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Often, patients with SMS are diagnosed with attention-deficit\/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and analysis<\/jats:title><jats:p>We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged\u2009\u2265\u20096\u00a0years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity\/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care.<\/jats:p><\/jats:sec><jats:sec><jats:title><jats:italic>Trial registration<\/jats:italic><\/jats:title><jats:p>This study is registered in the Netherlands Trial Register (NTR9125).<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13023-021-02003-z","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T07:02:39Z","timestamp":1631084559000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Methylphenidate for attention-deficit\/hyperactivity disorder in patients with Smith\u2013Magenis syndrome: protocol for a series of N-of-1 trials"],"prefix":"10.1186","volume":"16","clinical-trial-number":[{"clinical-trial-number":"ntr9125","registry":"10.18810\/dutch-trial-register"}],"author":[{"given":"A. 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The study will be conducted according to the principles of the Declaration of Helsinki (2013) and in accordance with the Dutch Medical Research Involving Human Subjects Act and Good Clinical Practice guidelines. The study is registered under EudraCT number 2020-004053-76, protocol no. NL73102.018.20, version 1.0, registration date 17 August 2020. Participants and caregivers who are interested will receive a letter with information. Subjects will be informed about the study and procedures by the treating physicians adjusted to their level of intellectual functioning. Subjects and\/or legal representatives will receive as much time as they need to consider their decision with a maximum of three months with regard to the progress of the study. As the study population includes children and as most of the SMS subjects have ID, the substitute decision maker(s) will provide written consent. The research team and an independent physician is available to be contacted for any question during the entire trial period.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"380"}}