RUXCOVID: A phase 3, randomized, placebo-controlled study evaluating the efficacy andsafety of ruxolitinib in patients with COVID-19-associatedcytokine storm

ABSTRACT

Background: Severe COVID-19 can result in pneumonia, with many patients (pts) requiring hospitalization andoxygen support. Severe COVID-19 may also be complicated by acute respiratory distress syndrome, sepsis andseptic shock, and/or multiorgan failure. Many of these pts have features consistent with cytokine release syndrome(CRS) and its associated hyperinflammation. Given their immunomodulatory effects, Janus kinase (JAK) inhibitorshave been suggested as a potential therapeutic option in pts with severe COVID-19. Ruxolitinib-a potentJAK1/JAK2 inhibitor approved for treating myelofibrosis, polycythemia vera, and steroid-refractory acute graft-vs.-host disease (GvHD;US only)-has been associated with reduced levels of inflammatory cytokines in disorderswhere cytokine dysregulation plays a role, including GvHD and secondary hemophagocytic lymphohistiocytosis.Additionally, findings from a small, randomized, phase 2 study (N = 43;Cao Y et al., J Allergy Clin Immunol 2020)showed that treatment with ruxolitinib plus standard of care (SOC) reduced CRS-associated hyperinflammation inpts with severe COVID-19 vs placebo plus SOC, with significant improvement seen in chest computed tomography(CT) features. Although no statistically significant differences were observed, ruxolitinib-treated pts also had anumerically shorter median time to clinical improvement, a lower proportion requiring intensive care/mechanicalventilation, and reduced mortality, with ruxolitinib having a favorable safety profile. Methods: RUXCOVID ( NCT04362137 ) is a global, randomized (21), double-blind, placebo-controlled, 29-day, phase 3 study evaluating the efficacy and safety of ruxolitinib plus SOC compared with placebo plus SOC in pts withCOVID-19. Pts are eligible for the study if they are ≥ 12 years old, have confirmed COVID-19, are hospitalized, andmeet ≥ 1 of the following pulmonary infiltrates (by chest x-ray or CT scan), respiratory frequency ≥ 30 breaths/min, requirement of supplemental oxygen, oxygen saturation (SpO ) ≤ 94% on room air, or arterial oxygen partialpressure (PaO )/fraction of inspired oxygen (FiO ) < 300 mm Hg (1 mm Hg = 0.133 kPa). Pts with a need forintensive care or intubation are not eligible. Pts will be randomized to ruxolitinib 5 mg twice daily or placebo andtreated for 14 days. Pts may be treated for an additional 14 days if no improvement occurs and the potential benefitoutweighs the potential risk per investigator assessment. The primary endpoint is the proportion of pts who die, develop respiratory failure (require mechanical ventilation), or require intensive care by day 29. Secondaryendpoints include improvement in clinical status, in-hospital outcomes, change in National Early Warning Score, change in SpOFiO ratio, mortality rate, change in inflammatory biomarkers, and safety. Target enrollment is 402pts. Sponsored by Novartis Pharmaceuticals and Incyte.