The ACTT-2 protocol was designed and written by a working group of ACTT investigators and sponsor (National Institute of Allergy and Infectious Diseases), with input from the manufacturer of baricitinib, Eli Lilly. Investigators and staff at the participating sites collected the data, which was then analyzed by statisticians at the Statistics and Data Center (Emmes) and the sponsor. The authors wrote the manuscript, and on behalf of the ACTT-2 study group, stress the accuracy, completeness of the data, and trial fidelity of the protocol.
Enrollment for 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), United Kingdom (1), and Denmark (1). Eligible patients were randomly assigned at a 1:1 ratio to receive either remdesivir and baricitinib or remdesivir and placebo. Randomization was stratified according to trial location and disease severity at enrollment (see Supplementary Appendix, available with the full text of this article at NEJM.org). Patients received intravenous remdesivir as a loading dose of 200 mg on day 1, followed by a maintenance dose of 100 mg daily on days 2 through 10 or until hospital discharge or death. Baricitinib was administered as a daily dose of 4 mg (either orally [two 2-mg tablets] or through a nasogastric tube) for 14 days or until discharge from hospital. Patients with an estimated glomerular filtration rate of less than 60 ml per minute received baricinib at a dose of 2 mg once daily. An identical placebo was given orally on the same schedule as the active drug. All patients received standard supportive care at the trial site hospital. Prevention of venous thromboembolism is recommended for all patients without major contraindications. If a hospital has a written policy for Covid-19 treatments, patients can receive those treatments. In the absence of a written policy, other experimental treatments and off-label use of marketed drugs intended for a specific treatment of Covid-19 have been prohibited. This included glucocorticoids, which were only allowed 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 central institutional review board as appropriate) and supervised by an independent data and safety monitoring board. Written informed consent was obtained from each patient or from the patient’s legal representative if the patient was unable to provide consent. Full details of experiment design, conduct, supervision, and analyzes are provided in the Protocol and Statistical Analysis Plan (available at NEJM.org).
All patients were assessed daily during their stay in the hospital, from day 1 through day 29. (See full description of procedures in the Supplementary Appendix). It is locked. The first draft of the manuscript was written by the first author, and all authors then contributed to subsequent copies. No unauthorized person contributed to the manuscript.
RESULTS AND STATISTICAL ANALYSIS
The primary outcome measure was recovery time, with recovery day defined as the first day, within 28 days after enrollment, in which the patient reached category 1, 2 or 3 on an eight-category ordinal scale. The competing death event was handled in a manner similar to the Fine-Gray competing risk approach.13 The classes are the same as those used in ACTT-11 They are listed in Table S1 in the Supplementary Appendix. The primary analysis was a stratified log-rank test of recovery time with remdesivir plus baricitinib compared with remdesivir plus placebo, divided according to the severity of the underlying disease (ie, the score on an ordinal scale of 4 or 5 versus 6 or 7 in the scoring).
The main secondary outcome measure was clinical status at day 15, based on an eight-category ordinal scale. Other secondary outcome measures included improvement time with one or two categories of ordinal score at baseline; Clinical status, as assessed on an ordinal scale on days 3, 5, 8, 11, 15, 22, and 29; Mean change in ordinal degree from day 1 to days 3, 5, 8, 11, 15, 22 and 29; discharge time or to a National Early Warning Score of 2 or less (on a scale of 0 to 20, with higher scores indicating greater clinical risk) and 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 receiving supplemental oxygen, non-invasive ventilation or high-flow oxygen, invasive ventilation or extracorporeal membrane oxygenation (ECMO) up to day 29 (if used at baseline); the occurrence and duration of new use of oxygen, new use of non-invasive ventilation or high-flow oxygen, and new use of invasive ventilation or ECMO; Duration of hospitalization up to day 29 (patients who stayed in hospital on day 29 had a value of 28 days); and deaths 14 and 28 days after registration. Secondary safety outcomes included grade 3 and 4 adverse events and serious adverse events that occurred up to day 29, discontinuation or temporary suspension of experimental product administration for any reason, and changes in estimated laboratory values over time. There was one initial hypothesis test. For secondary outcomes, no adjustments were made for multiplicity.
Pre-specified subgroups were defined according to gender, disease severity (as defined by stratification and ordinal score 4, 5, 6, and 7 at enrollment), age (18 to 39 years, 40 to 64 years, or 65 years), race, and ethnic group , duration of symptoms before randomization (measured as 10 days or >10 days, in interquartiles, and as a mean), site location, and presence of coexisting cases.