RCT severe COVID-19 patients requiring ≥6 L/min oxygen, showing worse recovery with the addition of celecoxib and famotidine to remdesivir and dexamethasone. The treatment group mean age was 9 years older, and the treatment group had more patients on high-flow nasal oxygen or ventilation at baseline (27% to 14%). Remdesivir and celecoxib have shown nephrotoxicity, hepatotoxicity, and cardiotoxicity, and the combination of both in late stage patients may further increase risk. Authors defined AKI as an adverse events of special interest for celecoxib, but do not report results (only RRT which depends on clinical condition and survival, and is only reported including non-concurrent controls). Celecoxib 400mg BID for 7 days, famotidine 80mg QID for 7 days followed by 40mg BID for 14 days. Publication was delayed over 1.5 years after completion without explanation.
This study is excluded in meta
contribution of famotidine unclear with combined treatment, remdesivir and celecoxib have shown nephrotoxicity, hepatotoxicity, and cardiotoxicity, and the combination of both in late stage patients may further increase risk.
risk of death, 67.0% higher, HR 1.67, p = 0.18, treatment 12 of 30 (40.0%), control 8 of 37 (21.6%), adjusted per study, day 60.
risk of no recovery, 100% higher, HR 2.00, p = 0.02, treatment 15 of 30 (50.0%), control 8 of 37 (21.6%), adjusted per study, inverted to make HR<1 favor treatment, day 60.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Files et al., 3 Mar 2023, Randomized Controlled Trial, USA, peer-reviewed, 91 authors, study period 30 July, 2020 - 11 June, 2021, this trial uses multiple treatments in the treatment arm (combined with celecoxib) - results of individual treatments may vary, trial NCT04488081 (history)
Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial
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.
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