The I-SPY COVID Adaptive Platform Trial for COVID-19 Acute Respiratory Failure: Rationale, Design and Operations

Abstract

IntroductionThe COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalized with severe COVID-19. The ISPY COVID 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 trial during the first phase of trial activity from April 2020 until December 2021.Methods and analysisThe ISPY COVID Trial is a multi-center open label phase 2 platform trial in the United States designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID Trial network includes academic and community hospitals with significant geographic diversity across the country. Enrolled patients are randomized 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 enrolls to a maximum of 125 patients per arm and is compared to concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrollment and adaptation of the trial design is ongoing.Ethics and disseminationISPY COVID 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 numberClinicaltrials.gov registration number NCT04488081Strengths and limitations of this studyThe ISPY COVID Trial was developed in early 2020 to rapidly and simultaneously evaluate therapeutics for severe COVID-19 on an adaptive open label phase 2 platformThe ISPY COVID Adaptive Platform Trial Network is an academic-industry partnership that includes academic and community hospitals spanning a wide geographic area across the United StatesOf December 2021, 11 investigational agent arms have been activated on the ISPY COVID Trial PlatformThe ISPY COVID Trial was designed to identify therapeutic agents with a large clinical effect for further testing in definitive efficacy trials—limitations to this approach include the risk of a type 2 error

ERS International Congress 2022: highlights from the Respiratory Intensive Care Assembly

“…Carolyn Calfee (San Francisco, United States of America) introduced adaptive trials (trials with pre-planned capabilities to adjust design factors) as a proposal to deal with the ARDS phenotype heterogeneity, the stratified randomization and a response adaptation . They had a considerable impact during COVID-19, for example, RECOVERY evaluated 10 treatments in 47,879 participants in 199 sites, or I-SPY-COVID as an adaptive platform for a phase-2 clinical trial to identify agents with potential therapeutic benefit [40,41].…”

Participants’ informed consent in adaptive, platform drug trials in hospitalized COVID-19 patients: Not all approaches are ethically acceptable

“…The I-SPY Covid Trial, which started in July 2020, evaluates in parallel up to four (repurposed and novel) medications vs a control (remdesivir; dexamethasone was added later) on top of the standard care for severe COVID-19 patients. Using a Bayesian approach, assessing 40-125 participants per group allowed dropping medications due to futility or ‘graduate’ for superiority [12] . Of the over 70 individual agents reviewed, 12 were included in 11 trial arms (one arm was a combination of two drugs); 8 arms have been already completed [12] .…”

“…Using a Bayesian approach, assessing 40-125 participants per group allowed dropping medications due to futility or ‘graduate’ for superiority [12] . Of the over 70 individual agents reviewed, 12 were included in 11 trial arms (one arm was a combination of two drugs); 8 arms have been already completed [12] .…”

“…Investigators seek participants’ informed consent only after they are assigned to a specific medication. Participants were informed about the assigned experimental medication but not about the other experimental agents being assessed as well as the existence of a control group [12] . Is the decision of the I-SPY Covid Trial investigators to utilize a post-randomization consent approach ethical?…”

“…Hence, unfeasibility or impracticality cannot be alleged. Claiming that post-randomization consent approach is more patient-centered, as it reduces burden on participants and surrogates [12] , is not an ethically valid reason to omit important information to patients (or their legal representatives) to decide whether to participate in an ad-RCT. A global response for the next pandemic requires, among others, uniform ethical approaches to on how, when and to what participants are consenting when they participate in ad-RCTs.…”