Discussion
hypoxemia, inflammation, death, hypotension
ADVERSE EVENTS, INFLAMMATION, CARDIOGENIC SHOCK, DISEASE, COVID-19 INFECTION, SECONDARY, CARDIAC EVENTS, INFLUENZA
In this single center Phase I/II trial of patients requiring hospitalization due to COVID-19, daily intravenous administration of 10 cc of purified hAF for up to 5 days did not significantly decrease CRP compared to placebo, nor did it result in significant differences in major clinical outcomes, including death, intubation, major cardiac events, or ECMO utilization. Additionally, secondary outcomes of change in other blood biomarkers of inflammation, including LDH, D-dimer and IL-6 were not significantly different with administration of hAF.A limitation to this study relates to the failure to achieve the pre-designated enrollment goal. At the end of the study period, the number of hospitalizations for patients with respiratory COVID-19 infections had dramatically decreased. Indeed, in the last 6 months of the study, only 2 patients were enrolled. In addition, during the nearly 2-year period of study, enrollment was challenged by many competing studies for this patient population at the University of Utah. Hence, with the guidance of the DSMB, it was decided to close the study and move forward with data analysis. To be clear, the study was halted not for safety reasons, but rather because of the logistical problem of study enrollment.The ability to detect notable differences in the primary and secondary outcomes may not have been limited as much by under enrollment (47 of a planned 60) as by other factors, including a lack of effect of 10 mL of intravenous hAF on systemic markers of inflammation for hospitalized patients with COVID19. It was notable that in our study, the time from onset of symptoms until initiation of study drug was nearly 10 days. Quite possibly, the initial surge of inflammation associated with COVID-19 had already started to wane within a given patient, as it is known that inflammatory markers in patients with influenza achieve peak innate immune response by Day 5, with relative near resolution by Day 8 [Despite the lack of a significant difference in serum inflammatory biomarkers, the incidence of adverse events (AE) in all patients was lower than had been reported during hospitalization for COVID-19 early in the pandemic, which surprised us. This may have been reflective of the numerous exclusion criteria for comorbidities that the trial utilized, resulting in a less morbid population than was typically hospitalized for COVID. As described in the results, serious AEs (SAEs) in the trial that were observed included death, cardiogenic shock, hypotension and severe hypoxemia. There was no evidence from our analyses that these SAEs were more likely in the hAF group than in the placebo group; this conclusion was substantiated by the independent unblinded DSMB, which adjudicated each SAE after occurrence and recommended continuing the trial each time, finding the SAE attributable to the disease process and not the hAF therapy. Further, in planning our trial, we powered it based on the assumption that there would be no SAEs attributable to hAF. Our trial showed that 8 patients experienced SAEs (7 who received hAF and 1 who received placebo). While this difference was not statistically significant (To our knowledge, this study is the rigorous assessment of the effect of intravenous hAF on outcomes. Human AF has a long history of successful administration as an effective treatment for other inflammatory conditions or for augmenting regenerative healing, though it was administered intra- or transdermally in these other situations. To our knowledge, beyond our pilot, in which we administered hAF via inhaled and intravenous routes (cite), this is the first study to systematically assess the efficacy and safety of intravenous administration.