I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations

Abstract

Introduction: The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.

Methods and analysis: The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing.

Ethics and dissemination: ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals.

Trial registration number: NCT04488081.

Keywords: COVID-19; adult intensive & critical care; clinical trials.

Figure 1

ISPY COVID-19 Trial design. Hospitalised patients with COVID-19 who require ≥6 L/min nasal oxygen or more (COVID-19 status ≥5) are eligible for the trial. Patients or surrogates that meet master protocol inclusion/exclusion are approached for willingness to participate in the randomised cohort of the trial. Those that voice interest are randomised, and then approached with the agent specific consent. All patients in the randomised cohort receive backbone therapy with or without an additional investigational agent. Enrolled participants are followed for the assessment of the primary outcomes of resolution of severe COVID-19 and mortality. Patients that are either not approached for the randomised cohort of the trial or decline individual investigation agent consent are tracked in the observational cohort.

Figure 2

Patient enrolment flow into the ISPY COVID-19 platform trial.

Figure 3

Modelling Recovery in the ISPY COVID-19 Trial. The figure shows examples of trial data based on simulations. Top panel: posterior cumulative incidence and survival functions (solid lines) and 95% quantile credible intervals (shaded area between dotted lines). Bottom panel: medians (solid lines) and 95% quantile credible intervals (shaded area between dotted lines) for the posterior distribution of the difference in the cumulative Incidence functions (investigational arm vs control).

Figure 4

Daily clinically important events systematically captured in participants. Daily forms are completed in ISPY participants relating to clinically important events occurring in the context of severe COVID-19. These events are then systematically reported across arms of the study for safety reports to the Data Monitoring Committee.

Figure 5

Severe laboratory abnormalities systematically captured in participants. Potentially significant daily laboratory data entered by study coordinators is systematically captured, graded and reported back to the Data Monitoring Committee to evaluate safety. In this simulated example, agent C appears to be associated with increased creatinine, suggesting renal toxicity.