Covid 19: A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients with COVID-19

ACTIV-3 Abstract: TICO (Therapeutics for Inpatients with COVID-19) is a master protocol to evaluate the safety and efficacy of multiple investigational agents aimed at modifying the host immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, or directly enhancing viral control in order to limit disease progression. Trials within this protocol will be adaptive, randomized, blinded and initially placebo-controlled. Participants will receive standard of care (SOC) treatment as part of this protocol. If an investigational agent shows superiority over placebo, SOC for the study of future investigational agents may be modified accordingly. The international trials within this protocol will be conducted in several hundred clinical sites. Participating sites are affiliated with networks funded by the United States National Institutes of Health (NIH) and the US Department of Veterans Affairs. The protocol is for a randomized, blinded, controlled platform trial that allows investigational agents to be added and dropped during the course of the study for efficient testing of new agents against control (i.e., placebo + SOC) within the same trial infrastructure. When more than one agent is being tested concurrently, participants will be randomly allocated across agents (as well as between the agent and its placebo) so the same control group will be used, when feasible. This Phase III platform design includes 2 stages. In the initial stage (stage 1), safety will be evaluated and two intermediate outcomes will be assessed to determine whether an agent advances to stage 2. Treatments considered to have demonstrated unacceptable risks relative to benefits or those which do not reach the efficacy threshold for the stage 1 intermediate outcomes will not advance to stage 2 (i.e. randomization between that investigational agent and placebo will cease). In some cases, stage 1 may include 2 or 3 doses of the same investigational agent (considered as separate agents), and frequent pharmacokinetic sampling may be employed as necessary.