ACTT-2

Incomplete

Kalil AC, et al. "Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19". The New England Journal of Medicine. 2020. (e-pub 2020-12-11):1-13.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among patients hospitalized for Covid-19 with lower respiratory tract infection, does remdesivir plus baricitinib lower the time to recovery compared to remdesivir alone?

Bottom Line

Baricitinib plus remdesivir lower recovery time and improves clinical status among Covid-19 patients hospitalized who require high-flow oxygen or noninvasive ventilation.

Guidelines

No guidelines have been published that reflect the results of this trial.

Design

• International, multicenter, double-blind, placebo-controlled, randomized controlled trial
• N=1,033 patients with Covid-19
  • Remdesivir plus Baricitinib (n=515)
  • Remdesivir plus placeboStandard (n=518)
• Setting: 67 trial sites in 8 countries including Unites States (55), Singapore (4), South Korea (2), Mexico (2), Japan (1), Spain (1), the United Kingdom (1), and Denmark (1).
• Setting: 60 trial sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore
• Enrollment: 8 May 2020 to 19 July 2020
• Analysis: Intention-to-treat
• Primary outcome: Time to recovery

Population

Eligibility criteria are included in the Supplemental Appendix.

Inclusion Criteria

• Age ≥18 years
• Laboratory-confirmed SARS-CoV-2 infection (as determined by a PCR)
• Evidence of lower respiratory tract infection at the time of enrollment based on one of the following:
  • Radiographic infiltrates by imaging study
  • SpO2 ≤94% on room air
  • Requiring supplemental oxygen, mechanical ventilation, or ECMO
• No limit to the duration of symptoms prior to enrollment
• Not participating in another Covid-19 treatment clinical trial through Day 29
• Practicing heterosexual abstinence or using study-specified contraception through Day 29 for women of childbearing potential

Exclusion Criteria

• ALT or AST >5x ULN
• Impaired renal function by eGFR or need for hemodialysis or hemofiltration
• Allergy to study product
• Pregnancy or breast-feeding
• Anticipated discharge from the hospital or transfer to another hospital within 72 hours of enrollment

Baseline Characteristics

• Mean age: 55.4 years
• Male sex: 63.1%
• Number of co-existing conditions: none 15.6%, one 27.2%, two or more 57.2%
• Median time from symptom onset to randomization: 8 days
• Ordinal score of disease severity: (4) 13.7%, (5) 54.6%, (6) 20.9%, (7) 10.7%, (missing score) 0.1%

Interventions

• 1:1 randomization to remdesivir plus baricitinib or remdesivir plus placebo
  • Remdesivir+baricitinib
    • Remdesivir: IV 200-mg loading dose on day 1, followed by IV 100 mg/d on days 2 through 10 or until hospital discharge or death
    • Baricitinib: 4-mg/d (either PO or NG tube) for 14 days or until hospital discharge; 2-mg/d if eGFR < 60 mL/min
  • Remdesivir+placebo: matching placebo administered according to the same schedule

Outcomes

Comparisons are remdesivir plus baricitinib vs. remdesivir plus placebo.

Primary Outcome

Time to recovery

7 vs. 8 days (RR 1.16, 95% CI 1.01–1.32; P=0.03)

Secondary Outcomes

Improvement in clinical status at day 15

Odds ratio 1.3 (95% CI 1.4-3.6)

Subgroup Analysis

Subgroup analyses were conducted

Adverse Events

Serious adverse events

16.0% vs 21.0%

Respiratory failure

3.7% vs 6.3%

Grade 3-4 adverse events

40.7% vs. 46.8%

Criticisms

• This study was not powered to detect a difference in mortality between the two groups. Because of this, we are unable to assess for appropriate size of the study groups, and type 1 and 2 errors.
• There was no explanation or discussion for why an ordinal score of 6 benefited the most compared to the other ordinal groups.
• While likely unavoidable, the funding, protocol development, and weekly protocol team calls by Gilead and Eli Lilly could have elicited bias.

Funding

• National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)
• Gilead Sciences, which is the manufacturer of remdesivir, provided the drug for use but did not provide any financial support.
• Eli Lilly, which is the manufacturer of baricitinib, provided the drug but did not provide any financial support.