Patient Selection
This Phase 2, randomized, controlled, open-label study was conducted across three centers in the United States (ClinicalTrials.gov number, NCT04345614). Patient enrolment took place from April 8, 2020 to May 13, 2020. Eligible patients were adults with a diagnosis of COVID-19 determined by reverse transcription polymerase chain reaction and pneumonia documented by chest imaging. In addition, patients were required to have ≥1 symptom consistent with COVID-19, such as fever, cough, sore throat, malaise, headache, muscle pain, dyspnea, confusion, or respiratory distress, and ≥1 clinical sign suggesting respiratory compromise, such as respiratory rate ≥30 breaths per minute, heart rate ≥125 bpm, SpO2 <93% on room air or requiring >2L oxygen by nasal cannula to maintain SpO2 ≥93%, or PaO2/FiO2 <300, imputed from pulse oximetry or determined by arterial blood gas.
Study Design
The initial study design included enrolment of 60 patients receiving low flow supplemental oxygen at screening into Arm A (severe COVID-19 pneumonia) and 60 patients receiving high flow supplemental oxygen through a high flow nasal cannula at screening into Arm B (critical COVID-19 pneumonia). In both arms, patients were randomly assigned in a 2:1 ratio to receive Auxora plus standard of care or standard of care alone. Auxora was administered on three consecutive days as a 4-hour continuous intravenous infusion. The initial dose was 2.0 mg/kg (max 250 mg) and subsequent doses were 1.6 mg/kg (max 200 mg) at 24 and 48 hours. All patients received local standard of care, including anti-viral agents, but investigational therapies and immunosuppressive medications were not permitted. At the discretion of the site investigators, patients treated with either Auxora or standard of care alone were able to receive convalescent plasma if they required invasive mechanical ventilation.
After admission, patients were assessed daily for the first ten days and then every 48 hours until Day 28 or discharge, whichever occurred first. On Day 30, all patients were assessed for mortality. Discharged patients were contacted by phone. All adverse events (AEs) and serious adverse events (SAEs) were recorded during hospitalization. The SpO2 and FiO2 at the time of the study visit and the lowest SpO2/FiO2 ratio documented over the previous 24 hours were recorded daily. The patient’s clinical status was also evaluated daily by assessing if the patient was alive, required invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), high flow supplemental oxygen or non-invasive ventilation, low flow supplemental oxygen, or other ongoing medical care in the previous 24 hours. The need for continued supplemental oxygen was also assessed at the time of discharge.
The trial protocol was approved by an institutional review board at each site and was overseen by an independent safety review committee (ISRC). Informed consent was obtained from either the patient or from the patient’s legally authorized representative if the patient was unable to provide consent. The ISRC was scheduled to perform a review for each arm after the first 12 patients were dosed with Auxora and then again after 24 patients were dosed. The analysis plan called for a separate evaluation of the safety and efficacy of the two arms as enrolment rates were expected to differ. The ISRC conducted an initial review on May 3, 2020 after the first 12 patients in Arm A were dosed with Auxora. At that time, six patients had received standard of care in Arm A. The ISRC recommended continuing the trial without changes. The US Food and Drug Administration (FDA) was sent the interim efficacy data presented here in response to questions about the ISRC review. The FDA provided guidance on May 12, 2020, to limit further enrolment in the open-label study and transition to a randomized, blinded, placebo-controlled study, and as such, both Arms A and B ceased further enrolment.
Statistical Analysis
All analyses were conducted in the Intention to Treat population. The primary objective was to determine the safety and tolerability of Auxora for patients with severe and critical COVID-19 pneumonia. The incidence, intensity, and relationship of AEs and SAEs, and the development of laboratory abnormalities that were clinically significant and required intervention were assessed. Mortality at Day 30 was evaluated as a safety outcome. For the purpose of safety and outcome analyses, patients from Arms A and B were analyzed together, comparing treatments with Auxora and standard of care with standard of care alone.
Efficacy outcome measures included recovery rate defined as the first day the patient satisfied criteria 6, 7, or 8 of the 8-point ordinal scale (Table 1). Additional efficacy outcome measures included the change in the 8-point ordinal scale over time, the proportion of patients requiring invasive mechanical ventilation, and a composite outcome of death or invasive mechanical ventilation. The number needed to treat (NNT) was calculated using the absolute risk reduction in the composite outcome in the Auxora group versus standard of care.
Efficacy analyses were performed in enrolled patients with severe COVID-19 pneumonia (Arm A) and in 3 subgroups of Arm A according to their baseline PaO2/FiO2 (1-100, 101-200, or ≥201). Baseline PaO2/FiO2 was defined as the lowest value in the 24 hours prior to screening. The PaO2 was imputed from the SpO2 using a published table based on Ellis’s inversion of the Severinghaus equation.16,17