new england

The
journal of medicine
established in 1812 March 4, 2021 vol. 384 no. 9

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

A.C. Kalil, T.F. Patterson, A.K. Mehta, K.M. Tomashek, C.R. Wolfe, V. Ghazaryan, V.C. Marconi,
G.M. Ruiz‑Palacios, L. Hsieh, S. Kline, V. Tapson, N.M. Iovine, M.K. Jain, D.A. Sweeney, H.M. El Sahly,
A.R. Branche, J. Regalado Pineda, D.C. Lye, U. Sandkovsky, A.F. Luetkemeyer, S.H. Cohen, R.W. Finberg,
P.E.H. Jackson, B. Taiwo, C.I. Paules, H. Arguinchona, N. Erdmann, N. Ahuja, M. Frank, M. Oh, E.-S. Kim,
S.Y. Tan, R.A. Mularski, H. Nielsen, P.O. Ponce, B.S. Taylor, L.A. Larson, N.G. Rouphael, Y. Saklawi, V.D. Cantos,
E.R. Ko, J.J. Engemann, A.N. Amin, M. Watanabe, J. Billings, M.-C. Elie, R.T. Davey, T.H. Burgess, J. Ferreira,
M. Green, M. Makowski, A. Cardoso, S. de Bono, T. Bonnett, M. Proschan, G.A. Deye, W. Dempsey, S.U. Nayak,
L.E. Dodd, and J.H. Beigel, for the ACTT-2 Study Group Members*​​

a bs t r ac t

BACKGROUND
Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflam- The authors’ full names, academic de-
mation. The effects of combination treatment with baricitinib, a Janus kinase grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
inhibitor, plus remdesivir are not known. Kalil at the University of Nebraska Medi-
cal Center, 985400 Nebraska Medicine,
METHODS Omaha, NE 68198-5400, or at ­akalil@​
We conducted a double-blind, randomized, placebo-controlled trial evaluating ­unmc​.­edu.
baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients * A complete list of members of the
received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). ACTT-2 Study Group is provided in the
The primary outcome was the time to recovery. The key secondary outcome was Supplementary Appendix, available at
clinical status at day 15. NEJM.org.

This article was published on December

RESULTS 11, 2020, and updated on January 5, 2021,
A total of 1033 patients underwent randomization (with 515 assigned to combina- at NEJM.org.
tion treatment and 518 to control). Patients receiving baricitinib had a median time N Engl J Med 2021;384:795-807.
to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days DOI: 10.1056/NEJMoa2031994
(95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; Copyright © 2020 Massachusetts Medical Society.

P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds
ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive
ventilation at enrollment had a time to recovery of 10 days with combination treat-
ment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08).
The 28-day mortality was 5.1% in the combination group and 7.8% in the control
group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events
were less frequent in the combination group than in the control group (16.0% vs.
21.0%; difference, −5.0 percentage points; 95% CI, −9.8 to −0.3; P = 0.03), as were
new infections (5.9% vs. 11.2%; difference, −5.3 percentage points; 95% CI, −8.7 to
−1.9; P = 0.003).
CONCLUSIONS
Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery
time and accelerating improvement in clinical status among patients with Covid-19,
notably among those receiving high-flow oxygen or noninvasive ventilation. The
combination was associated with fewer serious adverse events. (Funded by the
National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number,
NCT04401579.)
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 The n e w e ng l a n d j o u r na l of m e dic i n e

I
n May 2020, the first stage of the Adap- the sponsor. The authors wrote the manuscript,
tive Covid-19 Treatment Trial (ACTT-1), a and, on behalf of the ACTT-2 Study Group, vouch
randomized, double-blind, placebo-controlled for the accuracy and completeness of the data
trial, showed that remdesivir is an effective and for the fidelity of the trial to the protocol.
treatment for hospitalized adult patients with Enrollment into this double-blind, placebo-
coronavirus disease 2019 (Covid-19) pneumonia.1 controlled trial began on May 8, 2020, and
Despite the benefits of remdesivir, substantial ended on July 1, 2020. There were 67 trial sites in
morbidity and mortality due to Covid-19 remain. 8 countries: the United States (55 sites), Singa-
Emerging data suggest that disease severity may pore (4), South Korea (2), Mexico (2), Japan (1),
be due in part to a dysregulated inflammatory Spain (1), the United Kingdom (1), and Denmark
response.2 It is postulated that mitigating the (1). Eligible patients were randomly assigned in
immune response and preventing a hyperin- a 1:1 ratio to receive either remdesivir and barici-
flammatory state may further improve clinical tinib or remdesivir and placebo. Randomization
outcomes. Baricitinib, an orally administered, was stratified according to trial site and disease
selective inhibitor of Janus kinase (JAK) 1 and 2, severity at enrollment (see the Supplementary
was predicted with the use of artificial intelli- Appendix, available with the full text of this ar-
gence algorithms to be a potential therapeutic ticle at NEJM.org). Patients received remdesivir
against severe acute respiratory syndrome coro- intravenously as a 200-mg loading dose on day 1,
navirus 2 (SARS-CoV-2).3,4 Baricitinib inhibits the followed by a 100-mg maintenance dose admin-
intracellular signaling pathway of cytokines istered daily on days 2 through 10 or until hos-
known to be elevated in severe Covid-19, includ- pital discharge or death. Baricitinib was admin-
ing interleukin-2, interleukin-6, interleukin-10, istered as a 4-mg daily dose (either orally [two
interferon-γ, and granulocyte–macrophage colony- 2-mg tablets] or through a nasogastric tube) for
stimulating factor; acts against SARS-CoV-2 14 days or until hospital discharge. Patients with
through the impairment of AP2-associated pro- an estimated glomerular filtration rate of less
tein kinase 1 and the prevention of SARS-CoV-2 than 60 ml per minute received baricitinib at a
cellular entry and infectivity; and improves dose of 2 mg once daily. A matching oral pla-
lymphocyte counts in patients with Covid-19.3,5-8 cebo was administered according to the same
In three case series of patients with Covid-19, schedule as the active drug. All the patients re-
baricitinib treatment was associated with both ceived standard supportive care at the trial site
an improvement in oxygenation and a reduction hospital. Venous thromboembolism prophylaxis
in select inflammatory markers.9-11 Randomized, was recommended for all the patients without a
controlled trials are needed to further under- major contraindication. If a hospital had a writ-
stand the role of immunomodulation in patients ten policy for Covid-19 treatments, patients could
with Covid-19.12 After the successful completion receive those treatments. In the absence of a
of ACTT-1, we designed the next iteration of written policy, other experimental treatment and
ACTT (ACTT-2) to evaluate whether the combi- off-label use of marketed medications intended
nation of baricitinib plus remdesivir was superior as specific treatment for Covid-19 were prohib-
to remdesivir alone. ited. This included glucocorticoids, which were
permitted only for standard indications such as
Me thods adrenal insufficiency, asthma exacerbation, laryn-
geal edema, septic shock, and acute respiratory
Design distress syndrome.
The ACTT-2 protocol was designed and written The trial protocol was approved by the insti-
by a working group of the ACTT investigators tutional review board at each site (or a central-
and the sponsor (the National Institute of Allergy ized institutional review board as applicable) and
and Infectious Diseases), with input from the was overseen by an independent data and safety
manufacturer of baricitinib, Eli Lilly. Investiga- monitoring board. Written informed consent
tors and staff at participating sites gathered the was obtained from each patient or from the pa-
data, which were then analyzed by statisticians tient’s legally authorized representative if the
at the statistical and data center (Emmes) and patient was unable to provide consent. Full de-

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 Baricitinib plus Remdesivir for Adults with Covid-19

tails of the trial design, conduct, oversight, and brane oxygenation (ECMO) up to day 29 (if these
analyses are provided in the protocol and statis- were being used at baseline); the incidence and
tical analysis plan (available at NEJM.org). duration of new use of oxygen, new use of non-
invasive ventilation or high-flow oxygen, and new
Procedures use of invasive ventilation or ECMO; duration of
All patients were evaluated daily during their hospitalization up to day 29 (patients who re-
hospitalization, from day 1 through day 29. (See mained hospitalized at day 29 had a value of 28
the full description of procedures in the Supple- days); and mortality at 14 and 28 days after en-
mentary Appendix.) The trial team was unaware rollment. Secondary safety outcomes included
of the trial-group assignments until after all grade 3 and 4 adverse events and serious adverse
data queries were resolved and the database was events that occurred through day 29, discontinu-
locked. The first draft of the manuscript was ation or temporary suspension of trial-product
written by the first author, and then all the administration for any reason, and changes in
authors contributed to the subsequent versions. assessed laboratory values over time. There
No one who is not an author contributed to the was a single primary hypothesis test. For sec-
writing of the manuscript. ondary outcomes, no adjustments for multiplic-
ity were made.
Outcomes and Statistical Analysis Prespecified subgroups were defined accord-
The primary outcome measure was the time to ing to sex, disease severity (as defined for
recovery, with the day of recovery defined as the stratification and by an ordinal score of 4, 5, 6,
first day, during the 28 days after enrollment, on and 7 at enrollment), age (18 to 39 years, 40 to
which a patient attained category 1, 2, or 3 on 64 years, or ≥65 years), race, ethnic group, dura-
the eight-category ordinal scale. The competing tion of symptoms before randomization (mea-
event of death was handled in a manner similar sured as ≤10 days or >10 days, in quartiles, and
to the Fine–Gray competing-risk approach.13 The as the median), site location, and presence of
categories are the same as those used in ACTT-11 coexisting conditions.
and are listed in Table S1 in the Supplementary
Appendix. The primary analysis was a stratified R e sult s
log-rank test of the time to recovery with remde-
sivir plus baricitinib as compared with remdesi- Patients
vir plus placebo, stratified according to baseline Of 1067 patients assessed for eligibility, 1033 un-
disease severity (i.e., score on the ordinal scale derwent randomization; 515 were assigned to the
of 4 or 5 vs. 6 or 7 at enrollment). combination group, and 518 to the control group
The key secondary outcome measure was (Fig. 1). The intention-to-treat population includ-
clinical status at day 15, based on the eight- ed 706 patients with moderate disease (ordinal
category ordinal scale. Other secondary outcome score of 4 or 5 [not receiving ventilation]) and
measures included the time to improvement by 327 with severe disease (ordinal score of 6 or 7
one or two categories from the ordinal score at [receiving noninvasive or invasive ventilation]).
baseline; clinical status, as assessed on the ordi- Of those assigned to the combination group, 507
nal scale at days 3, 5, 8, 11, 15, 22, and 29; mean (98.4%) received treatment as assigned. Of those
change in the ordinal score from day 1 to days assigned to the control group, 509 (98.3%) re-
3, 5, 8, 11, 15, 22, and 29; time to discharge or ceived treatment as assigned. A total of 498 pa-
to a National Early Warning Score of 2 or less tients in the combination group and 495 in the
(on a scale from 0 to 20, with higher scores in- control group completed the trial through day
dicating greater clinical risk) that was main- 29, recovered, or died. The mean age of the pa-
tained for 24 hours, whichever occurred first; tients was 55.4 years, and 63.1% were male (Ta-
change in the National Early Warning Score ble 1). Overall, 48.0% of the patients were White,
from day 1 to days 3, 5, 8, 11, 15, 22, and 29; 15.1% were Black, 9.8% were Asian, and 1.0%
number of days of receipt of supplemental oxy- were American Indian or Alaska Native; 51.4%
gen, noninvasive ventilation or high-flow oxygen, were Hispanic or Latino (Table 1). The character-
and invasive ventilation or extracorporeal mem- istics of the U.S. patients are shown in Table S4.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

1067 Patients were assessed for eligibility

34 Were excluded
29 Were ineligible owing to meeting exclusion
criteria or not meeting inclusion criteria
5 Were eligible but were not enrolled

1033 Underwent randomization

515 Were assigned to receive baricitinib+RDV 518 Were assigned to receive placebo+RDV
508 Received infusion 509 Received infusion
507 Received tablet 509 Received tablet
7 Were enrolled but did not receive any treatment 9 Were enrolled but did not receive any treatment

66 Discontinued intervention (deaths and discharges 94 Discontinued intervention (deaths and discharges
excluded) excluded)
31 Were receiving tablets 39 Were receiving tablets
22 Had severe adverse event or adverse event other 33 Had severe adverse event or adverse event other
than death than death
4 Had protocol deviation 1 Had protocol deviation
3 Withdrew 1 Withdrew
1 Was withdrawn by investigator 3 Were withdrawn by investigator
1 Became ineligible after enrollment 1 Had a technical problem
5 Were receiving infusions 13 Were receiving infusions
1 Had severe adverse event or adverse event other 10 Had severe adverse event or adverse event other
than death than death
1 Had a technical problem 1 Had a technical problem
1 Was withdrawn by investigator 1 Was withdrawn by investigator
1 Became ineligible after enrollment 1 Had protocol deviation
1 Had other reason 50 Were receiving both trial products
33 Were receiving both trial products 25 Had severe adverse event or adverse event other
21 Had severe adverse event or adverse event other than death
than death 1 Had protocol deviation
1 Had protocol deviation 13 Withdrew
8 Withdrew 6 Were withdrawn by investigator
3 Were withdrawn by investigator 3 Were transferred to another hospital
84 Discontinued participation in trial early 1 Became ineligible after enrollment
23 Died 1 Had other reason
40 Were lost to follow-up 110 Discontinued participation in trial early
8 Withdrew 36 Died
1 Were withdrawn by investigator 41 Were lost to follow-up
1 Became ineligible after enrollment 16 Withdrew
7 Were enrolled but did not receive treatment 2 Were withdrawn by investigator
2 Had severe adverse event or adverse event other 1 Became ineligible after enrollment
than death 9 Were enrolled but did not receive treatment
2 Had other reason 1 Had severe adverse event or adverse event other
than death
1 Was transferred to another hospital
3 Had other reason

515 Were included in the intention-to-treat population 518 Were included in the intention-to-treat population
507 Were included in the as-treated population 509 Were included in the as-treated population
8 Were excluded from as-treated population owing 9 Were excluded from as-treated population owing
to not receiving at least 1 tablet to not receiving at least 1 tablet

Figure 1. Enrollment and Randomization.

RDV denotes remdesivir.

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 Baricitinib plus Remdesivir for Adults with Covid-19

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*

All Patients Baricitinib+RDV Placebo+RDV

Characteristic (N = 1033) (N = 515) (N = 518)
Age
Mean — yr 55.4±15.7 55.0±15.4 55.8±16.0
Distribution — no. (%)
<40 yr 173 (16.7) 87 (16.9) 86 (16.6)
40–64 yr 555 (53.7) 281 (54.6) 274 (52.9)
≥65 yr 305 (29.5) 147 (28.5) 158 (30.5)
Sex — no. (%)
Female 381 (36.9) 196 (38.1) 185 (35.7)
Male 652 (63.1) 319 (61.9) 333 (64.3)
Race — no. (%)†
Asian 101 (9.8) 49 (9.5) 52 (10.0)
Black 156 (15.1) 77 (15.0) 79 (15.3)
White 496 (48.0) 251 (48.7) 245 (47.3)
Other or unknown 280 (27.1) 138 (26.8) 142 (27.4)
Ethnic group — no. (%)†
Hispanic or Latino 531 (51.4) 263 (51.1) 268 (51.7)
Not Hispanic or Latino 486 (47.0) 246 (47.8) 240 (46.3)
Not reported or unknown 16 (1.5) 6 (1.2) 10 (1.9)
Body-mass index‡ 32.2±8.3 32.2±8.2 32.3±8.4
Median time (IQR) from symptom onset 8 (5–10) 8 (5–10) 8 (5–11)
to randomization — days
Disease severity — no. (%)
Moderate 706 (68.3) 358 (69.5) 348 (67.2)
Severe 327 (31.7) 157 (30.5) 170 (32.8)
Coexisting conditions — no./total no. (%)
None 155/994 (15.6) 64/496 (12.9) 91/498 (18.3)
One 270/994 (27.2) 148/496 (29.8) 122/498 (24.5)
Two or more 569/994 (57.2) 284/496 (57.3) 285/498 (57.2)
Score on ordinal scale — no. (%)
4. Hospitalized, not requiring supplemental 142 (13.7) 70 (13.6) 72 (13.9)
oxygen, requiring ongoing medical care
(Covid-19–related or otherwise)
5. Hospitalized, requiring supplemental oxygen 564 (54.6) 288 (55.9) 276 (53.3)
6. Hospitalized, receiving noninvasive ventila- 216 (20.9) 103 (20.0) 113 (21.8)
tion or high-flow oxygen devices
7. Hospitalized, receiving invasive mechanical 111 (10.7) 54 (10.5) 57 (11.0)
ventilation or ECMO
Geographic region — no. (%)
Asia 67 (6.5) 33 (6.4) 34 (6.6)
Europe 13 (1.3) 6 (1.2) 7 (1.4)
North America 953 (92.3) 476 (92.4) 477 (92.1)

* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. Covid-19 denotes coronavirus
disease 2019, ECMO extracorporeal membrane oxygenation, IQR interquartile range, and RDV remdesivir.
† Race and ethnic group were reported by the patients. With respect to “other” race, the categories that were used when
data on race were reported included American Indian or Alaska Native and Native Hawaiian or other Pacific Islander.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A Overall B Baseline Ordinal Score of 4

1.00 1.00 Placebo+RDV
P=0.03 Baricitinib+RDV
Proportion Recovered

Proportion Recovered
Baricitinib+RDV
0.75 0.75
Placebo+RDV

0.50 0.50

0.25 0.25

0.00 0.00
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Days Days
No. at Risk No. at Risk
Baricitinib+RDV 515 497 418 302 233 186 145 121 107 95 87 80 76 63 30 Baricitinib+RDV 70 66 53 29 18 13 9 4 4 4 4 2 2 2 0
Placebo+RDV 518 495 417 322 251 211 178 156 143 131 123 115 102 92 44 Placebo+RDV 72 64 46 28 19 12 7 2 1 1 1 1 0 0 0

C Baseline Ordinal Score of 5 D Baseline Ordinal Score of 6

1.00 Baricitinib+RDV 1.00
Baricitinib+RDV
Proportion Recovered

Proportion Recovered
0.75 Placebo+RDV 0.75

0.50 0.50
Placebo+RDV

0.25 0.25

0.00 0.00
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Days Days
No. at Risk No. at Risk
Baricitinib+RDV 288 276 213 133 91 64 41 31 25 22 20 20 17 12 5 Baricitinib+RDV 103 102 100 88 73 60 47 40 36 29 25 23 22 19 10
Placebo+RDV 276 267 211 146 95 71 57 47 43 37 35 33 28 26 12 Placebo+RDV 113 110 106 95 86 78 67 62 57 52 46 41 36 32 16

E Baseline Ordinal Score of 7

1.00
Proportion Recovered

0.75

Baricitinib+RDV
0.50

0.25

Placebo+RDV
0.00
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Days
No. at Risk
Baricitinib+RDV 54 53 52 52 51 49 48 46 42 40 38 35 35 30 15
Placebo+RDV 57 54 54 53 51 50 47 45 42 41 41 40 38 34 16

Figure 2. Kaplan–Meier Estimates of Cumulative Recoveries.

Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale
(not requiring oxygen; Panel B), in those with a baseline score of 5 (requiring oxygen; Panel C), in those with a baseline score of 6 (re-
ceiving high-flow oxygen or noninvasive mechanical ventilation; Panel D), and in those with a baseline score of 7 (receiving mechanical
ventilation or extracorporeal membrane oxygenation [ECMO]; Panel E). Shaded areas indicate 95% confidence intervals.

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 Baricitinib plus Remdesivir for Adults with Covid-19

Primary Outcome CI, 5.7 to 10.6) in the control group (hazard ra-
Patients who received combination treatment tio for death, 0.65; 95% CI, 0.39 to 1.09). The
with baricitinib plus remdesivir recovered a me- greatest numerical differences in mortality be-
dian of 1 day faster than patients who received tween patients in the combination group and
remdesivir and placebo (median, 7 days vs. 8 days; those in the control group were observed among
rate ratio for recovery, 1.16; 95% confidence in- those with a baseline ordinal score of 5 (1.9% vs.
terval [CI], 1.01 to 1.32; P = 0.03 by log-rank test 4.7%; hazard ratio, 0.40; 95% CI, 0.14 to 1.14) or
stratified according to actual baseline severity) 6 (7.5% vs. 12.9%; hazard ratio, 0.55; 95% CI,
(Fig. 2 and Table 2). When analyzed according to 0.22 to 1.38). The Kaplan–Meier estimates of
the severity entered at the time of randomization mortality at 14 days after randomization were
(moderate vs. severe), the hazard ratio was 1.15 1.6% in the combination group and 3.0% in the
(95% CI, 1.00 to 1.31; P = 0.047) (Table S6). The control group (hazard ratio, 0.54; 95% CI, 0.23
median time to recovery among patients receiv- to 1.28) (Table 2 and Fig. S2).
ing noninvasive ventilation or high-flow oxygen
(baseline ordinal score of 6) was 10 days in the Additional Secondary Outcomes
combination group and 18 days in the control The median time to an improvement by one
group (rate ratio for recovery, 1.51; 95% CI, 1.10 category on the ordinal scale was 6 days in the
to 2.08). Among patients with a baseline score of combination group and 8 days in the control
4 (no oxygen) and 5 (supplemental oxygen), the group (rate ratio, 1.21; 95% CI, 1.06 to 1.39), and
rate ratio for recovery was 0.88 (95% CI, 0.63 to the median time to discharge or a National
1.23) and 1.17 (95% CI, 0.98 to 1.39), respec- Early Warning Score of 2 or less for 24 hours
tively. For those receiving mechanical ventilation was 6 days and 7 days in the respective groups
or ECMO at enrollment (baseline ordinal score (rate ratio, 1.24; 95% CI, 1.07 to 1.44) (Table 3).
of 7), the rate ratio for recovery was 1.08 (95% The incidence of new use of oxygen was lower in
CI, 0.59 to 1.97) (Table 2 and Fig. 3). The rate the combination group than in the control group
ratio for recovery among the 223 patients who (22.9% vs. 40.3%; difference, −17.4 percentage
received glucocorticoids for clinical indications points; 95% CI, −31.6 to −2.1), as was the inci-
during the trial was 1.06 (95% CI, 0.75 to 1.48). dence of new use of mechanical ventilation or
A sensitivity analysis with a random effect for ECMO (10.0% vs. 15.2%; difference, −5.2 percent-
hospital site yielded similar results (conditional age points; 95% CI, −9.5 to −0.9). The median
random-effects estimate of rate ratio for recov- number of days of receipt of mechanical ventila-
ery, 1.16; 95% CI, 1.01 to 1.33; restricted maxi- tion or ECMO among the 128 patients in whom
mum likelihood–based random-effects estimate these interventions were started after enrollment
of variance, 0.0305) (Table S13). or who died with no observed new use was 16
days in the combination group and 27 days in
Key Secondary Outcome the control group (difference, −11.0; 95% CI,
The odds of improvement in clinical status at −17.7 to −4.3). The incidence of progression to
day 15 as assessed with the ordinal scale were death or noninvasive or invasive ventilation was
greater in the combination group than in the lower in the combination group than in the con-
control group (odds ratio for improvement, 1.3; trol group (22.5% vs. 28.4%; rate ratio, 0.77; 95%
95% CI, 1.0 to 1.6). Patients with a baseline or- CI, 0.60 to 0.98), as was the incidence of pro-
dinal score of 6 who received combination treat- gression to death or invasive ventilation (12.2%
ment were most likely to have clinical improve- vs. 17.2%; rate ratio, 0.69; 95% CI, 0.50 to 0.95).
ment at day 15 (odds ratio, 2.2; 95% CI, 1.4 to
3.6) (Table 2 and Fig. S1). Safety Outcomes
Grade 3 or 4 adverse events occurred in 207 pa-
Mortality tients (40.7%) in the combination group and 238
The Kaplan–Meier estimates of mortality at day (46.8%) in the control group (Table S11). A total
28 after randomization were 5.1% (95% CI, 3.5 of 25 grade 3 or 4 adverse events were judged by
to 7.6) in the combination group and 7.8% (95% the principal investigators to be related to com-

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 Table 2. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population.*

802
Outcome Overall Ordinal Score at Baseline
4 5 6 7
Baricitinib Placebo Baricitinib Placebo Baricitinib Placebo Baricitinib Placebo Baricitinib Placebo
(N = 515) (N = 518) (N = 70) (N = 72) (N = 288) (N = 276) (N = 103) (N = 113) (N = 54) (N = 57)
Recovery
No. of recoveries 433 406 67 69 262 243 82 73 22 21
Median time to recovery (95% CI) — days 7 8 5 4 5 6 10 18 NE NE
(6–8) (7–9) (4–6) (4–6) (5–6) (5–6) (9–13) (13–21) (25–NE) (26–NE)
Rate ratio (95% CI)† 1.16 (1.01–1.32 [P = 0.03]) 0.88 (0.63–1.23) 1.17 (0.98–1.39) 1.51 (1.10–2.08) 1.08 (0.59–1.97)
Mortality over first 14 days‡
Hazard ratio (95% CI) for data through day 0.54 (0.23–1.28) NE 0.73 (0.16–3.26) 0.21 (0.02–1.80) 0.69 (0.19–2.44)
14
No. of deaths by day 14 8 15 0 0 3 4 1 5 4 6
Kaplan–Meier estimate of mortality by day 1.6 3.0 0 0 1.1 1.5 1.0 4.6 7.6 11.3
14 — % (95% CI) (0.8–3.2) (1.8–5.0) (NE–NE) (NE–NE) (0.4–3.4) (0.6–3.9) (0.1–6.7) (2.0–10.8) (2.9–19.1) (5.3–23.5)
The

Mortality over entire trial period‡

Hazard ratio (95% CI) 0.65 (0.39–1.09) NE 0.40 (0.14–1.14) 0.55 (0.22–1.38) 1.00 (0.45–2.22)
No. of deaths by day 28 24 37 0 0 5 12 7 13 12 12
Kaplan–Meier estimate of mortality by day 5.1 7.8 0 0 1.9 4.7 7.5 12.9 23.1 22.6
28 — % (95% CI) (3.5–7.6) (5.7–10.6) (NE–NE) (NE–NE) (0.8–4.4) (2.7–8.1) (3.6–15.2) (7.7–21.3) (13.8–37.1) (13.5–36.4)

n engl j med 384;9

Ordinal score at day 15 (±2 days) — no. (%)§
1 177 (34.4) 165 (31.9) 33 (47.1) 44 (61.1) 114 (39.6) 101 (36.6) 27 (26.2) 17 (15.0) 3 (5.6) 3 (5.3)
2 177 (34.4) 163 (31.5) 25 (35.7) 20 (27.8) 120 (41.7) 115 (41.7) 30 (29.1) 24 (21.2) 2 (3.7) 4 (7.0)

nejm.org
3 8 (1.6) 3 (0.6) 5 (7.1) 2 (2.8) 2 (0.7) 1 (0.4) 0 0 1 (1.9) 0
n e w e ng l a n d j o u r na l

4 31 (6.0) 18 (3.5) 7 (10.0) 6 (8.3) 14 (4.9) 7 (2.5) 7 (6.8) 3 (2.7) 3 (5.6) 2 (3.5)

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of

5 43 (8.3) 50 (9.7) 0 0 18 (6.2) 27 (9.8) 15 (14.6) 20 (17.7) 10 (18.5) 3 (5.3)

6 20 (3.9) 19 (3.7) 0 0 9 (3.1) 1 (0.4) 7 (6.8) 16 (14.2) 4 (7.4) 2 (3.5)
7 48 (9.3) 83 (16.0) 0 0 8 (2.8) 19 (6.9) 15 (14.6) 28 (24.8) 25 (46.3) 36 (63.2)

March 4, 2021
8 11 (2.1) 17 (3.3) 0 0 3 (1.0) 5 (1.8) 2 (1.9) 5 (4.4) 6 (11.1) 7 (12.3)

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Odds ratio (95% CI) 1.3 (1.0–1.6) 0.6 (0.3–1.1) 1.2 (0.9–1.6) 2.2 (1.4–3.6) 1.7 (0.8–3.4)

* Patients in both groups received RDV in addition to either baricitinib or placebo. Neither the P value nor any confidence intervals have not been adjusted for multiple comparisons.
Percentages may not total 100 because of rounding. NE denotes not possible to estimate.
† Rate ratios for recovery and hazard ratios were calculated from the stratified Cox model. The P value for the primary outcome was calculated with the stratified log-rank test (overall model strati-
fied according to actual disease severity). Rate ratios for recovery greater than 1 indicate a benefit with baricitinib plus RDV; hazard ratios less than 1 indicate a benefit with baricitinib plus RDV.

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‡ Mortality over the first 14 days includes data from all patients who were still alive through 14 days after enrollment, with data censored on day 14, as if 14 days was the maximum
follow-up time. Mortality over the entire trial period uses the totality of the trial data and censors data from patients who completed follow-up alive at 28 days after enrollment.
§ The ordinal score at day 15 (±2-day visit window) is the patient’s worst score on the ordinal scale during the previous day. Scores on the ordinal scale are as follows: 1, not hospitalized, no
limitations of activities; 2, not hospitalized, limitation of activities, home oxygen requirement, or both; 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing
medical care (used if hospitalization was extended for infection-control reasons); 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (Covid-19–related or
other medical conditions); 5, hospitalized, requiring any supplemental oxygen; 6, hospitalized, receiving noninvasive ventilation or use of high-flow oxygen devices; 7, hospitalized, receiving
invasive mechanical ventilation or ECMO; and 8, death. Five deaths (three in patients receiving baricitinib plus RDV and two in patients receiving placebo plus RDV) occurred within the day
15 visit window but after 14 days — these deaths are included in the outcome of the ordinal score at day 15 but not in the outcome of mortality over the first 14 days. Odds ratios were cal-
culated with the use of a proportional odds model (overall model adjusted for actual disease severity). Odds ratios greater than 1 indicate a benefit with baricitinib plus RDV.
 Baricitinib plus Remdesivir for Adults with Covid-19

Subgroup No. of Patients Rate Ratio for Recovery (95% CI)

Overall 1033 1.16 (1.01–1.32)
Geographic region
North America 953 1.17 (1.02–1.35)
Europe 13 0.67 (0.21–2.18)
Asia 67 1.15 (0.70–1.91)
Race
White 496 1.13 (0.93–1.37)
Black 156 1.06 (0.75–1.50)
Asian 101 1.11 (0.73–1.68)
Other or unknown 280 1.34 (1.03–1.74)
Ethnic group
Hispanic or Latino 531 1.08 (0.89–1.31)
Not Hispanic or Latino 486 1.31 (1.08–1.60)
Age
18 to <40 yr 173 1.01 (0.74–1.38)
40 to <65 yr 555 1.24 (1.03–1.49)
≥65 yr 305 1.13 (0.86–1.47)
Sex
Male 652 1.23 (1.04–1.46)
Female 381 1.06 (0.85–1.32)
Duration of symptoms
≤10 days 764 1.13 (0.97–1.32)
>10 days 253 1.27 (0.97–1.67)
Disease severity (actual)
Moderate 706 1.11 (0.95–1.30)
Severe 327 1.32 (1.00–1.75)
Ordinal score at baseline
4 142 0.88 (0.63–1.23)
5 564 1.17 (0.98–1.39)
6 216 1.51 (1.10–2.08)
7 111 1.08 (0.59–1.97)
0.20 0.25 0.33 0.5 1.0 2.0 3.0 4.0 5.0

Placebo+RDV Better Baricitinib+RDV Better

Figure 3. Time to Recovery According to Subgroup.

The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer
treatment effects. Race and ethnic group were reported by the patients. With respect to “other” race, the categories
that were used when data on race were reported included American Indian or Alaska Native and Native Hawaiian or
other Pacific Islander.

bination treatment and 28 to control (Table S10). (16.0%) in the combination group, and six of
The most common grade 3 or 4 adverse events these events were thought to be related to the
occurring in at least 5% of all patients were hy- trial product (Table S7). Serious adverse events
perglycemia, anemia, decreased lymphocyte occurred in 107 patients (21.0%) in the control
count, and acute kidney injury (Table S10). The group, and five of these events were thought to
incidence of these adverse events was similar in be related to the trial product. The between-
the two treatment groups. The percentage of group difference was −5.0 percentage points
patients who were reported to have a serious or (95% CI, −9.8 to −0.3; P = 0.03). The incidences
nonserious adverse event of venous thromboem- of all serious adverse events, all adverse events,
bolism was similar in the combination group serious adverse events with fatal outcome, and
and the control group (21 patients [4.1%] and 16 adverse events leading to discontinuation of the
patients [3.1%], respectively; difference, 1.0 per- trial product were each lower in the combination
centage points; 95% CI, −1.3 to 3.3). group than in the control group. Overall, the
Serious adverse events occurred in 81 patients incidence of serious or nonserious adverse events

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Additional Secondary Outcomes.

Outcome Baricitinib+RDV Placebo+RDV Rate Ratio (95% CI)

Median time to event (95% CI) — days
Improvement by one category on ordinal scale 6.0 (5.0 to 7.0) 8.0 (7.0 to 9.0) 1.21 (1.06 to 1.39)
Improvement by two categories on ordinal scale 12.0 (12.0 to 13.0) 13.0 (NE) 1.20 (1.05 to 1.38)
Discharge or National Early Warning Score ≤2 for 24 hr* 6.0 (6.0 to 7.0) 7.0 (6.0 to 9.0) 1.24 (1.07 to 1.44)
Death or progression to noninvasive or invasive mechanical ventilation NE NE 0.77 (0.60 to 0.98)
Death or progression to invasive mechanical ventilation NE NE 0.69 (0.50 to 0.95)
New use of oxygen NE NE (3.0 to NE) 0.53 (0.29 to 0.98)
New use of invasive mechanical ventilation or ECMO NE NE 0.64 (0.44 to 0.93)
Use of noninvasive ventilation or high-flow oxygen NE NE 0.82 (0.60 to 1.13)
Difference (95% CI)
Hospitalization
Median duration of initial hospitalization (IQR) — days
With imputation of data for those who died† 8 (5 to 15) 8 (5 to 20) 0.0 (−1.1 to 1.1)
Among those who did not die 8 (5 to 13) 8 (5 to 15) 0.0 (−1.0 to 1.0)
Patients rehospitalized — % (95% CI) 3 (2 to 5) 2 (1 to 4) 1.0 (−1.1 to 3.1)‡
Oxygen
Median days receiving oxygen if receiving oxygen at baseline (IQR)
With imputation of data for those who died† 10 (4 to 27) 12 (4 to 28) −2.0 (−5.2 to 1.2)
Among those who did not die 9 (4 to 24) 10 (4 to 28) −1.0 (−3.8 to 1.8)
New use of oxygen during trial
No. of patients/total no. 16/70 29/72
Percent of patients (95% CI) 23 (15 to 34) 40 (30 to 52) −17.4 (−31.6 to −2.1)‡
Median days receiving oxygen (IQR) 3 (2 to 4) 3 (2 to 6) 0.0 (−2.2 to 2.2)
Noninvasive ventilation or high-flow oxygen
Median days of noninvasive ventilation or high-flow oxygen use during
trial if receiving these interventions at baseline (IQR)
With imputation of data for those who died† 4 (3 to 9) 5 (2 to 12) −1.0 (−2.9 to 0.9)
Among those who did not die 4 (3 to 6) 4 (2 to 9) 0.0 (−1.7 to 1.7)
New use of noninvasive ventilation or high-flow oxygen during trial
No. of patients/total no. 70/358 82/348
Percent of patients (95% CI) 20 (16 to 24) 24 (19 to 28) −4.0 (−10.1 to 2.1)‡
Median days of use during trial (IQR)†§ 6 (3 to 15) 5 (2 to 11) 1.0 (−1.6 to 3.6)
Mechanical ventilation or ECMO
Median days of mechanical ventilation or ECMO during trial if receiving
these interventions at baseline (IQR)
With imputation of data for those who died† 20 (9 to 28) 25 (11 to 28) −5.0 (−12.9 to 2.9)
Among those who did not die 13 (7 to 24) 16 (6 to 28) −2.0 (−11.4 to 7.4)
New use of mechanical ventilation or ECMO during trial
No. of patients/total no. 46/461 70/461
Percent of patients (95% CI) 10 (8 to 13) 15 (12 to 19) −5.2 (−9.5 to −0.9)‡
Median days of use during trial†§ 16 (8 to 28) 27 (12 to 28) −11.0 (−17.7 to −4.3)

* The National Early Warning Score includes six physiological measures; total scores range from 0 to 20, with higher scores indicating greater
clinical risk. Only patients with a score of more than 2 at baseline were included in this analysis.
† The value for patients who died was imputed as 28 days.
‡ Differences between percentages are given in percentage points.
§ This analysis includes imputation of data for patients who died with no observed new use.

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 Baricitinib plus Remdesivir for Adults with Covid-19

of new infection was lower in the combination mial infections, thrombosis, and errors in hos-
group (30 patients [5.9%]) than in the control pital drug administration. Moreover, faster recov-
group (57 patients [11.2%]) (difference, −5.3 ery also decreases the burden on the health care
percentage points; 95% CI, −8.7 to −1.9; system, potentially increasing capacity, which is
P = 0.003). Patients who received glucocorticoids of critical importance during a surge of cases.
after randomization had a higher incidence of In addition, the combination treatment showed
serious or nonserious new infection than those clinical benefits directly relevant to patient care,
who did not (56 of 223 patients [25.1%] vs. 44 of such as a difference of −17.4 percentage points
793 patients [5.5%]). in new use of oxygen (22.9% vs. 40.3%) and a
difference of −5.2 percentage points in new use
Discussion of mechanical ventilation or ECMO (10.0% vs.
15.2%). In fact, the odds of progression to death
The results of this randomized, double-blind, or invasive ventilation were 31% lower in the
placebo-controlled trial show that combination combination group than in the control group
treatment with the antiinflammatory drug bar- (hazard ratio, 0.69; 95% CI, 0.50 to 0.95), and
icitinib and the antiviral drug remdesivir was patients in the combination group had 11 fewer
safe and superior to remdesivir alone for the days receiving new mechanical ventilation than
treatment of hospitalized patients with Covid-19 those in the control group.
pneumonia. The beneficial effects of the combi- Despite concerns about immunosuppression,
nation treatment were seen both in the primary secondary infections, and thrombosis with use
outcome, with a 1-day shorter time to recovery, of JAK inhibitors, the addition of baricitinib was
and in the key secondary outcome, with a greater not associated with a significantly higher inci-
improvement in clinical status as assessed on dence of adverse events or thromboembolic
the ordinal scale. Although ACTT-2 was not events. In fact, patients receiving baricitinib plus
powered to detect a difference in mortality be- remdesivir had a significantly lower incidence
tween the two groups, both the survival rate and of adverse events, adverse events leading to dis-
the time-to-death analyses favored combination continuation of the trial drug, serious adverse
treatment. These clinical benefits were observed events, serious adverse events with a fatal out-
across different age groups, sexes, ethnic groups, come, and infection-related adverse events than
and races and were independent of symptom patients who received remdesivir alone. The con-
duration or disease severity at enrollment. The sistently lower incidence of adverse events with
large proportion of Hispanic or Latino patients baricitinib may be related to its action in reduc-
who were enrolled in the trial reflects the dis- ing inflammatory-mediated lung injury and
proportionate effect of the pandemic on racial improving lymphocyte counts, its antiviral prop-
and ethnic minorities with respect to high inci- erties, or its associated shorter recovery time
dences of hospitalization.14 and faster clinical improvement, all of which
The observed benefit of combination treat- could have reduced the risk of nosocomial in-
ment was most evident in patients with a base- fection. Another ongoing trial may provide more
line ordinal score of 5 (supplemental oxygen) or information regarding the effects of baricitinib
6 (high-flow oxygen or noninvasive ventilation), (ClinicalTrials.gov number, NCT04421027). In
among whom the median time to recovery was, summary, our results and the characteristics of
respectively, 1 and 8 days sooner with combina- baricitinib, including the fact that it is an oral
tion treatment than with placebo. Patients with drug with few drug–drug interactions and a
a baseline ordinal score of 6 who received com- good safety profile, lend itself to use in low-to-
bination treatment were twice as likely as those middle-income countries.
in the control group to have improved clinical The Randomized Evaluation of Covid-19
status at day 15 (odds ratio, 2.2; 95% CI, 1.4 to Therapy (RECOVERY) trial evaluated dexametha-
3.6). The faster recovery in patients who received sone in patients with Covid-1915 and showed a
baricitinib plus remdesivir suggests that the significant benefit in survival, most pronounced
combination treatment may have an effect in in patients receiving mechanical ventilation, and
lowering the hospital-associated risk of nosoco- a 1-day shorter hospital stay. Baricitinib and dexa-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

methasone have important biologic differences, The trial was sponsored and primarily funded by the NIAID,
National Institutes of Health (NIH), Bethesda, MD. This trial
and ACTT-2 and the RECOVERY trial have design
has been funded in part with federal funds from the NIAID
differences. Dexamethasone has a long half-life, and the National Cancer Institute, NIH, under contract
acts on glucocorticoid receptors, and reduces in- H HSN261200800001E 75N910D00024, task order number
­
75N91019F00130/75N91020F00010, and by the Department of
flammation through a broad-pathway approach
Defense, Defense Health Program. This trial has been support-
that has been associated with immunosuppres- ed in part by the NIAID of the NIH under award numbers
sion, hospital-acquired infections, gastrointesti- UM1AI148684, UM1AI148576, UM1AI148573, UM1AI148575,
UM1AI148452, UM1AI148685, UM1AI148450, and UM1AI148689
nal bleeding, hyperglycemia, and neuromuscular and by NIH Stimulating Access to Research in Residency grant
weakness, even with short courses.16 Baricitinib 5R38AI140299-02. The trial has also been funded in part by the
has a short half-life, acts on targeted critical governments of Japan, Mexico, Denmark, and Singapore. The
trial site in South Korea received funding from the Seoul Na-
pathways to reduce inflammation while mini- tional University Hospital. Support for the London International
mizing biologic redundancy with less immuno- Coordinating Centre was also provided by the United Kingdom
suppression, and may have antiviral activity.3 Medical Research Council (MRC_UU_12023/23).
Dr. Marconi reports receiving grant support from Bayer, grant
The two trials had different designs and cannot support and lecture fees from ViiV Healthcare and Gilead Sci-
be compared directly. The high mortality in the ences, and grant support and consulting fees from Eli Lilly; Dr.
control group of the RECOVERY trial and the Hsieh, receiving grant support from NeuroRx, Novartis, Takeda,
Humanigen, Eli Lilly, PTC Therapeutics, Octapharma, Fulcrum
low mortality in the control group of ACTT-2 Therapeutics, and Alexion Pharmaceuticals; Dr. Jain, receiving
suggest that these trials might not be generaliz- grant support and advisory board fees from Gilead Sciences and
able to the same patient population. Only a grant support from Regeneron Pharmaceuticals; Dr. Lye, serving
on an advisory board for Gilead Sciences; Dr. Sandkovsky, receiv-
randomized, double-blind, placebo-controlled, ing grant support from CytoDyn; Dr. Luetkemeyer, receiving
head-to-head comparison of baricitinib plus grant support, paid to the University of California, San Francisco,
remdesivir with dexamethasone plus remdesivir from AstraZeneca and Novartis; Dr. Amin, receiving grant sup-
port from Pulmotect, Blade Therapeutics, Takeda, Humanigen,
will allow the efficacy and safety differences Eli Lilly, PTC Therapeutics, Octapharma, Fulcrum Therapeutics,
between these two approaches to be fully under- and NeuroRx, grant support and consulting fees from Novartis,
stood. grant support, consulting fees, and lecture fees from Alexion
Pharmaceuticals, consulting fees and lecture fees from Bristol
Baricitinib plus remdesivir was superior to Myers Squibb, Pfizer, Portola Pharmaceuticals, Sunovion, and
remdesivir alone in reducing recovery time and AstraZeneca, and consulting fees from Boehringer Ingelheim,
accelerating improvement in clinical status, no- Mylan, Salix Pharmaceuticals, Nabriva Therapeutics, Paratek
Pharmaceuticals, Bayer, Tetraphase Pharmaceuticals, Achaogen,
tably among patients receiving high-flow oxygen
La Jolla Pharmaceutical, Millenium Pharmaceuticals, Ferring
or noninvasive mechanical ventilation. The com- Pharmaceuticals, PeraHealth, AseptiScope, Heartrite, and Spright-
bination was associated with fewer serious ad- ly; Dr. Watanabe, receiving grant support from Novartis, Takeda,
Humanigen, Eli Lilly, PTC Therapeutics, Octapharma, Fulcrum
verse events.
Therapeutics, and Alexion Pharmaceuticals; and Drs. Cardoso
and de Bono, being employed by Eli Lilly. No other potential
The content of this publication does not necessarily reflect conflict of interest relevant to this article was reported.
the views or policies of the Department of Health and Human Disclosure forms provided by the authors are available with
Services, the Uniformed Services University of the Health Sci- the full text of this article at NEJM.org.
ences, the Henry M. Jackson Foundation for the Advancement A data sharing statement provided by the authors is available
of Military Medicine, the Departments of the Army, Navy, or Air with the full text of this article at NEJM.org.
Force, the Department of Defense, or the Department of Veter- We thank the members of the ACTT-2 Study Team (see the
ans Affairs, nor does any mention of trade names, commercial Supplementary Appendix) for their many contributions in con-
products, or organizations imply endorsement by the U.S. ducting the trial, the members of the data and safety monitoring
Government. Gilead Sciences provided remdesivir for use in this board (Michael G. Ison, M.D. [chair], Northwestern University
trial but did not provide any financial support. Eli Lilly provided Feinberg School of Medicine; Nina Singh, M.D., University of
baricitinib for use in this trial but did not provide any financial Pittsburgh; Bernd Salzberger, M.D., Ph.D., University of Re-
support. Employees of Gilead Sciences and Eli Lilly participated gensburg; Wendy Leisenring, Sc.D., Fred Hutchinson Cancer
in discussions about protocol development and in weekly proto- Research Center; Peter Sasieni, Ph.D., King’s College London;
col team calls. The National Institute of Allergy and Infectious and Kelvin Kai-Wang To, M.B., B.S., M.D., University of Hong
Diseases (NIAID) ultimately made all decisions regarding trial Kong) for their oversight, and the patients for their altruism in
design and implementation. participating in this trial.

Appendix
The authors’ full names and academic degrees are as follows: Andre C. Kalil, M.D., M.P.H., Thomas F. Patterson, M.D., Aneesh K.
Mehta, M.D., Kay M. Tomashek, M.D., M.P.H., Cameron R. Wolfe, M.B., B.S., M.P.H., Varduhi Ghazaryan, M.D., Vincent C. Marconi,
M.D., Guillermo M. Ruiz‑Palacios, M.D., Lanny Hsieh, M.D., Susan Kline, M.D., Victor Tapson, M.D., Nicole M. Iovine, M.D., Ph.D.,
Mamta K. Jain, M.D., M.P.H., Daniel A. Sweeney, M.D., Hana M. El Sahly, M.D., Angela R. Branche, M.D., Justino Regalado Pineda,

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 Baricitinib plus Remdesivir for Adults with Covid-19

M.D., David C. Lye, M.B., B.S., Uriel Sandkovsky, M.D., Anne F. Luetkemeyer, M.D., Stuart H. Cohen, M.D., Robert W. Finberg, M.D.,
Patrick E.H. Jackson, M.D., Babafemi Taiwo, M.B., B.S., Catharine I. Paules, M.D., Henry Arguinchona, M.D., Nathaniel Erdmann,
M.D., Ph.D., Neera Ahuja, M.D., Maria Frank, M.D., Myoung‑don Oh, M.D., Eu‑Suk Kim, M.D., Seow Y. Tan, M.B., B.S., Richard A.
Mularski, M.D., M.S.H.S., Henrik Nielsen, M.D., Philip O. Ponce, M.D., Barbara S. Taylor, M.D., LuAnn Larson, R.N., B.S.N., Na-
dine G. Rouphael, M.D., Youssef Saklawi, M.D., Valeria D. Cantos, M.D., Emily R. Ko, M.D., Ph.D., John J. Engemann, M.D., Alpesh N.
Amin, M.D., Miki Watanabe, M.D., Joanne Billings, M.D., M.P.H., Marie‑Carmelle Elie, M.D., Richard T. Davey, M.D., Timothy H.
Burgess, M.D., M.P.H., Jennifer Ferreira, Sc.M., Michelle Green, M.P.H., Mat Makowski, Ph.D., Anabela Cardoso, M.D., Stephanie
de Bono, M.D., Ph.D., Tyler Bonnett, M.S., Michael Proschan, Ph.D., Gregory A. Deye, M.D., Walla Dempsey, Ph.D., Seema U. Nayak,
M.D., Lori E. Dodd, Ph.D., and John H. Beigel, M.D.
The authors’ affiliations are as follows: the University of Nebraska Medical Center, Omaha (A.C.K., L.L.); University of Texas Health
San Antonio, University Health, and the South Texas Veterans Health Care System, San Antonio (T.F.P., P.O.P., B.S.T.), UT Southwest-
ern Medical Center, Parkland Health and Hospital System (M.K.J.) and Baylor Scott and White Health (U.S.), Dallas, and Baylor College
of Medicine, Houston (H.M.E.S.) — all in Texas; Emory University (A.K.M., N.G.R., Y.S., V.C.M., V.D.C.) and Grady Memorial Hospi-
tal (V.D.C.), Atlanta, and Atlanta Veterans Affairs Medical Center, Decatur (V.C.M.) — both in Georgia; the National Institute of Al-
lergy and Infectious Diseases, National Institutes of Health (K.M.T., V.G., R.T.D., M.P., G.A.D., W.D., S.U.N., L.E.D., J.H.B.), and the
Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences (T.H.B.), Bethesda, and Emmes
(J.F., M.G., M.M.) and Clinical Monitoring Research Program Directorate, Frederick National Laboratory (T.B.), Rockville — both in
Maryland; Duke University, Durham, NC (C.R.W., E.R.K., J.J.E.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán,
(G.M.R.-P.) and Instituto Nacional de Enfermedades Respiratorias (J.R.P.), Mexico City; University of California Irvine, Irvine (L.H.,
A.N.A., M.W.), Cedars–Sinai Medical Center, Los Angeles (V.T.), University of California, San Diego, La Jolla (D.A.S.), University of
California, San Francisco, San Francisco (A.F.L.), University of California, Davis, Davis (S.H.C.), and Stanford University, Stanford
(N.A.) — all in California; University of Minnesota Medical School, Minneapolis (S.K., J.B.); University of Florida, Gainesville (N.M.I.,
M.-C.E.); University of Rochester, Rochester, NY (A.R.B.); National Center for Infectious Diseases, Tan Tock Seng Hospital, Lee Kong
Chian School of Medicine, and Yong Loo Lin School of Medicine (D.C.L.), and Changi General Hospital (S.Y.T.), Singapore; University
of Massachusetts Medical School, Worcester (R.W.F.); University of Virginia, Charlottesville (P.E.H.J.); Northwestern University, Chi-
cago (B.T.); Penn State Health Milton S. Hershey Medical Center, Hershey, PA (C.I.P.); Providence Sacred Heart Medical Center, Spo-
kane, WA (H.A.); University of Alabama at Birmingham, Birmingham (N.E.); Denver Health and Hospital Authority, Denver (M.F.);
Seoul National University Hospital, Seoul (M.O.), and Seoul National University Bundang Hospital, Seongnam (E.-S.K.) — both in
South Korea; Kaiser Permanente Northwest, Portland, OR (R.A.M.); Aalborg University Hospital, Aalborg, Denmark (H.N.); and Eli
Lilly, Indianapolis (A.C., S.B.).

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