This study evaluated the efficacy and safety of ruxolitinib, a JAK1/2 inhibitor, for coronavirus disease 2019.
We conducted a prospective, multicenter, single-blind, randomized controlled phase II trial involving patients with severe coronavirus disease 2019.
Forty-three patients were randomly assigned (1:1) to receive ruxolitinib plus standard-of-care treatment (22 patients) or placebo based on standard-of-care treatment (21 patients). After exclusion of 2 patients (1 ineligible, 1 consent withdrawn) from the ruxolitinib group, 20 patients in the intervention group and 21 patients in the control group were included in the study. Treatment with ruxolitinib plus standard-of-care was not associated with significantly accelerated clinical improvement in severe patients with coronavirus disease 2019, although ruxolitinib recipients had a numerically faster clinical improvement. Eighteen (90%) patients from the ruxolitinib group showed computed tomography improvement at day 14 compared with 13 (61.9%) patients from the control group (P = .0495). Three patients in the control group died of respiratory failure, with 14.3% overall mortality at day 28; no patients died in the ruxolitinib group. Ruxolitinib was well tolerated with low toxicities and no new safety signals. Levels of 7 cytokines were significantly decreased in the ruxolitinib group in comparison to the control group.
Although no statistical difference was observed, ruxolitinib recipients had a numerically faster clinical improvement. Significant chest computed tomography improvement, a faster recovery from lymphopenia, and favorable side-effect profile in the ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population.
This randomized trial found that ruxolitinib added to SoC treatment was not associated with significantly accelerated clinical improvement in severe patients with COVID-19, although ruxolitinib recipients had a numerically faster clinical improvement compared with the control group. Ruxolitinib recipients showed significantly faster improvement in the chest CT at D14 compared with the control group (18 [90%] vs 13 [61.9%]; P = .0495). The 28-day mortality was 14.3% in the comparison group. No death or deterioration occurred in ruxolitinib recipients. These data provide a rationale for further trials to determine whether ruxolitinib treatment can reduce the overall incidence of deterioration and death. Patients treated with ruxolitinib showed a significantly shorter lymphocyte recovery than those in the control group (5 [IQR, 2-7] days vs 8 [IQR, 2-11] days; P = .033). We assume that a faster recovery from lymphopenia is of clinical relevance because lymphopenia was associated with poor prognosis. A shorter duration of lymphopenia in ruxolitinib recipients was consistent with a higher mean peak level of IgM specific for SARS-CoV-2 in patients treated with ruxolitinib. Among 4 patients from the control group who experienced clinical deterioration, 3 were transferred to the ICU and required invasive mechanical ventilation. Three patients in the control group eventually died of respiratory failure. The demographic and clinical characteristics of the patients were balanced between the 2 groups at enrollment. The use of corticosteroids and antivirals was comparable between the control and ruxolitinib groups. Therefore, it was unlikely that the baseline characteristics and treatments of the 2 groups would affect the end points of our study.
The present randomized trial also found that ruxolitinib with SoC treatment was well tolerated with low hematological and nonhematological toxicities. All ruxolitinib recipients completed the full course of administration until discharge, whereas the control group needed more intensive supportive treatments after enrollment due to the deterioration in some cases. The addition of ruxolitinib based on SoC did not increase the risk of adverse events compared with the control group. The overall incidence of adverse events was similar between the 2 groups. Interestingly, although most of the adverse events occurred at grade 1 or 2, adverse events at grade 3 or 4 and serious adverse events were more common in the control group due to the progressive deterioration in patients with COVID-19 in this group. Among all ruxolitinib recipients, only 2 adverse events at grade 3 occurred and were transient and reversible. There were no unexpected adverse events and previously unknown events in ruxolitinib recipients. One of the major concerns related to the use of ruxolitinib in the treatment of COVID-19 is its therapeutic action in reducing systemic inflammation, and potential to unfavorably delay the clearance of viral loads and impair the generation of SARS-CoV-2–specific antibodies. In the current study, there was no significant difference in viral RNA loads or duration as well as IFN-α2 and IFN-γ levels between ruxolitinib recipients and the control group. Interestingly, the mean peak level of IgM specific for SARS-CoV-2 was profoundly higher in the ruxolitinib group compared with the control group, whereas no significant difference was found in the mean peak IgG against SARS-CoV-2 between the 2 groups. The favorable side-effect profile observed in the current trial provides a rationale for the initiation of a large-scale clinical trial at the same or higher ruxolitinib dose regimens in efforts to improve outcomes.
In the present study, we found that the addition of ruxolitinib to SoC treatment could significantly mitigate exuberant cytokine storm featured in severe COVID-19, which justified the use of ruxolitinib for reduction of systemic inflammation. In 2 published autopsy reports,it was identified that the severe immune injury was also involved in other organs without obvious viral inclusions, thus indicating the important role of cytokines storm instead of the direct viral damage to the whole body. The infiltrated immune cells in alveoli were mostly macrophages and monocytes, which was in accordance with our findings on cytokines changes. In particular, the levels of 7 cytokines—IL-6, nerve growth factor β, IL-12(p40), migration inhibitory factor, MIP-1α, MIP-1β, and VEGF—were markedly decreased in patients who received ruxolitinib in comparison to the control group. Among these cytokines, IL-6 has been reported as a critical cytokine driving proinflammatory activity in cytokine-mediated organ dysfunction and tissue damage35 and IL-6–directed therapy as the cornerstone of cytokine-based therapy after chimeric antigen receptor T-cell therapy. IL-12(p40), MIP-1α, and MIP-1β are critical chemokines for the recruitment of activated monocytes/macrophages and other cells to the site of infection. VEGF, which has been reported to recruit monocytes/macrophages, participates in increased capillary permeability syndrome that characterizes some types of viral pneumonia.
These results indicate that ruxolitinib may exert its inhibitory effect by targeting multiple critical cytokines rather than any specific cytokine, and these cytokines could be used as surrogate biomarkers in future ruxolitinib trials.
The present study has several limitations. First, the sample size was small due to no eligible patients available at the end of the pandemic at our trial centers and the few end points reached statistical significance. The safety profile during this study was favorable, but further testing in larger patient cohorts with different ethnicity or disease status is required. Second, there are some limitations related to the ordinal scale that was used to evaluate primary end points. Because of the severity of the epidemic, even if the patients had a significant improvement in the CT scan as well as clinical symptoms, they still asked for nasal cannula oxygen (<2 L/min) until being discharged from hospital, which may contribute to the nonstatistically significant P value of clinical improvement. Finally, critically ill patients or patients with invasive ventilator dependence were not included in this study because of the lack of previous data and our concerns on the unknown safety profile of ruxolitinib treatment in pneumonia. Therefore, our conclusion is confined to patients with severe COVID-19. Nevertheless, this study is the first randomized controlled trial on the use of ruxolitinib in patients with severe COVID-19 based on a novel therapeutic rationale. These findings are hypothesis-generating and require additional larger controlled studies to confirm the possibility of a treatment benefit of ruxolitinib. However, these early data were promising and informative to future trials with ruxolitinib or other JAK1/2 inhibitors.
The favorable side-effect profile combined with a reduction in inflammation and significant chest CT improvements in the ruxolitinib plus SoC treatment group should inform future trials in a larger population to assess with ruxolitinib or other JAK1/2 inhibitors in patients with COVID-19
Reference & Source information: https://www.jacionline.org/
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