RESULTS
Overall, 384 patients with moderately severe COVID-19 were included in
our study. There were 212 males (55.2%), and the median age was 60
years (IQR 48–70). All patients were Caucasians. Median duration of
hospital stay until death or discharge was 16 days (IQR 14-20). 131
patients (34.1%) received tofacitinib in addition to standard of care,
and 253 patients (65.9%) were treated with standard of care alone.
Baseline clinical and demographic characteristics of patients with low
and normal oxygen saturation who received tofacitinib or standard of
care alone are presented in Tables 1 and 2.
Patients with reduced oxygen
saturation. At enrolment, oxygen saturation at rest on ambient air was
93% or lower in 257 patients (group 1), of whom 72 received tofacitinib
on top of standard of care treatment. Patients in the tofacitinib and
control groups were well-matched by age, gender, body mass index,
comorbidities, oxygen saturation, and various laboratory parameters,
including white blood cells, neutrophils, lymphocytes, serum lactate
dehydrogenase and eGFR. Median CRP levels were high in both groups.
Patients who were treated with tofacitinib had less extensive
ground-glass opacification on CT compared to controls, although almost
all patients maintained target oxygen saturation using nasal oxygen and
did not require high-flow oxygen or non-invasive ventilation. Baseline
differences in both groups were observed. In particular, two-times more
patients received glucocorticoids in the tofacitinib group than in the
control group (43.7% and 21.1%, respectively; p=0.001).
Overall, the primary composite end-point of death or mechanical
ventilation was reached in 9 (12.5%) of 72 patients who were treated
with tofacitinib and 26 (14.1%) of 185 patients who received standard
of care treatment alone (HR 0.92, 95% CI 0.33-2.56). Invasive
mechanical ventilation was initiated in 5 (6.9%) patients in the
tofacitinib group versus 24 (13.0%) patients in the control group (HR
0.46; 95 CI 0.11-1.99), whereas 8 (11.1%) versus 21 (11.4%) patients
in the two groups, respectively, died in the hospital (HR 1.25; 95 CI
0.44-3.54).
Unweighted Kaplan-Meier estimates showed no beneficial effect of
treatment with tofacitinib compared with standard of care only (Fig. 1).
Also, we found no differences between groups for the mortality end-point
or requirement for invasive mechanical ventilation. In Cox regression
analysis, addition of tofacitinib to standard of care did not result in
a reduced risk of either primary or secondary outcomes (Table 3).
Patients with normal oxygen saturation. At baseline, oxygen
saturation at rest was normal (94% or higher) in 127 patients. 59 of
them were treated with tofacitinib in addition to standard of care, and
68 patients received only standard of care treatment. Various
parameters, including age, gender, body mass index, comorbidities,
oxygen saturation, white blood cells, neutrophils, and lymphocytes
counts, serum creatinine level, were well balanced across groups. Like
in group 1, patients in the tofacitinib group had less extensive
ground-glass opacification on CT and a lower median CRP level compared
to the control group. The proportions of patients who received treatment
with glucocorticoids and low-molecular weight heparins in the
tofacitinib group were significantly higher than in the control group.
The primary composite end-point of death or invasive mechanical
ventilation was met in 1 (1.7%) of 59 patients who received tofacitinib
plus standard of care treatment and 3 (4.4%) of 68 patients who were
treated with standard of care alone (HR 0.83; 95 CI 0.07-9.44). No
patient in the tofacitinib group required invasive mechanical
ventilation, whereas 3 (4.4%) controls were intubated during hospital
stay (p=0.25). One patient (1.7%) in the tofacitinib group deceased
compared to 3 (4.4%) patients in the control group (HR 1.10; 95 CI
0.10-12.46).
Kaplan-Meier analysis showed no beneficial effect of tofacitinib added
to standard of care treatment compared with standard of care alone (Fig.
2). The mortality rates and requirement for invasive mechanical
ventilation also did not differ between the two groups. In Cox
regression analysis, addition of tofacitinib to standard of care
treatment was not associated with a reduced risk of either composite
primary or secondary end-points compared with standard of care treatment
(Table 3).
Patients treated with glucocorticoids. In total, 118 patients
from the study population were treated with intravenous dexamethasone
(supplemental table S1). Among 70 patients with reduced oxygen
saturation, the primary end point of death or mechanical ventilation
occurred in 4 (12.9%) of 31 patients in the tofacitinib group and 11
(28.2%) of 39 patients in the control group. Mechanical ventilation was
required in 1 (3.2%) and 10 (25.6%) patients, respectively, whereas 4
(12.9%) patients treated with tofacitinib and glucocorticoids and 9
(23.1%) patients who received glucocorticoids alone died. All the
differences in the end points rates between the two groups did not reach
statistical significance in the univariate Cox analysis. Among 48
patients with normal oxygen saturation, the composite end point was met
in 1 (3.0%) of 31 patients who were treated with tofacitinib in
addition to glucocorticoids and in 2 (13.3%) of 15 patients who
received glucocorticoids alone. The differences in the primary and
secondary end point rates between the two groups were insignificant in
the univariate Cox analysis.
Safety. Adverse events were reported in 34 (26.0%) of 131
patients treated with tofacitinib (Table 4). Treatment with tofacitinib
was discontinued in 7 (5.3%) patients due to rapid respiratory
deterioration (n=2) or serious adverse events (n=5) that included
ST-elevation myocardial infarction (n=1), bacterial sepsis (n=2),
jugular vein thrombosis (n=1), and bacterial colitis (n=1).