A Pilot Open-label Study of Aldose Reductase Inhibition with AT-001 (caficrestat) in Patients Hospitalized for COVID-19 Infection: Results from a Registry-based Matched-control Analysis

BACKGROUND: Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway, a trigger of the inflammatory cascade. We hypothesized that aldose reductase inhibition with AT-001 (caficrestat) might represent a novel therapeutic approach to reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS: We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 (caficrestat) in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg twice daily for up to 14 days. Safety, tolerability, survival and length of hospital stay were collected from the electronic medical record and compared with data from two matched control groups selected from a deidentified contemporaneous registry of COVID-19 patients at the same institution. RESULTS: AT-001 (caficrestat) was safe and well tolerated in the 10 participants who received the study drug. The in-hospital mortality observed in the AT-001 (caficrestat) group was 20% vs. 31% in matched control-1 and 27% in matched control-2. The mean length of hospital stay observed in the AT-001 (caficrestat) group was 5 days vs. 10 days in matched control group-1 and 25 days in matched control-2. Conclusions: In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, aldose reductase inhibition with AT-001 (caficrestat) was safe and well tolerated. Exposure to AT-001 (caficrestat) was associated with a trend of reduced mortality and shortening of the length of hospital stay. While the observed trend did not reach statistical significance. The present study provides the rationale for investigating potential benefit of AT-001 (caficrestat) in COVID 19 affected patients in future studies.