Discussion
pneumonia, non-critically ill COVID-19 infection, SAEs, infection, viral infections, non-critically ill, sepsis
DISEASE PROGRESSION, PNEUMONIA, DISEASE, VIRAL INFECTION, COMPLICATION, INFECTION, SECONDARY, SEPSIS
This randomized trial found that C1INH treatment added to SOC was not associated with clinical improvement or faster recovery from COVID-19 in comparison with SOC alone in hospitalized, non-critically ill patients. The overall mortality in this trial (7%) was substantially lower than the one previously reported in the dexamethasone trial (23%), published by the RECOVERY collaborative group (The conduction of this trial was justified by scientific rationales and a previous pilot study (First, the administration of ConA may have been too late in the course of COVID-19. Because of the short half-life of ConA, repeated administration of ConA over 3 days was chosen. The dosage chosen was supposed to increase the C1INH concentrations by at least 50%. Pharmacokinetic analyses revealed that C1INH concentrations were already markedly elevated at baseline in both arms, which is in agreement with our previous data (Second, the dosing regimen may have been unable to inhibit the CS in COVID-19 sufficiently and for a prolonged period of time. C1INH concentrations doubled initially after the first administration of ConA but returned to almost baseline before the 4th administration. The exact concentration required to inhibit the complement and other cascades and the optimal target are unknown both in the specific context of COVID-19 and in hyperinflammation secondary to infection in general. Of note, COVID-19 is characterized by a local activation of plasma cascades that progresses to a systemic activation early in the disease (Third, in COVID-19, the potential inhibitory role of C1INH may have been overestimated when considering activation through the classical and alternative pathway (Fourth, cross-activation of the CS downstream of the lectin and classical pathway proteases may play a considerable role in COVID-19 disease progression. For example, factor XIa inhibited the regulatory complement factor H of the alternative pathway enhancing alternative pathway activity (The CS has been a target of a number of randomized controlled trials in COVID-19. However, only retrospective data from patients requiring continuous positive airway pressure support (This trial was designed early during the pandemic. As such, it was decided that instead of defining futility margins for a rather small-scale trial including a diverse patient population, a regular review of the DSMB might be more appropriate, as the included patients would potentially receive various new treatments with poorly known safety profiles as time evolved. Instead, two adaptive interim analyses after 40 and 80 patients were carried out. Although more SAEs occurred in the intervention arm, the majority of them were noted after the intervention period. In agreement with external evaluations, we attributed most SAEs to COVID-19 or a complication of it (e.g., pneumonia or sepsis). This interpretation is also supported by the observation of more severe COVID-19 at baseline and throughout the study period in the intervention arm. Of note and in contrast to C5 inhibitory strategies, C1INH treatment has not been associated with an increased risk for bacterial or viral infections or any effect on viral replication (Our study has limitations. These include the premature closure of the trial, the lack of prespecified futility margins, the small number of patients in the control arm (due to the 2:1 randomization), and the imbalances in baseline characteristics and disease severity observed between the groups at baseline (potentially due to the 2:1 randomization and stratification in the setting of a limited number of enrolled patients). Almost 50% of patients were recruited in one center, reflecting an uneven distribution between the institutions. It was an open-label trial, and as such, it may have been prone to bias. The SOC treatment allowed the use of remdesivir and dexamethasone, which may have diminished the possible effect of ConA. Last but not least, follow-up phone calls might potentially have been less accurate than in-person follow-up visits when assessing for AEs. Despite these limitations, this is the largest study to investigate a treatment strategy that interferes with the CS, KKS, and CAS in hospitalized COVID-19 patients. In addition, we provide patient-matched laboratory data regarding the inability of ConA to limit the activation of these plasma cascades in COVID-19.In conclusion, ConA did not significantly accelerate clinical improvement or reduce mortality in hospitalized patients with non-critically ill COVID-19 infection. The chosen dose and regimen of ConA used in this study are insufficient to limit complement activation in COVID-19. It remains unclear whether or not higher dosages, a longer treatment regimen, or an earlier intervention time point with ConA in COVID-19 could have prevented disease progression.