Design and implementation of the multi-arm, multi-stage Therapeutics for Inpatients with COVID-19 (TICO) platform master protocol: An Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative.

Background: The SARS-CoV-2 pandemic is a public health emergency. Safe and effective therapies are urgently needed. Methods: Therapeutics for Inpatients with COVID-19 (TICO), is a global multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. The protocol design allows multiple therapeutic agents to be evaluated in an efficient and scientifically rigorous manner, with efficiencies delivered by the MAMS design, and began by studying neutralizing monoclonal antibodies. TICO employs an agile and robust approach to futility and safety evaluation at 300 patients enrolled (Stage 1), with subsequent expansion to full sample size and an expanded target population (Stage 2) if the agent shows an acceptable safety profile and evidence of efficacy. Two ordinal outcomes applied early (Day 5) determine the efficacy signals of the investigational agents(s) and progression to Stage 2. These ordinal outcomes assess both respiratory and other organ failure events, recognizing the broad range of COVID-19 morbidity. In Stage 2, overall efficacy is assessed using the primary outcome of time to sustained recovery, assessed over 90 days. This approach to early futility assessment using an early intermediate outcome and a primary endpoint out to 90 days allows the study team to make rapid decisions on safety and potential efficacy of novel agents while ultimately focusing on patient-centered, longer-term outcomes. The implementation of TICO across a global network allows for continued enrollment despite variations in geographic epidemiology. Study Status: The TICO master protocol moved from conception to first patient enrolled in approximately 9 weeks, a testament to the expedited regulatory and ethics review, coupled with flexible and responsive study operations. The first agent to be tested using this protocol, LY-CoV-555, enrolled N=326 participants before undergoing Stage 1 futility and safety assessment. Two additional agents will enter the study in November 2020, with other agents planned. Conclusion: The TICO MAMS platform trial has been implemented efficiently across a global network of sites and several trial networks. It will generate results rapidly for multiple novel neutralizing monoclonal antibodies and other therapeutics agents.