Phase I Clinical Trial to Evaluate the Safety of Baricitinib to Prevent Respiratory Insufficiency Progression in Oncohematological Patients Affected with COVID-19 - BARCOVID19 Study

INTRODUCTION. The coronavirus disease (COVID-19) might cause lower respiratory tract infection, progressing to severe acute respiratory distress syndrome (ARDS) and respiratory failure. High mortality rates among oncohematological patients receiving anticancer therapies had been described, varying from 29 to 39% approximately. Baricitinib, a reversible Janus-associated kinase 1 and 2 (JAK) inhibitor, was purposed as a feasible treatment option in this setting. It combines an immunomodulatory effect and antiviral activity, theoretically preventing endocytosis and viral assembly.

PATIENTS AND METHODS. We designed a phase I safety run-in cohort study aimed to determine the dose-limiting toxicity of baricitinib in terms of the rate of serious adverse events (SAE) in a group of oncohematological patients with COVID-19. The drug was administered on an inpatient basis, at an oral dose of 4 mg daily for 7 days, associated with the institutional standard of care (dexamethasone, remdesivir, and tocilizumab).

RESULTS. A total sample of six patients with a median age of 66 years old (range 57-79), were enrolled, with 66% of them receiving active anticancer treatment. Three patients had hematological malignancies (2 acute myeloid leukemia and 1 chronic lymphocytic leukemia), and three patients had solid tumors (Undifferentiated non-small cell lung carcinoma, colon carcinoma, and rectal carcinoma).

Patients had a median basal oxygen saturation of 90% (range, 86-98%). Oxygen supplementation was given through a nasal cannula or venturi mask to 4 out of 6 patients. Laboratory findings included lymphopenia (median value 0.93 x10E9/L; range 0.18-3.39 x10E9/L) with acute phase reactants, such as Lactate dehydrogenase or LDH (median value 470.4 U/L; range 168-1070 U/L), C-reactive protein or CRP (median value 171.8 mg/L; range 7.5-453 mg/L) and ferritin (median value 2106.6 µg/L; range 737-5149 µg/L). All patients had a normal renal function. Chest X-ray showed in all cases, bilateral infiltrates compatible with a viral infection.

The whole cohort received corticosteroids, but only three patients received remdesivir. On day +2, none of the participants needed a reduction in the doses, maintaining normal renal and liver function. All patients received baricitinib during the course of 6 days. On day +14, a decrease in the mean values of the inflammatory parameters was reported with levels of LDH, CRP, and ferritin of 319 U/L (range 152-425 U/L), 10.27 mg/L (range 0.6-20 mg/L), and 1005 µg/L (range 502-1291 µg/L), respectively.

The most common Adverse Event (AE) presented were bacterial-associated infections (5 out of 6 patients), including bilateral bacterial pneumonia, urinary tract infection, bacteremia, or bronchial prosthesis infection.

The mortality rate was 33%. The main causes were the progression of the oncohematological disease and respiratory insufficiency. As none of the AE were directly attributed to baricitinib, the incidence of AE and SAE due to the drug is considered to be less than 33%.

CONCLUSION. In summary, the present study results demonstrated that baricitinib is a safe treatment in oncohematological patients with COVID-19. Further studies with a larger population would be needed to evaluate the real benefits of its use in this scenario.