Narsoplimab treatment results in critically ill COVID 19 patients in I-SPY COVID Trial

 Analysis in the randomized patient population shows that the addition of narsoplimab to treatment of critically ill patients with COVID-19 reduces the mortality risk (hazard ratio [HR]=0.81, with probability [HR <1] equal to 0.77). narsoplimab showed the largest reduction in mortality risk to date across all drugs reported from the i-spy covid trial

There were 91 patients randomized to the narsoplimab arm of the trial across 27 participating US sites. The 91 randomized patients were compared to the 116 patients concurrently randomized to the control arm. All patients received standard of care including dexamethasone and remdesivir. Bayesian statistics were prespecified and employed for analyses.

Narsoplimab was to be administered at a dose of 4 mg/kg given as a 30-minute intravenous infusion (up to a maximum of 370 mg per infusion) twice weekly for the earlier of a total of 4 weeks (i.e., 9 doses) or until hospital discharge. However, in approximately half of the patients who died in the narsoplimab group, narsoplimab was not given or was prematurely stopped, with those patients dying 9 to 35 days later.

Despite narsoplimab treatment exposure in a limited number of patients in this trial, a substantial efficacy signal was observed in reducing the risk of mortality for critically ill COVID-19 patients.

Narsoplimab was not observed to shorten the time to recovery in critically ill patients with COVID-19 in this study. The study did not identify any new safety signals for narsoplimab in the setting of critically ill COVID-19 patients.

The I-SPY COVID Trial was designed for rapid screening of agents that show promise for two primary endpoints in critically ill COVID-19 patients: the time to recovery (defined as reduction in oxygen demand) and the risk of mortality. The study utilizes QLHC’s adaptive platform trial design methodology, which focuses on the simultaneous, efficient assessment of multiple investigational agents. To streamline enrollment and allow rapid assessment of multiple drugs as required during the pandemic, the platform trial’s initial design included a requirement that patients be randomized prior to consenting to trial participation.

While the motivation for this sequence and the analysis of the consented population is outlined in The I-SPY COVID Adaptive Platform Trial for COVID-19 Acute Respiratory Failure: Rationale, Design and Operations, such analyses have risk of bias. To protect against potential bias associated with analysis only in the consented population, QLHC also prespecified analyses based on all randomized patients (the industry-standard intent-to-treat population).

Substantial imbalance in the consented population was detected and created a marked and statistically significant bias against the narsoplimab arm, rendering analysis of the consented population meaningless. However, as pre-specified by the analysis plan, the I-SPY trial’s data monitoring committee terminated the narsoplimab arm based on the biased analyses in the consented population prior to reaching the maximum of 125 patients. Neither the trial’s futility nor graduation criteria had been met in the analysis of the randomized population at the time the narsoplimab arm was terminated.

Avoiding similarly biased outcomes in future trial arms, QLHC subsequently revised the protocol for its I-SPY COVID Trial to obtain patient consent prior to randomization.