Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial
D Clark Files, Neil Aggarwal, Timothy Albertson, Sara Auld, Jeremy R Beitler, Paul Berger, Ellen L Burnham, Carolyn S Calfee, Nathan Cobb, Alessio Crippa, Andrea Discacciati, Martin Eklund, Laura Esserman, Eliot Friedman, Sheetal Gandotra, Kashif Khan, Jonathan Koff, Santhi Kumar, Kathleen D Liu, Thomas R Martin, Michael A Matthay, Nuala J Meyer, Timothy Obermiller, Philip Robinson, Derek Russell, Karl Thomas, Se Fum Wong, Richard G Wunderink, Mark M Wurfel, Albert Yen, Fady A Youssef, Anita Darmanian, Amy L Dzierba, Ivan Garcia, Katarzyna Gosek, Purnema Madahar, Aaron M Mittel, Justin Muir, Amanda Rosen, John Schicchi, Alexis L Serra, Romina Wahab, Kevin W Gibbs, Leigha Landreth, Mary Larose, Lisa Parks, Adina Wynn, Caroline A G Ittner, Nilman S Mangalmurti, John P Reilly, Donna Harris, Abhishek Methukupally, Siddharth Patel, Lindsie Boerger, John Kazianis, Carrie Higgins, Jeff Mckeehan, Brian Daniel, Scott Fields, James Hurst-Hopf, Alejandra Jauregui, Lamorna Brown Swigart, Daniel Blevins, Catherine Nguyen, Alexis Suarez, Maged A Tanios, Farjad Sarafian, Usman Shah, Max Adelman, Christina Creel-Bulos, Joshua Detelich, Gavin Harris, Katherine Nugent, Christina Spainhour, Philip Yang, Angela Haczku, Erin Hardy, Richart Harper, Brian Morrissey, Christian Sandrock, G R Scott Budinger, Helen K Donnelly, Benjamin D Singer, Ari Moskowitz, Melissa Coleman, Joseph Levitt, Ruixiao Lu, Paul Henderson, Adam Asare, Imogene Dunn, Alejandro Botello Barragan
eClinicalMedicine, doi:10.1016/j.eclinm.2023.101889
Background An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Methods Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6 L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (<6 L/min oxygen for two consecutive days) and mortality. Data were evaluated biweekly in comparison to pre-specified criteria for graduation (i.e., likely efficacy), futility, and safety, with an adaptive sample size of 40-125 individuals per agent and a Bayesian analytical approach. Criteria were designed to achieve rapid screening of agents and to identify large benefit signals. Concurrently enrolled controls were used for all analyses. https://clinicaltrials.gov/ct2/show/NCT04488081. Findings The first 7 agents evaluated were cenicriviroc (CCR2/5 antagonist; n = 92), icatibant (bradykinin antagonist; n = 96), apremilast (PDE4 inhibitor; n = 67), celecoxib/famotidine (COX2/histamine blockade; n = 30), IC14 (anti-CD14; n = 67), dornase alfa (inhaled DNase; n = 39) and razuprotafib (Tie2 agonist; n = 22). Razuprotafib was dropped from the trial due to feasibility issues. In the modified intention-to-treat analyses, no agent met pre-specified efficacy/ graduation endpoints with posterior probabilities for the hazard ratios [HRs] for recovery ≤1.5 between 0.99 and 1.00. The data monitoring committee stopped Celecoxib/Famotidine for potential harm (median posterior HR for recovery 0.5, 95% credible interval [CrI] 0.28-0.90; median posterior HR for death 1.67, 95% CrI 0.79-3.58). Interpretation None of the first 7 agents to enter the trial met the prespecified criteria for a large efficacy signal. Celecoxib/Famotidine was stopped early for potential harm. Adaptive platform trials may provide a useful approach to rapidly screen multiple agents during a pandemic.
Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi. org/10.1016/j.eclinm.2023.101889.
References
Angus, Derde, Al-Beidh, Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial, JAMA
Beigel, Tomashek, Dodd, Remdesivir for the treatment of Covid-19 -final report, N Engl J Med
Calfee, Clinical trial design during and beyond the pandemic: the I-SPY COVID trial, Nat Med
Douin, Siegel, Grandits, Evaluating primary endpoints for COVID-19 therapeutic trials to assess recovery, Am J Respir Crit Care Med
Files, Matthay, Calfee, I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations, BMJ Open
Griffiths, Fitzgerald, Jaki, AGILE-ACCORD: a randomized, multicentre, seamless, adaptive phase I/II platform study to determine the optimal dose, safety and efficacy of multiple candidate agents for the treatment of COVID-19: a structured summary of a study protocol for a randomised platform trial, Trials
Group, Horby, Lim, Dexamethasone in hospitalized patients with Covid-19, N Engl J Med
Matthay, Thompson, Ware, The Berlin definition of acute respiratory distress syndrome: should patients receiving highflow nasal oxygen be included?, Lancet Respir Med
Organization, WHO R&D blueprint: COVID-19 therapeutic trial synopsis
Sinha, Furfaro, Cummings, Latent class analysis reveals COVID-19-related acute respiratory distress syndrome subgroups with differential responses to corticosteroids, Am J Respir Crit Care Med
Wang, Zhang, Du, Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, Lancet
Woodcock, Araojo, Thompson, Puckrein, Integrating research into community practice -toward increased diversity in clinical trials, N Engl J Med
Woodcock, Lavange, Master protocols to study multiple therapies, multiple diseases, or both, N Engl J Med
