Combining factorial and multi-arm multi-stage platform designs to evaluate multiple interventions efficiently

BACKGROUND: Factorial designs and multi-arm multi-stage (MAMS) platform designs have many advantages, but the practical advantages and disadvantages of combining the two designs have not been explored. METHODS: We propose practical methods for a combined design within the platform trial paradigm where some interventions are not expected to interact and could be given together. RESULTS: We describe the combined design and suggest diagrams that can be used to represent it. Many properties are common both to standard factorial designs, including the need to consider interactions between interventions and the impact of intervention efficacy on power of other comparisons, and to standard multi-arm multi-stage designs, including the need to pre-specify procedures for starting and stopping intervention comparisons. We also identify some specific features of the factorial-MAMS design: timing of interim and final analyses should be determined by calendar time or total observed events; some non-factorial modifications may be useful; eligibility criteria should be broad enough to include any patient eligible for any part of the randomisation; stratified randomisation may conveniently be performed sequentially; and analysis requires special care to use only concurrent controls. CONCLUSION: A combined factorial-MAMS design can combine the efficiencies of factorial trials and multi-arm multi-stage platform trials. It allows us to address multiple research questions under one protocol and to test multiple new treatment options, which is particularly important when facing a new emergent infection such as COVID-19.