Auxora vs. placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial

Abstract

Background: Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia.

Methods: CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO₂/FiO₂ ratio > 75 and ≤ 300. The PaO₂/FiO₂ was imputed from a SpO₂/FiO₂ determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early.

Results: The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO₂/FiO₂≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO₂/FiO₂ ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia.

Conclusions: Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted. Trial registration NCT04345614.

Fig. 1

Patient Enrolment and Randomization. *Reasons for screen failure included PaO₂/FiO₂ ≤ 75 (n = 3), at least 1 of the following signs at Screening or noted in the 24 h before Screening: SpO2 < 92% on room air; PaO₂/FiO₂ = 300 when receiving low flow supplemental oxygen (n = 3), do not intubate order (n = 2), prohibited medication (n = 1), history of organ or hematologic transplant, HIV, Active hepatitis B, or hepatitis C infection (n = 1); ^†One patient in the Auxora arm and one patient in the placebo arm who had a baseline imputed PaO₂/FiO₂ ≤ 200 at baseline did not receive any doses

Fig. 2

Proportion of Patients with a Baseline Imputed PaO₂/FiO₂ ≤ 200 in Each Ordinal Scale Category Over Time. A higher proportion of patients receiving Auxora were discharged, and a lower proportion progressed to invasive mechanical ventilation, ECMO, and death at Day 60 (Odds Ratio, 0.647; 95% CI 0.405, 1.031; P = 0.0672) and Day 30 (Odds Ratio, 0.617; 95% CI 0.387, 0.983; P = 0.0423). Efficacy outcome measured with the 8-point ordinal scale included recovery rate defined as the first day the patient satisfied criteria 6, 7, or 8 and change in the 8-point ordinal scale over time. The proportions are compared between the two treatment groups using a proportional odds model with a fixed factor of treatment groups. ECMO, Extracorporeal membrane oxygenation

Fig. 3

Proximal Role of CRAC Channel-mediated IFN-γ in COVID-19 Pneumonia. Tissue resident alveolar macrophages respond to SARS-CoV-2 infection in the lung by producing T-cell chemoattractants. Arriving T cells produce IFNγ, leading to further alveolar macrophage activation and recruitment of monocyte-derived alveolar macrophages [15, 16]. The feedback loop leads to a rapid increase in proinflammatory cytokines, diffuse alveolar injury, severe endothelialitis, ARDS, and multiorgan dysfunction and failure [14, 17, 18]. Auxora abrogates the release of multiple proinflammatory cytokines from human lymphocytes, including IL-6, IL-17, and IFNγ that are implicated in COVID-19 alveolitis [16, 27]. Adapted from Grant RA, et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature. 2021;590(7847);635–641. IL, interleukin; IFNγ, interferon-gamma; ROS, reactive oxygen species