*	48, 1395	− 0.003 [− 0.008, 0.003]	0.295	0	48, 1427	− 0.004 [− 0.011, 0.003]	0.287	0	41, 957	− 0.025 [− 0.045, − 0.005]	0.015	31.62
	% academic sites	46, 1340	− 0.196 [− 0.435, 0.044]	0.11	10.66	47, 1383	− 0.08 [− 0.397, 0.236]	0.619	0	41, 957	− 0.117 [− 0.461, 0.227]	0.505	0
	No. arms	52, 1497	− − 0.036 [− 0.208, 0.136]	0.684	0	52, 1492	0.035 [− 0.182, 0.252]	0.753	0	Insufficient data
	Duration (weeks)	52, 1497	0.002 [− 0.007, 0.012]	0.669	0	52, 1492	− 0.009 [− 0.021, 0.003]	0.124	5.63	45, 1063	0.00 3[− 0.009, 0.015]	0.677	0
	Washout (ref. no)	46, 1404	− 0.064 [− 0.204, 0.076]	0.369	0	47, 1339	− 0.006 [− 0.165, 0.153]	0.943	0	39, 995	− 0.021 [− 0.248, 0.205]	0.855	0
	Sample size**	52, 1497	0 [− 0.001, 0.001]	0.967	0	52, 1492	− 0.002 [− 0.003, − 0.001]	0.004	29.38	45, 1063	− 0.001 [− 0.004, 0.001]	0.213	9.89
	% participants on placebo	52, 1497	0.172 [− 0.625, 0.968]	0.673	0	52, 1492	− 0.333 [− 1.31, 0.643]	0.503	0	45, 1063	0.401 [− 0.981, 1.783]	0.569	0
	Rater (ref. clinician)***	51, 1491	− 0.164 [− 0.315, − 0.012]	0.034	21.48	51, 1483	0.131 [− 0.033, 0.294]	0.117	12.20	43, 1009	− 0.148 [− 0.361, 0.065]	0.174	0
	Sequence generation (ref. unclear)	52, 1497	0.147 [− 0.047, 0.34]	0.138	6.46	52, 1492	− 0.043 [− 0.302, 0.216]	0.743	0	45, 1063	0.243[− 0.048, 0.533]	0.102	1.70
	Allocation concealment (ref. unclear)	52, 1497	− 0.045 [− 0.228, 0.138]	0.631	0	52, 1492	− 0.012 [− 0.233, 0.208]	0.912	0	45, 1063	− 0.252 [− 0.485, − 0.019]	0.034	17.23
	Blinding (ref. unclear/high)	52, 1497	0.083 [− 0.068, 0.235]	0.28	0	52, 1492	0.006 [− 0.191, 0.202]	0.953	0	45, 1063	− 0.019 [− 0.269, 0.231]	0.881	0
	Missing outcome (ref. unclear/high)	52, 1497	− 0.141 [− 0.293, 0.01]	0.067	12.03	52, 1492	− 0.052 [− 0.247, 0.143]	0.6	0	45, 1063	− 0.162 [− 0.362, 0.038]	0.111	12.72
	Selective reporting (ref. unclear/high)	52, 1497	− 0.014 [− 0.254, 0.227]	0.912	0	52, 1492	− 0.156 [− 0.471, 0.160]	0.333	0.33	Insufficient data
	Other bias (ref. unclear/high)	52, 1497	− 0.160 [− 0.299, − 0.021]	0.024	27.38	52, 1492	− 0.091 [− 0.303, 0.120]	0.398	0	45, 1063	− 0.033 [− 0.254, 0.188]	0.768	0
Participant	Age group (ref. adults/mixed)	52, 1497	− 0.057 [− 0.27, 0.155]	0.597	0	52, 1492	− 0.107 [− 0.323, 0.109]	0.33	1.55	45, 1063	0.148 [− 0.124, 0.42]	0.287	9.35
	Mean age	51, 1478	0.002 [− 0.011, 0.014]	0.809	0	51, 1486	0.003 [− 0.008, 0.014]	0.547	0	45, 1063	− 0.007 [− 0.021, 0.007]	0.297	7.37
	% female	50, 1453	0.131 [− 0.65, 0.911]	0.743	0	50, 1482	− 0.282 − 1.114, 0.55]	0.507	0	45, 1063	0.277 [− 0.650, 1.203]	0.559	0
	% intellectual disability	17, 620	− 0.328 [− 0.672, 0.017]	0.063	42.21	21, 672	0.128 [− 0.335, 0.59]	0.588	0	14, 316	0.382 [− 0.105, 0.869]	0.124	20.87
	% Caucasian or Hispanic	29, 963	0.036 [− 0.351, 0.423]	0.855	0	29, 971	− 0.157 [− 0.715, 0.402]	0.583	0	21, 545	− 0.42 [− 1.204, 0.364]	0.294	0
	Associated conditions at baseline (ref. no)	52, 1497	− 0.068 [− 0.212, 0.075]	0.351	3.45	52, 1492	0.111 [− 0.065, 0.287]	0.216	5.83	45, 1063	− 0.012 [− 0.242, 0.218]	0.919	0
	Baseline mean BMI	12, 445	− 0.063 [− 0.156, 0.029]	0.179	19.01	12, 461	− 0.02 [− 0.132, 0.091]	0.720	0	8, 254	− 0.033 [− 0.122, 0.057]	0.476	0
	Baseline mean CGI− S	26, 917	− 0.042 [− 0.25, 0.167]	0.694	0	26, 925	0.033 [− 0.227, 0.292]	0.805	0	17, 513	− 0.077 [− 0.442, 0.288]	0.678	0
	Baseline mean ABC− Irritability	31, 917	− 0.017 [-0.028, − 0.006]	0.002	100	30, 884	− 0.005 [− 0.022, 0.013]	0.608	0	17, 340	− 0.006 [− 0.035, 0.023]	0.68	0
	Minimum threshold of core symptoms for inclusion (ref. no)**	52, 1497	0.085 [− 0.094, 0.264]	0.358	0.88	52, 1492	− 0.346 [− 0.516, − 0.175]	< 0.001	53.85	Insufficient data

A negative coefficient represent an increase of placebo response. For dichotomous covariates, the reference level is mentioned. Meta-regression with dichotomous covariates were not performed when there were less than five data points for a level of the covariate (e.g., placebo lead-in or number of medications). For continuous covariates, the covariate refer to a change of 1 point of the variable, e.g., per year for publication year: decrease of placebo response in social-communication difficulties by 0.016 per year, % percentage of intellectual disability: increase of placebo response in social-communication difficulties by − 0.328 from 0 to 1 (100%) of the participants had intellectual disability. *The effect of number of sites on placebo response in overall core symptoms was not significant (k = 40, coefficient 0.0182 [− 0.268, 0.0631], p = 0.4287), when one outlier study with 26 sites was excluded (Bolognani 2019). **Placebo response in repetitive behaviors was not found to be predicted by sample size (k = 49, coefficient − 0.001 [− 0.002, 0.000], p = 0.052), flexible-dosing (k = 48, coefficient − 0.073 [− 0.189, 0.043], p = 0.218) and using a minimum threshold of core symptoms (k = 49, coefficient − 0.083 [− 0.24, 0.073], p = 0.2950), when three antidepressant trials (Herscu 2019, King 2009, and Reddihough 2019) were excluded. ***In the meta-regression of type of rater, Niederhofer 2003 was not included in social-communication difficulties (aggregated caregiver/teacher rating of ABC-L/SW), Saad 2015 was not included in overall core symptoms (it was not clear if CARS was rated only by parents or also filled by clinicians), and Anagnostou_2012 was not included in overall core symptoms and repetitive behaviors (SRS and RBS-R might have been rated as self-reports)

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