Abstracts

Rationale: Rett syndrome (RTT) is a profoundly disabling disorder affecting 1 in 10,000 females characterised by: developmental regression, loss of purposeful hand and communication abilities after a period of normal development. In the majority this is caused by a mutation of the MECP2 gene. Epilepsy affects 60-90% of RTT patients and is often intractable. The cannabinoid, cannabidivarin (CBDV), has shown efficacy in mouse models of epilepsy and neurodevelopmental disorders including MECP knockout mice. Non-clinical safety studies of CBDV have been conducted in animals to support the hypothesis that repeated dosing for 6 months or longer in humans should be safe. In ongoing human adult trials, CBDV was well tolerated . In ongoing human trials, CBDV was well tolerated following single oral doses and with daily dosing and the overall incidence of adverse events was low.The primary objective of this study is to determine the safety and maximum tolerated and recommended Phase 2 dose of CBDV. Secondary objectives include; pharmacokinetic and pharmacodynamic profiling; median percentage seizure frequency reduction at 3 and 6 months compared with baseline; Rett Syndrome: Symptom Severity Index scores, Rett symptom Behaviour Questionnaire at 3 and 6 months compared with baseline, and EEG at baseline and 6 months. Methods: The study design is of a a combined Phase 1 study and with a Phase 2 open label clinical trial, of an oral solution form of CBDV (GW Pharma). The first part will be a Phase 1, dose-finding intrapatient escalation study with enrollment to continue until determination of the Maximum Tolerated Dose. This involves sequentially ascending doses utilising an accelerated intra-patient titration 3+3 study design. The second part will be a Phase 2, opened labelled 6 months prospective cohort of patients assigned the recommended phase 2 dose of CBDV.  This will examine chronic safety and efficacy of dosing in this population. Patients will remain on study treatment unless they experience no benefit at 3 or 6 months, worsening of epilepsy, unacceptable toxicity, or other reason for discontinuation.Eligibility criteria will include females with a clinical diagnosis of RTT confirmed with a mutation of the MECP2 gene, age 1-17 years, minimum weight of 10kg and intractable epilepsy. Subjects will be enrolled primarily from a dedicated large RTT Clinic and from individual genetic and neurologist clinics.Total sample size is a maximum of 30. Seizures will be classified, coded then evaluated using a daily patient diary for a 4 week baseline period then throughout the study.Adverse events are any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment. The severity of an AE will be classed by its ‘Grade’ using the CTCAE v3.0 which displays Grades 1 through 5. Subjects will be reviewed clinically with safety bloods/ECG initially on a weekly to second weekly basis. Depending on the phase of the trial this will then become monthly until conclusion. Safety and efficacy data will be reviewed by an independent DSMB throughout both phases of the study. Results: A formal protocol has been developed and approved by the SCHN Institutional Human Research and Ethics Board. Enrolment will commence in July 2018. Phase 1 data will be expected to be available by Q1 2019. Conclusions: Initial safety and efficacy data of the novel agent cannabidivarin will be established in a cohort of RTT patients with intractable epilepsy. Funding: Cannabidivarin solution will be provided free of charge by GW Pharmaceuticals.