Page 99 - Demo

Cannabidiol for severe behavioral manifestations in TSC, MPS III, and FXS974specific documents and the Case Report Forms (CRFs) will be securely stored with restricted access limited to nominated research staff. Assessments will be entered in the CRFs set up in Castor Electronic Data Capture (EDC). All questionnaires can be filled out digitally (Castor EDC) or by using paper forms. Automatic reminders will be sent when a questionnaire has not been completed on time. Participant burden will be limited as much as possible by using a subscale of the ABC for weekly questionnaires and having contact moments by video-conference or phone instead of a visit. A participant identification code list will be used with unique participant identifiers not deducible to participants. Only four investigators and a methodologist and biostatistician will have access to the key and source data. Data will be stored for 25 years in a secured database and body material will be stored for 5 years. Statistical methodsIndividual treatment effects for participants will be quantified as summary statistics. A mixed model analysis will be applied for statistically testing the effectiveness of the intervention at group level combining data from the individual N-of-1 trials.80 The mixed model will account for betweensubjects heterogeneity in interventional effects by including a random treatment effect.The mean treatment effect on the primary outcome irritability subscale of the ABC will be estimated and tested using a linear mixed model. The model will contain a fixed effect for the average treatment effect (CBD or placebo), random effects for patients, cycle within patient, and treatment (within patient). A mixed model analysis with similar model structure will be performed for the secondary study parameters. Because of the many data points per period, small amounts of missing data will not pose problems for the mixed model analysis, assuming missingness is random. The Imer package of R will be used for mixed model analyses. An analysis based on a summary measure will be performed if issues such as singularity arise. A two-sided significance level of 5% will be used. Annelieke Muller sHL.indd 97 14-11-2023 09:07