Covid-19 Living Data

Trial NCT04470427
Publication El Sahly H, N Engl J Med, 2021
Dates: 2020-07-27 to 2020-10--23
Funding: Public/non profit (Office of the Assistant Secretary for Preparedness and Response, National Institute of Allergy and Infectious Diseases (NIAID / NIH), Biomedical Advanced Research and Development Authority (BARDA / U.S. Department of Health and Human Services))
Conflict of interest: Yes

Methods
	RCT
	Location : Multicenter / United States Follow-up duration (months): 5.3
	• 100 mcg mRNA-1273 (n=15209) • Placebo (n = 15206)
Inclusion criteria	Adults, ≥ 18 years of age at time of consent, who are at high risk of SARS-CoV-2 infection, defined as adults whose locations or circumstances put them at appreciable risk of exposure to SARS-CoV-2 and COVID-19 informed consent Able to comply with study procedures based on the assessment of the Investigator Female participants of nonchildbearing potential may be enrolled in the study Female participants of childbearing potential may be enrolled in the study if the participant fulfills all the following criteria - negative pregnancy test at Screening and on the day of the first dose (Day 1) practiced adequate contraception or has abstained from all activities that could result in pregnancy for at least 28 days prior to the first dose (Day 1) agreed to continue adequate contraception through 3 months following the second dose (Day 29) not currently breastfeeding Healthy adults or adults with pre-existing medical conditions who are in stable condition. A stable medical condition is defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 3 months before enrollment.
Exclusion criteria	Acutely ill or febrile 72 hours prior to or at Screening pregnant or breastfeeding Known history of SARS-CoV-2 infection Prior administration of an investigational coronavirus (SARS-CoV, MERS-CoV) vaccine or current/planned simultaneous participation in another interventional study to prevent or treat COVID-19 Demonstrated inability to comply with the study procedures immediate family member or household member of this study’s personnel Known or suspected allergy or history of anaphylaxis, urticaria, or other significant adverse reaction to the vaccine or its excipients Bleeding disorder considered a contraindication to intramuscular injection or phlebotomy Has received or plans to receive a non-study vaccine within 28 days prior to or after any dose of IP (except for seasonal influenza vaccine) Has participated in an interventional clinical study within 28 days prior to the day of enrollment Immunosuppressive or immunodeficient state, asplenia, recurrent severe infections (HIV- positive participants with CD4 count ≥350 cells/mm3 and an undetectable HIV viral load within the past year [low level variations from 50-500 viral copies which do not lead to changes in antiretroviral therapy [ART] are permitted]) Has received systemic immunosuppressants or immune-modifying drugs for >14 days in total within 6 months prior to Screening (for corticosteroids ≥ 20 mg/day of prednisone equivalent) Has received systemic immunoglobulins or blood products within 3 months prior to the day of screening Has donated ≥ 450 mL of blood products within 28 days prior to Screening.
Interventions
	Intervention 2 IM doses of 100-mcg mRNA-1273 D0/D27
	Control 2 IM doses of saline placebo, D0/D27
Participants
	Randomized 30415 participants
	Characteristics of participants Type of participants: Healthy volunteers N=30415 15974 males Children: 0 Pregnant women: 0 Mean age: 51.3 Age range: 18-95
	Description of participants Healthy adults with no known history of SARS-CoV-2 infection in 99 centers in the US
Primary outcome
	In the register 1. Number of Participants with a First Occurrence of COVID-19 Starting 14 Days after Second Dose of mRNA-1273 [ Time Frame: Day 29 (second dose) up to Day 759 (2 years after second dose) ]; 2. Number of Participants with Adverse Events (AEs) or Medically Attended AEs (MAAEs) Leading to Withdrawal [ Time Frame: Up to Day 759 (2 years after second dose) ]; 3. Number of Participants with Solicited Local and Systemic Adverse Reactions (ARs) [ Time Frame: Up to Day 8 (7 days after first dose) and up to Day 36 (7 days after second dose) ]; 4. Number of Participants with Unsolicited AEs [ Time Frame: Up to Day 57 (28 days after each dose) ]
	In the report Vaccine efficacy in preventing a first occurrence of Covid-19 with onset at least 14 days after the second injection
Documents available	Protocol Yes. In English Statistical plan Yes Data-sharing stated: Yes, With publication of the final study results in 2022 Data accessibility: NR
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	Some concerns
General comment	In addition to the two published reports (El Sahly HM, N Engl J Med, 2021 and Baden LR, N Engl J Med, 2020), the FDA and sponsor briefing documents, the trial registry, protocol, supplementary appendices and sponsor media statement and trial website were used in data extraction. Based on the Baden LR et al report: Mortality in the FDA and sponsor briefing documents vs in the published article were not the same. The publication reported on the fatal unsolicited adverse events 28 days after any injection while the FDA and sponsor briefing documents reported mortality that resulted from serious adverse events, up to December 3rd, 2020. Furthermore, we now report data for withdrawal from the study due to adverse events taken from unsolicited adverse events 28 days after any vaccination in the overall safety set. We are requesting information (particular of the denominators) from the authors concerning similar data presented in Table 16 of the sponsor document. There were no substantive differences between the publication or FDA/sponsor briefing documents and the trial registry and protocol in population, procedures and interventions. The outcomes and timepoints reported were appropriate for an interim analysis of safety and efficacy of a large trial with follow up planned to continue up to two years. Quote: "The case-driven study design required 151 COVID-19 cases to trigger the final scheduled efficacy analysis. Two interim analysis timepoints were pre-specified; the first upon accrual of 53 cases and the second upon accrual of 106 cases." "The initial EUA request was based on data from the pre-specified interim analysis (November 11, 2020 data cutoff) with a median follow-up duration of 7 weeks after dose 2; this interim analysis data is the primary basis of this EUA review and conclusions. Data and analyses from a November 25, 2020 data cut with a median duration of at least 2 months follow-up after completion of the 2-dose primary vaccination series was submitted as an amendment to the EUA request on December 7, 2020. The FDA has not independently verified the complete safety data from the primary analysis, aside from all new deaths (including those reported through December 3, 2020) and SAEs." This trial was updated on October 11th 2021 with results from the El Sahly et al report which reports data from a cutoff date of March 26, 2021. This trial was further updated on September 2nd, 2022 after publication of immunogenicity results.