Background: Duchenne muscular dystrophy has a deep drug development pipeline, with increasing numbers of interventions being developed, and over 30 active clinical trials ongoing. Among neuromuscular diseases, only ALS has more interventions being developed. However, drug development has been slow, given the lack of transformational therapeutics that show efficacy with short duration treatment, the heterogeneity of the disease, the small number of eligible patients for current trials, concern regarding randomization to placebo, and endpoints that are only responsive to treatment effects in certain stages of the disease. Trials therefore have had prolonged enrollment periods and longer times to complete as participants wait for read-outs.
Objectives: We are developing a platform trial that broadens inclusion criteria and reduces overall time to test a drug candidate. Key to achieving success are standardization of many operational processes, novel statistical methods allowing pooling of placebo data across multiple arms of the trial, and adaptive design of the master protocol.
Approach: Over the past two years, a multi-stakeholder group (trialists, statisticians, regulatory experts, clinicians, parents, industry) was assembled to discuss the scientific rationale for the trial, draft an Adaptive Platform Trial for Duchenne Muscular Dystrophy (APT-DMD) protocol, and determine the feasibility and acceptance of the concept. Each stakeholder had unique concerns and perspectives that had to be overcome, first through general understanding of the concept and then robust discussions of the trade-offs that are necessary to realize the desired benefits of a platform trial. This was accomplished through core group meetings, regulatory interactions, discussions with industry and webinars for the community. These efforts culminated in a multi-stakeholder public meeting where the platform trial protocol was presented, regulators provided high level rationale and support for the concept, and all stakeholders had the opportunity to ask questions, discuss details, and provide feedback.
Results: The APT-DMD protocol generated much discussion at the stakeholder meeting, and was favorably accepted. The trial will be a perpetual, randomized, double-blind, placebo-controlled, multi-arm platform trial, which will allow for customization for different interventions being tested in Phase 2 through post marketing data collection trials and can include seamless transitions between phases when appropriate. A shared placebo group across all arms and interim analyses will be used across the platform for intervention specific adaptations including assessing futility and early stopping for efficacy. Several trial elements, such as some eligibility criteria and additional endpoints are being modified based on feedback. The core team are now formalizing the scientific leadership for the proposed trial, finalizing the protocol, requesting a pre-IND meeting, establishing a governance structure and developing a business and operational plan for sustainability.
Conclusions: APT-DMD provides an opportunity for the efficient conduct of multiple studies in parallel to meet the needs of all stakeholders in the clinical trial ecosystem. As the project moves to the next stage of planning, continued education and engagement across all stakeholder groups will be critical to ensuring success. The current status will be discussed.