Designing an exploratory phase 2b platform trial in NASH with correlated, co-primary binary endpoints

Abstract

Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and a disease with high unmet medical need. Platform trials provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. In this article, we describe some of the activities of the EU-PEARL consortium (EU Patient-cEntric clinicAl tRial pLatforms) regarding the use of platform trials in NASH, in particular the proposed trial design, decision rules and simulation results. For a set of assumptions, we present the results of a simulation study recently discussed with two health authorities and the learnings from these meetings from a trial design perspective. Since the proposed design uses co-primary binary endpoints, we furthermore discuss the different options and practical considerations for simulating correlated binary endpoints.

Needs assessment for creation of a platform trial network in metabolic-dysfunction associated steatohepatitis

“…The population of interest is another crucial determinant in the setup of a PT in MASH. Although the master protocol developed during EU-PEARL was based on a Phase 2b design for non-cirrhotic patients (fibrosis stages 2 and 3) 18 , relying on histologic endpoints and therefore requiring liver biopsies and the corresponding logistical complexity, at present it appears that focusing on cirrhotic patients could be a promising alternative. The main reasons are two: drug owners have started focusing their attention on cirrhotic patients and several trials on MASH cirrhosis have been launched in the last two years, and using non-invasive endpoints, including clinical events, is more feasible in the cirrhotic population.…”

“…In addition to assessing the readiness of sites to conduct clinical trials in MASH and therefore their feasibility as potential recruiting sites within a MASH IRP, we expanded the scope to gather information on other relevant areas. These include respondents’ awareness regarding PTs and their peculiarities, feedback on the master protocol we developed to carry out a Phase 2b PT in MASH 18 , the potential interest in participating in a future MASH IRP and their willingness to be involved according to the funding sources of such IRP (e.g., whether they would be willing to be part of research consortium to apply for European Commission grants or just would be open to participate as recruiting sites once funding is secured). The full survey can be consulted in the Supplementary Information File (Supplementary Note 1 ).…”

“…All surveyed sites are willing to participate in a future platform trial, with some expressing interest in industry-funded trials or research consortiums for funding the MASH IRP. The statistical considerations and overall design rationale for the master protocol to be applied during the platform trial can be found elsewhere 17 , 18 , as well as the governance aspects, the business plan and feasibility of the platform trial 19 .…”

Regulatory Issues of Platform Trials: Learnings from EU‐PEARL

“…The EMA was supportive of many of the proposed features of the study design including: A randomization process that accounts for patient choice with respect to which cohorts they would be willing to participate in. The Bayesian decision criteria based on clinically meaningful effect sizes for futility and efficacy 37 The use of shared concurrent controls across cohorts who meet the eligibility criteria if the accrual rate across cohorts allows overlap of the recruitment periods. …”

“…• The Bayesian decision criteria based on clinically meaningful effect sizes for futility and efficacy. 37 • The use of shared concurrent controls across cohorts who meet the eligibility criteria if the accrual rate across cohorts allows overlap of the recruitment periods.…”