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Cannabidiol for severe behavioral manifestations in TSC, MPS III, and FXS834individual patients36,37 and enhance treatment precision when intervention effects are heterogeneous between individuals.38,39 In this way, structured and evidence-based treatment decisions can be made for an individual patient. Aggregating the results of several N-of-1 trials in different rare, complex, and heterogeneous disorders yields treatment effect estimates40,41and contributes to the generalizability to future patients with these RGNDs, but potentially also to patients with other RGNDs.42Aim and objectivesWe aim to conduct a series of N-of-1 trials to obtain scientific evidence of the effectiveness of treatment with CBD for TSC, MPS III, and FXS. The primary objective is the treatment effect of CBD compared with placebo on irritability. Secondary objectives include assessment of the effect of CBD on psychiatric and behavioral manifestations, disease-specific manifestations, parental stress, seizure frequency, and adverse effects. Personalized outcome measures will be included as well to enable us to take comorbidities into account and to focus on personalized goals. It is hypothesized that CBD has positive effects on severe behavioral manifestations, although interindividual differences in treatment effect might be expected. Baseline characteristics, such as diagnosis, accurate comorbid symptoms, and CYP enzymes enable better interpretation of results and treatment response in these heterogeneous populations with diverse neurobiological and behavioral phenotypes. Thus, a detailed description of the baseline characteristics and demographic information, as well as an extensive set of outcome measures, will provide detailed information about which manifestations may specifically be affected, and help to unravel the mechanism of action of CBD in behavioral manifestations. With that knowledge, CBD may be used as a treatment for other disorders presenting with severe behavioral manifestations. The extensive set of outcome measures will ensure that all essential clinical characteristics of the included patients will be covered. Using a strong methodology, this trial could be considered as both a confirmatory trial for irritability and exploratory for other behavioral and psychiatric outcomes. The current series of trials is part of a project which aims to create more knowledge about the suitability of N-of-1 trials and personalized outcome measures for rare disorders in order to facilitate care as well as regulatory decision-making.43,44Annelieke Muller sHL.indd 83 14-11-2023 09:07