Covid-19 living Data

Baricitinib+Remdesivir vs Remdesivir (RCT)

Hospitalized patients

FOREST PLOTS -2022-11-04

Studies description

Trial NCT04401579
Publication ACTT-2 - Kalil AC, N Engl J Med (2020) (published paper)
Dates: 2020-05-08 to 2020-07-01
Funding: Public/non profit (National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), National Cancer Institute, NIH, Department of Defense, Defense Health Program, the governments of Japan, Mexico, Denmark, and Si)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Denmark, Japan, Mexico, Singapore, South Korea, Spain, UK, USA Follow-up duration (days): 29
Inclusion criteria	Admitted to a hospital with symptoms suggestive of COVID-19 Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures Subject (or legally authorized representative) understands and agrees to comply with planned study procedures Male or non-pregnant female adult > / = 18 years of age at time of enrollment Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay in any specimen, as documented by either of the following: 1. PCR positive in sample collected < 72 hours prior to randomization OR 2. PCR positive in sample collected >/= 72 hours prior to randomization, documented inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited testing capacity, results taking >24 hours, etc.) AND progressive disease suggestive of ongoing SARS-CoV-2 infection Illness of any duration, and at least one of the following: 1. Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR 2. SpO2 < / = 94% on room air, OR 3. Requiring supplemental oxygen, OR 4. Requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 29 Agrees to not participate in another clinical trial for the treatment of COVID-19 through Day 29.
Exclusion criteria	Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit of normal Estimated glomerular filtration rate (eGFR) < 30 ml/min or patient is receiving hemodialysis or hemofiltration at time of screening Neutropenia (absolute neutrophil count <1000 cells/microliter) (<1.0 x 10^3/microliter or <1.0 GI/L) Lymphopenia (absolute lymphocyte count <200 cells/microliter) (<0.20 x 10^3/microliter or <0.20 GI/L) Pregnancy or breast feeding Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours Allergy to any study medication Received three or more doses of remdesivir, including the loading dose, outside of the study under the EUA (or similar mechanism) for COVID-19 Received convalescent plasma or intravenous immunoglobulin [IVIg]) for COVID-19, the current illness for which they are being enrolled Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib, genfinitib), in the 1 week prior to screening Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells (e.g., abatacept) in the 4 weeks prior to screening Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any targeting multiple cell lines including B-cells) in the 3 months prior to screening Received other immunosuppressants in the 4 weeks prior to screening and in the judgement of the investigator, the risk of immunosuppression with baricitinib is larger than the risk of COVID-19 Received >/= 20 mg/day of prednisone or equivalent for >/=14 consecutive days in the 4 weeks prior to screening Use of probenecid that cannot be discontinued at study enrollment Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required) Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations is allowed for all subjects Have a history of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 12 weeks prior to screening or have a history of recurrent (>1) VTE (DVT/PE) Immunocompromised patients, patients with a chronic medical condition, or those taking a medication that cannot be discontinued at enrollment, who, in the judgment of PI, are at increased risk for serious infections or other safety concerns given the study products.
Interventions
	Treatment Baricitinib+Remdesivir Baricitinib: 4 mg orally or by nasogastric tube once a day for 14 days. Remdesivir: 200 mg IV on day 1 followed by 100 mg once a day for the next 9 days
	Control Placebo+Remdesivir 200 mg IV on day 1 followed by 100 mg once a day for the next 9 days
Participants
	Randomized participants : Baricitinib+Remdesivir=515 Placebo+Remdesivir=518
	Characteristics of participants N= 1033 Mean age : NR 652 males Severity : Mild: n=142 / Moderate: n=564 / Severe: n=216 Critical: n=111
Primary outcome
	In the register Time to recovery [ Time Frame: Day 1 through Day 29 ]; Time to Recovery by Race [ Time Frame: Day 1 through Day 29 ];Time to Recovery by Ethnicity [ Time Frame: Day 1 through Day 29 ];Time to Recovery by Sex [ Time Frame: Day 1 through Day 29 ]
	In the report 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
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the published article, the supplementary appendix, trial registry, study protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. There were no substantive differences between the published article and the trial registry, study protocol and statistical analysis plan in study procedures, population and interventions. While most outcomes were reported as planned, RT-PCR results during the study follow up period were not. The study achieved its pre-stated sample size. Data from a secondary analysis of this trial was published on April 27th 2022 (Fintzi J, Open Forum Infect Dis, 2022). On November 3rd, 2022, this study was updated with results published in the registry.