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Chapter 488Blinding, treatment allocation, randomizationParticipants, parents, caregivers, physicians and researchers will all be blinded during the trial. The random allocation sequence will be generated for block randomization in a 1:1 ratio and implemented by the hospital pharmacist and sequentially numbered packages. Unblinding will occur when a participant has completed the two cycles or in case of a serious adverse event (SAE) that cannot be treated without knowing which treatment the patient was receiving. Investigators involved in data analysis will remain blinded until the end of the follow-up period. Interventions and dosing schedulePatients will receive a pharmaceutical formulation of highly purified CBD derived from Cannabis sativa L. (100 mg/mL) oral solution (Epidyolex® [Jazz Pharmaceuticals]) alternately with a placebo distributed by the Amsterdam UMC hospital pharmacist. CBD reduced TSC-associated seizures versus placebo with similar efficacy between the 25 and 50 mg/kg/d doses.20Given that the safety profile of 25 mg/kg/d was superior to 50 mg/kg/d, the lower dose range suggests a superior benefit-to-risk ratio. Standard rules for the use of CBD are in force. Participants can continue their psychopharmacological medications.Dose titration phasePrior to the N-of-1 trials and following the baseline period, a dose titration phase will take place, comprising escalating doses of CBD with twice daily administration from 2.5 mg/kg/day up to 25 mg/kg/day. Dose escalation steps involve an increase of 2.5 mg/kg/day. Adverse effects during the dose titration phase will be checked twice a week by a video or phone call. Also, hepatic enzyme levels will be measured at baseline and weekly from the third week of the titration phase, unless indication requires deviation. In case of adverse effects, or if the hepatic enzyme levels are ≥2 higher than the levels measured at baseline, the lower dose (2.5 mg/kg lower) will be taken. The final dosage will be based on the dose titration phase, with the highest dosage applied during this phase with the least adverse effects. The length of the dose titration phase will vary depending on the final dosage, followed by a taper and washout period. Annelieke Muller sHL.indd 88 14-11-2023 09:07