Publication Beigel JH, N Engl J Med, 2020 (published paper)
Dates: 21feb2020 to 2020-04-20
Funding: Public/non profit (National Institute of Allergy and Infectious Diseases and others)
Conflict of interest: No
Blinding: double blinding
Multicenter / USA, Denmark, UK, Greece, Germany, Korea, Mexico, Spain, Japan, Singapore |
Follow-up duration (days): 28
|Inclusion criteria||Participants had to meet one of the following criteria suggestive of lower respiratory tract infection at the time of enrollment: radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO2) ≥ 94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). There was no limit to the duration of symptoms prior to enrollment. Participants had to have a laboratory-confirmed SARS-CoV-2 infection as determined by a positive reverse transcription, polymerase-chain-reaction (RT-PCR) assay result from any respiratory specimen collected <72 hours prior to randomization. During the study, this criterion was modified due to limitations in testing capacity to also allow a RT-PCR positive specimen that was collected ≥72 hours prior to randomization if the site was unable to obtain a repeat sample and if the participant had progressive disease consistent with ongoing SARS-CoV-2 infection. Other inclusion criteria included agreeing not to participate in another COVID-19 treatment clinical trial through Day 29 and practicing heterosexual abstinence or using study-specified contraception through Day 29 for women of childbearing potential.|
|Exclusion criteria||Alanine aminotransferase (ALT) or an aspartate aminotransferase (AST) > 5 times the upper limit of the normal range; impaired renal function as determined by calculating an estimated glomerular filtration rate (eGFR), or need for hemodialysis or hemofiltration; allergy to study product; pregnancy or breast-feeding; and anticipated discharge from the hospital or transfer to another hospital within 72 hours of enrollment|
200 mg IV on day 1, followed by 100 mg IV daily for up to 9 additional days
Placebo (100 mg)
Duration : 10 days
1062 participants (n1=541 / n2= 521)
|Characteristics of participants|
Mean age : 58.9
Severity : Mild: n=138 / Moderate: n=435/ Severe: n=193 Critical: n=285
|In the register|
Time to recovery [ Time Frame: Day 1 through Day 29 ]
|In the report|
Time to recovery, defined as the first day, during the 28 days after enrollment, on which a patient satisfied categories 1, 2, or 3 on the eight-category ordinal scale
Yes. In English
|Risk of bias
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
In addition to all available versions of the published/pre-print article, the study registry, protocol, and statistical analysis plan were used in data extraction and risk of bias assessment.
The final report was published in the New England Journal of Medicine on October 8, 2020 and the data (for 29 day follow-up). Data were also posted on the registry website, clinicaltrials.gov on September 25th, 2020 which contained data through day 29 of follow-up.
The original report, published on May 22, 2020, presented preliminary results up to day 14. After interim data analysis, the data and safety monitoring board recommended that the preliminary primary analysis report and mortality data be provided to trial team members from the National Institute of Allergy and Infectious Diseases (NIAID). These results were made public and were accessible to the treating physicians, who could request to be made aware of the treatment assignment of trial participants who had not completed day 29 if clinically indicated. Participants assigned to the placebo group could be given remdesivir.
The study had a larger sample size than the target sample size specified in the trial registry (n=800). There was no change from the trial registration in the intervention and control treatments. The primary outcome measurement changed from the first version to the protocol, and is described in the second version of the protocol (both are provided in the article appendix). The authors provide an explanation for this decision, which took place before interim analysis, and was proposed by statisticians who had no knowledge of outcome data.
This trial was updated on February 9th, 2021 after contact with authors.