The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) —also known as coronavirus 2019 (COVID-19)— is now a pandemic and a world health problem, as stated by World Health Organization (WHO).¹ One of the main concerns —besides its death rate ranging from 0.5 to 10% and hospitalization rates from 10 to 20%— is that its contagion rate is exceptionally high, that is to say, a reproduction rate of 2.2 expecting this way an exponential growth.^1,2

Coronavirus protein S binds to host cells through angiotensin receptor 2 (ACE2); thus, releasing viral RNA. This RNA is identified in the cytoplasm at the intracellular level. This cellular complex generates different signaling cascades that activate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and interferon regulatory factor 3, also known as IRF3 with further production of type I interferons (IFN-a/b) and a series of pro-inflammatory cytokines.^1,3

The immune response is essential for the control and resolution of COVID infection, but at the same time, is to be blamed as responsible for its severe complications. In COVID-19 patients, levels of different cytokines are high. This cytokine storm is one of the main physiopathological factors in the critical condition of many patients.^1,4 IL-2R expression and serum levels of IL-6 are significantly different when comparing the severity of infection in critical patients who commonly have higher levels.⁵

In the search for a specific cytokine storm therapy, STAT3 y STAT5A pathways are likely to be targeted through JAK inhibitors that affect STAT pathways.⁶ JAKs had demonstrated effectivity in several pathologies characterized by high inflammatory responses. Thus, ruxolitinib, a JAK1/JAK2 inhibitor, is approved in polycythemia vera, myelofibrosis, and graft versus host disease (GVHD). It has been used off-label in other pro-inflammatory states like systemic mastocytosis, juvenile dermatomyositis, and hemophagocytic syndrome. JAK2 inhibition significantly suppresses T cytotoxic cell proliferation and inhibits IL-6.⁷

Ruxolitinib inhibits IFN-g and antigen presentation reducing overall cytokine production.^7,8 It is a drug with oral absorption (bioavailability of 95%), and that reaches the plasma peak at 1-2 hours. Its half-life is 1.8-3 hours with an increase to 5 hours in case of hepatic failure. Thus, it is a drug with a rapid onset of the effect and better control of its adverse events.⁹ It has been used in hematology, in some autoimmune diseases, and the severe acute respiratory syndrome caused by COVID-19 in the city of Livorno, Italy. It showed favorable responses in this latter clinical condition, without deaths and with adequate tolerance in eight patients.¹⁰

Baricitinib, another JAK 1/2 inhibitor, improved clinical and respiratory parameters within two weeks, and no adverse events were recorded.¹¹

With this in mind and due to the urgent need for finding effective treatments for COVID-19 severe respiratory syndrome patients, we are undertaking this open-label study.

Study Type

Open-label proof-of-concept interventional study (Figure 1).

Hypothesis

The treatment of SARS-CoV2 with ruxolitinib can resolve the excessive inflammatory response and stop the manifestations of a severe acute respiratory syndrome; the improvement is ≥75% percent of the patients treated.

Main Study Objectives

Primary Objective

Measure the efficacy of ruxolitinib in patients with pulmonary lesions caused by SARS-CoV-2.

Secondary Objectives

• Measure the intrahospital length
• Measure the proinflammatory response by serum parameters (interleukine-6, C-reactive protein, lactate dehydrogenase, erythrocyte sedimentation rate, ferritin)
• Measure the incidence of the requirement of mechanical ventilation
• Measure mortality caused by COVID-19
• Measure adverse events caused by ruxolitinib

Intervention

Ruxolitinib will be given at a dose of 5 mg oral each 12 hours for 15 days.

Population

The selection criteria include:

• Age ≥ 18 years
• Confirmed COVID-19 diagnosis by PCR
• Presence of pulmonary lesion characterized by:

• Tachypnea defined as >20 rpm AND
• SpO2 <90% measured by pulse oximeter in case of FiO2 21% OR PaO2 <65 mmHg measured by arterial blood gas in case of oxygen supplementation AND
• Chest X-ray or CT-scan with pulmonary changes compatibles with COVID-19

• Informed consent

The exclusion criteria are:

• Pregnancy or breastfeeding
• End-Stage Chronic Renal Disease (ECRD) with CrCl <15 mL/min
• Charlson index ≥4 points
• Thrombocytopenia ≤20,000 cells/mm³
• Neutropenia ≤500 cells/mm³
• Active infection of HIV, hepatitis C, hepatitis B, herpes zoster or mycobacterium tuberculosis
• Concomitant use of tocilizumab, baricitinib and interferon

Those patients who would voluntarily drop out of the study will be eliminated from the study cohort.

Sample Size

According to the national report on the COVID-19 status on April 1, there are an estimated 1,378 confirmed cases with 7% requiring in-hospital care for being severe and/or assisted mechanical ventilation. Thus, there would be 96 patients representing our study universe. With an estimated confidence interval of 95% and an acceptable margin of error of 0.05, the number of patients to study (n) is 77.

Risk for participants

The risks for the participants at the study are the serious adverse events reported for ruxolitinib. The most relevant and frequent are anemia, thrombocytopenia, neutropenia, and bacterial infections, which will be the safety matters to observe in the patients treated.

Duration

The intervention is programmed to last 15 days. The main objective of the study will be obtained after the two-week treatment. Follow-up in search of adverse events will be monitored for two more weeks. The treatment will be terminated by protocol in case of severe adverse events graduated ≥3 by the Common terminology of adverse events version 5.0. (CTAE 5.0) or if the subject voluntarily withdraws his or her consent to participate in the study.