Background <p>Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) affect most patients with TSC and encompass a range of psychiatric, intellectual, neuropsychological, and behavioral manifestations of the disease. Epilepsy Comorbidities (EpiCom), an ongoing, phase 3b/4, open-label study, is assessing the effects of adjunctive therapy with a plant-derived, highly purified pharmaceutical formulation of cannabidiol (Epidiolex^® [US]/Epidyolex^® [EU], 100 mg/mL oral solution) on TAND, including behavioral outcomes, in participants with TSC-associated seizures. EpiCom was designed in collaboration with the TSC community including patients, caregivers, and healthcare professionals (HCPs), to incorporate stakeholder perspectives into study design and execution.</p> Objective <p>To describe how collaboration among patient advocacy groups (PAGs), HCPs, and the clinical trial sponsor helped optimize the co-creation and execution of the EpiCom study.</p> Methods <p>HCPs and PAG advisors, including caregivers of individuals with TSC, were identified across the USA and Europe and invited to participate in an advisory board meeting to discuss the challenges faced by the TSC community. Surveys collected PAG and HCP input on topics, including study objectives, outcome assessments, study design, eligibility criteria, and recruitment. PAG and HCP advisory board meetings were then conducted to capture patient/caregiver and HCP perspectives on the EpiCom study design, including the objectives, feasibility, resources needed for successful execution, and strategies to engage the patient community throughout the study. A joint PAG–HCP Steering Committee comprising 5 PAG representatives and 15 HCPs from the USA, Canada, and Europe was formed to guide study objectives and PAG engagement, and to provide study oversight.</p> Results <p>Advisory board meetings (9 PAG advisors; 14 HCPs) provided insight into the needs of the TSC community and ways to enhance collaboration with patients and caregivers. Feedback from the advisory boards and steering committee meetings refined the EpiCom study objectives and informed recruitment strategies, study duration, patient- and HCP-friendly study design considerations, preferred data collection methods, and communication plans. These insights supported the development of a decentralized clinical trial framework aimed at reducing participant burden and barriers. PAG input guided the decision to broaden study eligibility criteria by removing seizure severity and intelligence quotient requirements and include remote assessments to facilitate capturing data in everyday settings. HCP input guided inclusion of clinical outcome measures, including the use of the novel TAND Self-Report Quantified Checklist to assess behavioral changes.</p> Conclusions <p>Proactively involving PAGs, caregivers, and HCPs enabled the co-creation of a study that explicitly addresses outcomes important to the broader TSC community. This patient- and caregiver-informed approach of EpiCom also highlights the need for stronger collaboration between industry and PAGs in clinical trials, including the opportunities and challenges of trial implementation.</p> ClinicalTrials.gov Registration Number <p>NCT05864846 (May 9, 2023).</p> Graphical Abstract <p></p>