The I-SPY COVID trial, an adaptive platform trial, has demonstrated the value of rapidly screening and triaging potential treatments for severe COVID-19. Initiated in March 2020, the trial aimed to address the unmet need for a mechanism to efficiently evaluate numerous therapeutic approaches proposed during the pandemic. The study design leveraged experience and infrastructure from the I-SPY2 trial in breast cancer.
Adaptive Platform Design
The I-SPY COVID trial evaluates up to four novel therapeutic agents in parallel, each on a therapeutic backbone (currently remdesivir and steroids) appropriate for severe COVID-19, defined as requiring ≥6 liter min−1 nasal cannula oxygen. The therapeutic backbone also serves as a separate contemporaneous control arm. A master protocol permits agents to enter and leave the study through a simple protocol amendment. The primary study outcome is time to durable recovery (at least two days at WHO COVID level 4 or below, e.g., <6 liter min−1 nasal cannula oxygen), with a co-primary endpoint of time to mortality.
Bayesian Analytic Framework
Using a Bayesian analytic framework, between 40 and 125 patients are enrolled for each therapeutic arm, with pre-specified criteria for graduation (that is, declaring a therapy to be likely efficacious) or futility. The trial has expanded to more than 30 sites across the United States and has enrolled over 2,100 patients. The trial’s agents committee has considered over 70 agents for evaluation; 10 of these agents entered the study, with 6 meeting the pre-determined futility threshold, 1 being halted due to logistical difficulties in drug administration and 3 actively being tested at the time of writing.
Key Lessons and Implications
The I-SPY COVID trial highlights the unique niche for phase 2 clinical trials that can rapidly evaluate repurposed or novel agents with preliminary safety data. The open-label design and comparative effectiveness approach, which forgoes placebo, permit flexibility, particularly with variable routes of administration (intravenous, subcutaneous, inhaled). The trial sought strong signals of efficacy, accepting the risk of missing more modest benefits in exchange for the goal of rapidly cycling and testing several agents at a time. Subsequent phase 3 studies will be required for agents that graduate from the trial.
Stakeholder Cooperation
Cooperation across a wide variety of stakeholders was essential for both spurring innovation and speeding implementation. In addition to academic research hospitals, the trial intentionally recruited community-based sites that do not traditionally participate in clinical trials to enhance enrollment of a broad population. Engagement with trialists and statisticians experienced in adaptive Bayesian trial design, patient advocates, regulatory agencies familiar with the complexities of platform trials, and companies willing to provide their repurposed and novel agents (via the COVID R&D Consortium) was fundamental.
Concurrent Control Arm
Studying a variety of agents across many months in a global pandemic has also highlighted the enormous advantages of platform trials that employ a concurrent control arm able to evolve with changes in the standard of care. The standard of care for severe COVID has shifted dramatically over the course of the pandemic, beginning with remdesivir in late spring 2020 and the addition of dexamethasone shortly thereafter. Different viral variants have also emerged during the pandemic, which may also influence outcomes, as have effective vaccines. For these reasons, concurrent controls are critical as a means to reduce temporal bias.
Balancing Pragmatism, Safety, and Discovery
The I-SPY COVID trial takes a moderately pragmatic approach to streamlined data collection, with a standardized method to ascertain adverse events and outcomes across all arms. An observational cohort of patients who meet trial criteria but are not randomized provides a real-world comparator arm. The trial is working to automate data collection from electronic medical records in order to ease the burden of conducting time-sensitive research when resources may be overstretched. I-SPY COVID is also unique in its biomarker development initiative, which incorporates the collection and study of biospecimens to investigate the biologic heterogeneity of severe COVID-19 that may influence outcomes and/or treatment effects.
