Protocol for EpiCom: A phase 3b/4 study of behavioral outcomes following adjunctive cannabidiol for the management of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND)

Abstract

Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) affect ≈90% of individuals with TSC and significantly reduce their quality of life (QoL). However, there are limited studies assessing pharmacotherapy for TAND. A plant-derived highly purified pharmaceutical formulation of cannabidiol (CBD; Epidiolex®/Epidyolex® oral solution) is approved for seizures associated with TSC. Anecdotal evidence also suggests psychiatric, neuropsychological, and behavioral benefits of CBD. EpiCom (Epilepsy Comorbidities; NCT05864846; EU-CT, 2023-507426-17), a multicenter, open-label, phase 3b/4 study, with hybrid decentralized approach, was designed in collaboration with patient advisory groups and healthcare professionals to evaluate behavioral and other outcomes following adjunctive CBD treatment in individuals with TSC-associated seizures. EpiCom will enroll participants, aged 1-65 years (United States [US]) or 2-65 years (United Kingdom [UK], Canada, and Poland), who are starting CBD for seizures and have moderate/severe behavioral challenges according to the Caregiver Global Impression of Severity scale at screening. Participants will receive CBD (up to 25 mg/kg/d based on individual response and tolerability) in addition to their standard of care (SoC) for 26 weeks, after which participants may choose to continue CBD with SoC or SoC alone for an additional 26 weeks. Key efficacy endpoints include change from baseline on the Aberrant Behavior Checklist (e.g., irritability subscale) and the most problematic behavior on the TAND-Self-Report, Quantified Checklist. Changes in executive function, sleep, QoL, family functioning, seizure outcomes (severity, responder rates, seizure-free days), retention rate, and safety will be evaluated. The trial will enroll ≈75 participants at ≈20 sites across the US, the UK, Canada, and Poland. EpiCom will assess the changes in behavioral and other outcomes associated with TAND and seizure outcomes, including overall symptom severity and treatment retention, following adjunctive CBD treatment in individuals with TSC-associated seizures. The results will inform future studies evaluating pharmacotherapy for behavioral outcomes in similar populations.

Fig 1. Schedule of assessments.

^aThe ED visit is only for participants who wish to discontinue the study and the study intervention (CBD-OS). These participants should initiate a 10-day tapering off of CBD-OS and then complete an end-of-taper visit, followed by a safety follow-up phone call. Participants who withdraw from the study before week 26 should complete assessments scheduled for the 26-week interim review visit, and participants who withdraw from the study after week 26 but before week 52 should complete assessments scheduled for the 52-week final review visit. ^bOnly for participants who wish to discontinue CBD-OS before the end of Treatment Period 1 or Treatment Period 2 but remain on study. These participants should initiate a 10-day tapering off of CBD-OS and then complete an end-of-taper visit, followed by a safety follow-up phone call. For participants who wish to remain on CBD-OS after the study, the 52-week final review visit is the last study visit. ^cOnly for participants who discontinue CBD-OS (after the 26-week interim review visit, 52-week final review visit, EOT visit, or ED visit). ^dMay be a phone call. ABC: Aberrant Behavior Checklist; ABCL: Adult Behavior Checklist; AE: adverse event; ASM: antiseizure medication; ASR: Adult Self Report; BRIEF-2: Behavior Rating Inventory of Executive Function-2; BRIEF-A: Behavior Rating Inventory of Executive Function for Adults; BRIEF-P: Behavior Rating Inventory of Executive Function Preschool; CareGI-S: Caregiver Global Impression of Severity; CBCL: Child Behavior Checklist; CBD-OS: cannabidiol oral solution; CGI-S: Clinician Global Impression of Severity; CSHQ: Children’s Sleep Habits Questionnaire; C-SSRS: Columbia–Suicide Severity Rating Scale; ED: early discontinuation; EOT: end of treatment; PedsQL: Pediatric Quality of Life Inventory; PedsQL FIM: Pediatric Quality of Life Survey Family Impact Module; PGI-S: Patient Global Impression of Severity; PROMIS: Patient-Reported Outcomes Measurement Information System; PSQI: Pittsburgh Sleep Quality Index; SAE: serious adverse event; TAND-SQ: Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Self-report Quantified Checklist; WOCBP: women of childbearing potential.

Fig 2. The process used to co-design the study with the TSC community.

HCP: healthcare professional; PAGs: patient advisory groups; TAND: TSC-associated neuropsychiatric disorders; TSC: tuberous sclerosis complex; USA: United States of America.

Fig 3. Study schema.

*Participants who decide to discontinue CBD after the 26-week interim review visit but remain on study will form the SoC treatment arm. These participants will taper off CBD and complete a safety follow-up. ^†Participants who decide to discontinue CBD after the 52-week final review visit will taper off CBD and complete a safety follow-up. For participants who wish to remain on CBD after the study, the 52-week final review visit is the last study visit. CBD: cannabidiol; SoC: standard of care.