Cyclosporine treatment of ARDS due to severe COVID-19: The I-SPY COVID Adaptive Platform Trial

Rationale Aberrant host response to SARS-CoV-2 infection causes severe lung injury and acute respiratory distress syndrome (ARDS) with resultant multiorgan failure and death. Cyclosporine, a calcineurin inhibitor with potent immunosuppressant and direct antiviral properties, was hypothesized to reduce cytokine-driven injury in hospitalized patients with severe COVID-19 ARDS. Objectives To evaluate whether cyclosporine improves time to recovery and reduces mortality in critically ill patients with COVID-19, using the I-SPY COVID adaptive platform trial design. Methods In this phase 2, multicenter, open-label, randomized controlled trial, non-intubated and intubated adults with confirmed COVID-19 requiring ≥6L/min oxygen received oral cyclosporine 5mg/kg/day in two divided doses for 5 days, added to standard backbone therapy (dexamethasone and remdesivir), or standard therapy alone. Co-primary endpoints were time to recovery and time to death, assessed using Bayesian proportional-hazard models with pre-specified graduation thresholds. Results Of 238 randomized patients (110 cyclosporine, 128 control), 28-day recovery rates were 65.9% vs. 71.1% and 28-day mortality rates were 10.7% vs. 11.3%, respectively. The posterior probability that cyclosporine improved recovery was 6% (graduation threshold >97.5%) and that it reduced mortality was 59.6% (graduation threshold >90%), meeting neither pre-specified efficacy criterion. Serious adverse events were more frequent with cyclosporine (17.3% vs. 7.0%, p = 0.016). No significant differences in inflammatory plasma biomarkers were observed between groups. Conclusions Cyclosporine did not meet pre-specified efficacy thresholds for recovery or mortality in severe COVID-19 ARDS and was associated with a higher rate of serious adverse events. These results do not support its addition to standard care in this population.