Addition of a secondary objective/end point to evaluate change in duration of subtypes of seizures as assessed by the Caregiver Global Impression of Change in Seizure Duration. Clarification of the exclusion criteria addressing previous and current use of cannabinoids. Additional collection of a full record of genetic testing and prior antiepileptic drugs taken as part of the participant’s medical history for safety assessment and to aid/confirm diagnosis of Dravet Syndrome. Clarification that the baseline period must be a minimum of 28 days in order to capture sufficient baseline data. Clarification that the safety follow-up period must be a minimum of 28 days after end of treatment in order to capture sufficient safety data. Clarification of subtypes of seizures and definition of “countable partial seizures” in order to aid identification of seizure types. Clarification that the cognitive assessment battery will only be performed at sites that have the expertise to conduct the test. Pre-randomization pregnancy test to be performed using urine rather than serum in order to provide an immediate result for assessment of inclusion/exclusion criteria. Inclusion of the Pediatric Cannabinoid Withdrawal Scale for children 4–17 years of age.

Cases of Drug-Induced Liver Injury must be a criterion for withdrawal from study treatment.

Specified participants be stratified by age across treatment arms. Added assessment of growth and development through measurement of height, body weight, serum insulin-like growth factor 1 levels, and Tanner staging. Added measurement of effects of menstruation. Amended statistical methods for analysis of primary and secondary end points. Added blood sampling for pharmacokinetics (PK) analyses of cannabidiol and major metabolites. Added measurement of serum triglycerides in clinical laboratory assessments. Added electrocardiogram and clinical laboratory assessments at the ‘End of Taper’ visit for participants who withdrew early and tapered the investigational medicinal product (IMP) and for participants who opted not to enter the open-label extension. Increased the number of participants per treatment group from 40 to 50 (total increase from 120 to 150) and amended assumption that participants in the placebo group would experience a mean reduction in convulsive seizure frequency of 10 to 18%. Added eligibility criterion excluding participants taking felbamate for <1 year. Felbamate was also listed as a prohibited therapy if taken for <1 year. Clarified use of the Epilepsy study consortium to verify each participant’s seizure subtypes and diagnosis of Dravet syndrome. Amended wording to allow participants who suspended IMP dosing due to an adverse event to resume dosing prior to complete recovery, provided that the adverse event was well tolerated. Added secondary end points to align the protocol with the open-label extension and edited primary and secondary end points to clarify that total number of convulsive and non-convulsive seizures would be measured. Clarified when the Cognitive Assessment Battery should be administered. Clarified that even though participants may achieve target dose before the end of the 2-week titration period, the titration period was 2 weeks to ensure all participants achieved stable dosing.

Updated statistical analyses of the primary and secondary end points to include the full treatment period (titration plus maintenance period). Updated the lower age limit for Tanner Staging to include adolescent participants aged 10–17 (inclusive) or earlier if clinically indicated by the onset of menarche or other signs of precocious puberty. Replaced wording of concomitant AED blood sampling in the event of an adverse event with a secondary objective/end point requesting the investigator monitor plasma concomitant AED levels and discuss results with the GW medical monitor. Samples were only to be taken if the risk/benefit outcome was favorable, in the investigator’s opinion. Reclassified effects on menstruation as a safety measure. Amended responder and sensitivity analyses to state the average number of seizures per 28 days rather than per week. Clarified the convulsive seizure inclusion criterion to state that only the first 28 days of the baseline period counted towards a participant’s eligibility. Removed the Socioeconomic Scale test item (parent measure) from the Cognitive Assessment Battery as it was not possible to standardize this end point across different countries. Clarified blood sampling for PK was only to be taken from participants weighing ≥20 kg. Sampling times and windows were also clarified. Clarified the age restriction for Columbia-Suicide Severity Rating Scale suitability to include consideration of developmental delays as well as age.

Increased the number of participants per treatment group from 50 to 62 (a total increase from 150 to 186). Changed the statistical analyses of seizure data to use nonparametric rather than parametric methods. Added assessments of plasma and urine concentrations of tetrahydrocannabinol and its major metabolites, and urine concentrations of cannabidiol and its major metabolites. Amended the PK parameters to allow for accurate determination of the defined parameters. Clarified that any clinical symptoms of concern resulting from possible drug-drug interactions should be discussed with the GW medical monitor and if required, adjustments to AEDs would be permitted. Broadened the mode of IMP administration to encompass participants who have difficulty swallowing.