Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

Design

The ACTT-2 protocol was designed and written by a working group of the ACTT investigators and the sponsor (the National Institute of Allergy and Infectious Diseases), with input from the manufacturer of baricitinib, Eli Lilly. Investigators and staff at participating sites gathered the data, which were then analyzed by statisticians at the statistical and data center (Emmes) and the sponsor. The authors wrote the manuscript, and, on behalf of the ACTT-2 Study Group, vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Enrollment into this double-blind, placebo-controlled trial began on May 8, 2020, and ended on July 1, 2020. There were 67 trial sites in 8 countries: the United States (55 sites), Singapore (4), South Korea (2), Mexico (2), Japan (1), Spain (1), the United Kingdom (1), and Denmark (1). Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir and baricitinib or remdesivir and placebo. Randomization was stratified according to trial site and disease severity at enrollment (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Patients received remdesivir intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death. Baricitinib was administered as a 4-mg daily dose (either orally [two 2-mg tablets] or through a nasogastric tube) for 14 days or until hospital discharge. Patients with an estimated glomerular filtration rate of less than 60 ml per minute received baricitinib at a dose of 2 mg once daily. A matching oral placebo was administered according to the same schedule as the active drug. All the patients received standard supportive care at the trial site hospital. Venous thromboembolism prophylaxis was recommended for all the patients without a major contraindication. If a hospital had a written policy for Covid-19 treatments, patients could receive those treatments. In the absence of a written policy, other experimental treatment and off-label use of marketed medications intended as specific treatment for Covid-19 were prohibited. This included glucocorticoids, which were permitted only for standard indications such as adrenal insufficiency, asthma exacerbation, laryngeal edema, septic shock, and acute respiratory distress syndrome.

The trial protocol was approved by the institutional review board at each site (or a centralized institutional review board as applicable) and was overseen by an independent data and safety monitoring board. Written informed consent was obtained from each patient or from the patient’s legally authorized representative if the patient was unable to provide consent. Full details of the trial design, conduct, oversight, and analyses are provided in the protocol and statistical analysis plan (available at NEJM.org).

Procedures

All patients were evaluated daily during their hospitalization, from day 1 through day 29. (See the full description of procedures in the Supplementary Appendix.) The trial team was unaware of the trial-group assignments until after all data queries were resolved and the database was locked. The first draft of the manuscript was written by the first author, and then all the authors contributed to the subsequent versions. No one who is not an author contributed to the writing of the manuscript.

Outcomes and Statistical Analysis

The primary outcome measure was the time to recovery, with the day of recovery defined as the first day, during the 28 days after enrollment, on which a patient attained category 1, 2, or 3 on the eight-category ordinal scale. The competing event of death was handled in a manner similar to the Fine–Gray competing-risk approach.¹³ The categories are the same as those used in ACTT-1¹ and are listed in Table S1 in the Supplementary Appendix. The primary analysis was a stratified log-rank test of the time to recovery with remdesivir plus baricitinib as compared with remdesivir plus placebo, stratified according to baseline disease severity (i.e., score on the ordinal scale of 4 or 5 vs. 6 or 7 at enrollment).

The key secondary outcome measure was clinical status at day 15, based on the eight-category ordinal scale. Other secondary outcome measures included the time to improvement by one or two categories from the ordinal score at baseline; clinical status, as assessed on the ordinal scale at days 3, 5, 8, 11, 15, 22, and 29; mean change in the ordinal score from day 1 to days 3, 5, 8, 11, 15, 22, and 29; time to discharge or to a National Early Warning Score of 2 or less (on a scale from 0 to 20, with higher scores indicating greater clinical risk) that was maintained for 24 hours, whichever occurred first; change in the National Early Warning Score from day 1 to days 3, 5, 8, 11, 15, 22, and 29; number of days of receipt of supplemental oxygen, noninvasive ventilation or high-flow oxygen, and invasive ventilation or extracorporeal membrane oxygenation (ECMO) up to day 29 (if these were being used at baseline); the incidence and duration of new use of oxygen, new use of noninvasive ventilation or high-flow oxygen, and new use of invasive ventilation or ECMO; duration of hospitalization up to day 29 (patients who remained hospitalized at day 29 had a value of 28 days); and mortality at 14 and 28 days after enrollment. Secondary safety outcomes included grade 3 and 4 adverse events and serious adverse events that occurred through day 29, discontinuation or temporary suspension of trial-product administration for any reason, and changes in assessed laboratory values over time. There was a single primary hypothesis test. For secondary outcomes, no adjustments for multiplicity were made.

Prespecified subgroups were defined according to sex, disease severity (as defined for stratification and by an ordinal score of 4, 5, 6, and 7 at enrollment), age (18 to 39 years, 40 to 64 years, or ≥65 years), race, ethnic group, duration of symptoms before randomization (measured as ≤10 days or >10 days, in quartiles, and as the median), site location, and presence of coexisting conditions.

Patients

Of 1067 patients assessed for eligibility, 1033 underwent randomization; 515 were assigned to the combination group, and 518 to the control group (Figure 1). The intention-to-treat population included 706 patients with moderate disease (ordinal score of 4 or 5 [not receiving ventilation]) and 327 with severe disease (ordinal score of 6 or 7 [receiving noninvasive or invasive ventilation]). Of those assigned to the combination group, 507 (98.4%) received treatment as assigned. Of those assigned to the control group, 509 (98.3%) received treatment as assigned. A total of 498 patients in the combination group and 495 in the control group completed the trial through day 29, recovered, or died. The mean age of the patients was 55.4 years, and 63.1% were male (Table 1). Overall, 48.0% of the patients were White, 15.1% were Black, 9.8% were Asian, and 1.0% were American Indian or Alaska Native; 51.4% were Hispanic or Latino (Table 1). The characteristics of the U.S. patients are shown in Table S4.

Primary Outcome

Patients who received combination treatment with baricitinib plus remdesivir recovered a median of 1 day faster than patients who received remdesivir and placebo (median, 7 days vs. 8 days; rate ratio for recovery, 1.16; 95% confidence interval [CI], 1.01 to 1.32; P=0.03 by log-rank test stratified according to actual baseline severity) (Figure 2 and Table 2). When analyzed according to the severity entered at the time of randomization (moderate vs. severe), the hazard ratio was 1.15 (95% CI, 1.00 to 1.31; P=0.047) (Table S6). The median time to recovery among patients receiving noninvasive ventilation or high-flow oxygen (baseline ordinal score of 6) was 10 days in the combination group and 18 days in the control group (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). Among patients with a baseline score of 4 (no oxygen) and 5 (supplemental oxygen), the rate ratio for recovery was 0.88 (95% CI, 0.63 to 1.23) and 1.17 (95% CI, 0.98 to 1.39), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 1.08 (95% CI, 0.59 to 1.97) (Table 2 and Figure 3). The rate ratio for recovery among the 223 patients who received glucocorticoids for clinical indications during the trial was 1.06 (95% CI, 0.75 to 1.48). A sensitivity analysis with a random effect for hospital site yielded similar results (conditional random-effects estimate of rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.33; restricted maximum likelihood–based random-effects estimate of variance, 0.0305) (Table S13).

Key Secondary Outcome

The odds of improvement in clinical status at day 15 as assessed with the ordinal scale were greater in the combination group than in the control group (odds ratio for improvement, 1.3; 95% CI, 1.0 to 1.6). Patients with a baseline ordinal score of 6 who received combination treatment were most likely to have clinical improvement at day 15 (odds ratio, 2.2; 95% CI, 1.4 to 3.6) (Table 2 and Fig. S1).

Mortality

The Kaplan–Meier estimates of mortality at day 28 after randomization were 5.1% (95% CI, 3.5 to 7.6) in the combination group and 7.8% (95% CI, 5.7 to 10.6) in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). The greatest numerical differences in mortality between patients in the combination group and those in the control group were observed among those with a baseline ordinal score of 5 (1.9% vs. 4.7%; hazard ratio, 0.40; 95% CI, 0.14 to 1.14) or 6 (7.5% vs. 12.9%; hazard ratio, 0.55; 95% CI, 0.22 to 1.38). The Kaplan–Meier estimates of mortality at 14 days after randomization were 1.6% in the combination group and 3.0% in the control group (hazard ratio, 0.54; 95% CI, 0.23 to 1.28) (Table 2 and Fig. S2).

Additional Secondary Outcomes

The median time to an improvement by one category on the ordinal scale was 6 days in the combination group and 8 days in the control group (rate ratio, 1.21; 95% CI, 1.06 to 1.39), and the median time to discharge or a National Early Warning Score of 2 or less for 24 hours was 6 days and 7 days in the respective groups (rate ratio, 1.24; 95% CI, 1.07 to 1.44) (Table 3). The incidence of new use of oxygen was lower in the combination group than in the control group (22.9% vs. 40.3%; difference, −17.4 percentage points; 95% CI, −31.6 to −2.1), as was the incidence of new use of mechanical ventilation or ECMO (10.0% vs. 15.2%; difference, −5.2 percentage points; 95% CI, −9.5 to −0.9). The median number of days of receipt of mechanical ventilation or ECMO among the 128 patients in whom these interventions were started after enrollment or who died with no observed new use was 16 days in the combination group and 27 days in the control group (difference, −11.0; 95% CI, −18.3 to −3.7). The incidence of progression to death or noninvasive or invasive ventilation was lower in the combination group than in the control group (22.5% vs. 28.4%; rate ratio, 0.77; 95% CI, 0.60 to 0.98), as was the incidence of progression to death or invasive ventilation (12.2% vs. 17.2%; rate ratio, 0.69; 95% CI, 0.50 to 0.95).

Safety Outcomes

Grade 3 or 4 adverse events occurred in 207 patients (40.7%) in the combination group and 238 (46.8%) in the control group (Table S11). A total of 25 grade 3 or 4 adverse events were judged by the principal investigators to be related to combination treatment and 28 to control (Table S10). The most common grade 3 or 4 adverse events occurring in at least 5% of all patients were hyperglycemia, anemia, decreased lymphocyte count, and acute kidney injury (Table S10). The incidence of these adverse events was similar in the two treatment groups. The percentage of patients who were reported to have a serious or nonserious adverse event of venous thromboembolism was similar in the combination group and the control group (21 patients [4.1%] and 16 patients [3.1%], respectively; difference, 1.0 percentage points; 95% CI, −1.3 to 3.3).

Serious adverse events occurred in 81 patients (16.0%) in the combination group, and six of these events were thought to be related to the trial product (Table S7). Serious adverse events occurred in 107 patients (21.0%) in the control group, and five of these events were thought to be related to the trial product. The between-group difference was −5.0 percentage points (95% CI, −9.8 to −0.3; P = 0.03). The incidences of all serious adverse events, all adverse events, serious adverse events with fatal outcome, and adverse events leading to discontinuation of the trial product were each lower in the combination group than in the control group. Overall, the incidence of serious or nonserious adverse events of new infection was lower in the combination group (30 patients [5.9%]) than in the control group (57 patients [11.2%]) (difference, −5.3 percentage points; 95% CI, −8.7 to −1.9; P=0.003). Patients who received glucocorticoids after randomization had a higher incidence of serious or nonserious new infection than those who did not (56 of 223 patients [25.1%] vs. 44 of 793 patients [5.5%]).