Covid-19 Living Data

Trial NCT04640168
Publication ACTT-4 - Wolfe CR, Lancet Respir Med (2022) (published paper)
Dates: 2020-12-01 to 2021-04-13
Funding: Public/non profit (Gilead Sciences provided remdesivir for use in this trial but did not provide any financial support. Eli Lilly provided baricitinib for use in this trial but did not provide any financial support. Employees of Gilead Sciences and Eli Lilly participated in discussions about protocol development and in weekly protocol team calls. Input from the manufacturer of baricitinib, Eli Lilly, Indianapolis, IN, USA, was considered by the investigators. The National Institute of Allergy and Infectious Diseases (NIAID) ultimately made all decisions regarding trial design and implementation. The trial was sponsored and primarily funded by the NIAID, National Institutes of Health. This trial has also been funded in part by the National Cancer Institute, US Department of Defense, Defense Health Program, the governments of Japan, Mexico, and Singapore, Seoul National University Hospital, and Seoul National University Bundang Hospital.)
Conflict of interest: No

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / USA, South Korea, Mexico, Singapore, Japan Follow-up duration (days): 60
Inclusion criteria	Informed consent patients 18 years of age or older hospitalized with symptoms suggestive of COVID-19 laboratory-confirmed SARS-CoV-2 infection as determined by a positive reverse transcription, polymerase-chain-reaction (RT-PCR) assay or other commercial assay (e.g., antigen test, NAAT assay) result from any respiratory specimen <14 days prior to randomization new or increased requirement for supplemental oxygen by low flow, high flow, or non-invasive mechanical ventilation modalities in the 7 days prior to randomization agreeing not to participate in another blinded COVID-19 clinical trial through Day 29 practicing heterosexual abstinence or using study-specified contraception through Day 29 for women of childbearing potential.
Exclusion criteria	On mechanical ventilation or ECMO at time of randomization having an anticipated hospital discharge or transfer to another hospital within 72 hours of randomization having a positive test for influenza virus during current COVID-19 illness having a current diagnosis of active or latent tuberculosis treated for less than 4 weeks with appropriate therapy having a serious infection (besides COVID-19) or being in an immunosuppressed state that could constitute a risk when taking either study product having known deep vein thrombosis (DVT) or pulmonary embolism (PE) during the current COVID-19 illness having neutropenia (absolute neutrophil count <700 cells/mgL), lymphopenia (absolute lymphocyte count <200 cells/mgL), or impaired renal function as determined by calculating an estimated glomerular filtration rate (eGFR) or need for hemodialysis or hemofiltration having allergy to study product being pregnant or breast-feeding and having a history of prior enrollment in ACTT-3 or ACTT-4 received as treatment for the current COVID-19 illness including more than one dose of baricitinib convalescent plasma or intravenous immunoglobulin a tyrosine kinase inhibitor or monoclonal antibodies targeting cytokines, b-cells, or t-cells received ≥20 mg prednisone per day for 2 weeks or more, or a live-attenuated vaccine in the 4 weeks prior to screening or ≥6 mg dexamethasone in one day, on more than one day, in the seven days prior to randomization.
Interventions
	Treatment Baricitinib+Remdesivir Baricitinib - 4 mg once a day orally or by nasogastric tube for up to 14 days ; Remdesivir initial dose 200 mg once intravenously - Maintenance dose 100 mg once a day intravenously for up to 10 days.
	Control DEX+Remdesivir Dexamethasone 6 mg once a day intravenously for up to 10 days ; Remdesivir initial dose 200 mg once intravenously - Maintenance dose 100 mg once a day intravenously for up to 10 days.
Participants
	Randomized participants : Baricitinib+Remdesivir=516 DEX+Remdesivir=494
	Characteristics of participants N= 1010 Mean age : NR 590 males Severity : Mild: n=1 / Moderate: n=856 / Severe: n=153 Critical: n=0 Number of vaccinated participants: 21
Primary outcome
	In the register The proportion of subjects not meeting criteria for one of the following two ordinal scale categories at any time: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [ Time Frame: Day 1 through Day 29 ]
	In the report The difference in mechanical ventilation-free survival by day 29.
Documents available	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 trial registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. The registry primary outcome reflects the reported primary outcome. The trial (n = 1010) did not achieve its target sample size (n = 1382) because a preplanned futility analysis led to early stopping as the DSMB determined that it was unlikely that the study would show a significant difference between the two study groups if the trial continued.