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 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 analysisThe 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 disseminationISPY 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 numberNCT04488081.

Trend in Clinical Trial Participation During COVID-19: A Secondary Analysis of the I-SPY COVID Clinical Trial

“…This secondary analysis used de-identified data from the I-SPY COVID clinical trial (ClinicalTrials.gov identifier: NCT04488081), for which detailed design and methods have been published previously ( 8 , 9 ). The trial was overseen by a central institutional review board (IRB) at the Wake Forest School of Medicine (IRB00066805, “I-SPY COVID TRIAL: An Adaptive Platform Trial to Reduce Mortality and Ventilator Requirements for Critically Ill Patients,” approved on July 9, 2020).…”

Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial

“…A detailed description of the study rationale and protocol have been previously published. 5,6 The study is conducted under a central IRB mechanism (Wake Forest University Health Sciences IRB00066805). Briefly, the study consists of a randomised cohort consisting of eligible patients who consent to participation and an observational cohort in which no treatment is assigned but clinical data are collected through medical records.…”

“…Celecoxib/famotidine, dornase alfa, and IC14 were the next agents that were ready for testing and selected by the Agents Committee, as previously described. 6 The doses and duration of the agents were those proposed by industry partners and investigators and generally drawn from studies in other populations (see Supplemental Table S2). Given the urgent nature of the pandemic, dose finding studies were not a part of this trial.…”

Advancing Precision Medicine for the Diagnosis and Treatment of Acute Respiratory Distress Syndrome

“…The massive increase in the incidence of ARDS during the COVID-19 pandemic created an urgent need to evaluate many potential treatments for COVID-19 disease including therapies specifically targeting COVID-19 induced ARDS. This critical care research community swiftly responded to this need by implementing large platform trials, including I-SPY COVID, the ACTIV suite of trials, and RECOVERY which were sponsored by the US and the UK [ 79 , 80 ]. Additionally, the WHO sponsored trial consortium quickly pivoted its plans for the REMAP-CAP trial to focus on the evaluating the efficacy of the numerous agents that had been proposed as treatments for COVID-19 [ 81 ].…”