Trial EudraCT, 2022-000063-51; NCT05249829
Publication Lee l, medRxiv, 2023
Dates: 2022-04-02 to 2022-06-17
Funding: Private (Moderna, Inc.)
Conflict of interest: Yes
| Methods | |
| RCT | |
| Location :
Multicenter / UK Follow-up duration (months): * | |
| 50 mcg mRNA-1273.214 = 1422 50 mcg mRNA-1273 = 1402 |
|
| Inclusion criteria | Male or female; at least 16 years of age at the time of consent; Investigator’s assessment that the participant understood and was willing and physically able to comply with protocol-mandated follow-up, including all procedures; Participant provided written informed consent for participation in this study, including all evaluations and procedures as specified in the protocol; Female participants of nonchildbearing potential were enrolled in the study. Nonchildbearing potential was defined as postmenopausal or permanently sterilized; a follicle stimulating hormone level could be measured at the discretion of the investigator to confirm postmenopausal status, if necessary. Female participants of childbearing potential were enrolled in the study if the participant fulfilled all the following criteria: a. Had a negative pregnancy test at screening and on the day of vaccination prior to vaccine dose being administered on day 1, b. Had practiced adequate contraception or abstained from all activities that could result in pregnancy for at least 28 days prior to the first dose (day 1) - adequate female contraception was defined as consistent and correct use of a local health authority approved contraceptive method in accordance with the product label, c. Had agreed to continue adequate contraception through 90 days following vaccine administration; Had received 2 prior doses of one of the following approved/authorized Covid-19 vaccines: Moderna, Pfizer/BioNTech, Oxford/AstraZeneca, Janssen. A heterologous vaccine regimen was acceptable; Participants who received the fourth dose as part of the study must have previously received a mRNA vaccine (Moderna or Pfizer/BioNTech) as the third dose of a Covid-19 vaccine. Participants who received the third dose as part of the study may have previously received 2 doses of an approved/authorized mRNA or a non-mRNA Covid-19 vaccine (a heterologous vaccine regimen is acceptable). |
| Exclusion criteria | Had close contact (without personal protective equipment) as defined by the Centers for Disease Control and Prevention (CDC) in the past 14 days to someone diagnosed with SARS-CoV-2 infection or Covid-19 within 10 days of the close contact. Participants could be rescreened after 14 days provided that they remain asymptomatic; Participant was acutely ill or febrile (temperature ≥38.0°C/100.4°F) 72 hours prior to or at the Screening Visit or day 1. Participants meeting this criterion could be rescheduled within the 28-day screening window and will retain their initially assigned participant number; Had tested positive for SARS-CoV-2 by an authorized/approved lateral flow/rapid antigen or PCR test within 90 days of Screening; Had received a Covid-19 vaccine within 90 days of the Screening Visit; Had received a total of 4 doses or more of Covid-19 vaccine; Had received a Covid-19 vaccine at a dose different from the authorized/approved dose; History of a diagnosis or condition that, in the judgment of the Investigator, was clinically unstable or may affect participant safety, assessment of safety endpoints, assessment of immune response, or adherence to study procedures. Clinically unstable was defined as a diagnosis or condition requiring significant changes in management or medication within the 2 months prior to screening and includes ongoing workup of an undiagnosed illness that could lead to a new diagnosis or condition; Reported history of congenital or acquired immunodeficiency, immunosuppressive condition, or immune-mediated disease requiring immunosuppressive treatment or other immunosuppressive condition; Dermatologic conditions that could affect local solicited AR assessments (eg, tattoos, psoriasis patches affecting skin over the deltoid areas); Reported history of anaphylaxis or severe hypersensitivity reaction after receipt of any components of mRNA vaccine; Reported history of bleeding disorder that is considered a contraindication to intramuscular injection or phlebotomy; Any medical, psychiatric, or occupational condition, including reported history of substance abuse, that, in the opinion of the Investigator, might pose additional risk due to participation in the study or could interfere with the interpretation of study results; Had received systemic immunosuppressants or immune-modifying drugs for >14 days in total within 181 days prior to screening (for corticosteroids ≥10 mg/day of prednisone or equivalent) or was anticipating the need for immunosuppressive treatment at any time during participation in the study; Had received or planned to receive any licensed vaccine ≤28 days prior to the study injection (day 1) or planned to receive a licensed vaccine within 28 days after the study injection (with the exception that approved seasonal influenza vaccine may be received by at least 7 days and preferably 14 days apart from the study injection); Had received systemic immunoglobulins or blood products within 90 days prior to the Screening Visit or plans to receive during the study; Diagnosis of malignancy within the previous 10 years (excluding nonmelanoma skin cancer); Had donated ≥ 450 mL of blood products within 28 days prior to the Screening Visit or planned to donate blood products during the study; Had participated in an interventional clinical study within 28 days prior to the Screening Visit based on the medical history interview or planned to do so while participating in this study; Was an immediate family or household member of study personnel, study site staff, or Sponsor personnel. |
| Interventions | |
| Intervention
1 IM dose of 50 mcg (25 mcg each component) mRNA-1273.214 ,at least 90 days (median 5.5 months) after 1st boost with a mRNA vaccine + any prime vaccination. |
|
| Control
1 IM dose of 50 mcg mRNA-1273, at least 90 days (median 5.4 months) after 1st boost with a mRNA vaccine + any prime vaccination. | |
| Participants | |
| Randomized 2,824 participants | |
| Characteristics of participants Type of participants: Aged at least 16 years including healthy, elderly and/or stable co-morbidities N=2,824 1435 males Children: 0 Pregnant women: 0 Immunocompromized patients: 0 Mean age: Age range: 18-89 | |
| Description of participants Healthy or stable co-morbidities, at least 16 years who had previously received 2 injections of an authorized Covid-19 primary series vaccine with or without an mRNA-based booster as the third dose in 28 centres in UK. | |
| Primary outcome | |
| In the register 1) Number of Participants with Solicited Local and Systemic Reactogenicity Adverse Reactions (ARs) [Time Frame: Up to Day 8 (7 days post-vaccination)]; 2) Number of Participants with Unsolicited Adverse Events (AEs) [Time Frame: Up to Day 29 (28 days post-vaccination)]; 3) Number of Participants with Serious AEs (SAEs) [Time Frame: Day 1 to end of study (Day 359)]; 4) Number of Participants with Medically Attended AEs (MAAEs) [Time Frame: Day 1 to end of study (Day 359)]; 5) Number of Participants with AEs Leading to Withdrawal [Time Frame: Day 1 to end of study (Day 359)]; 6) Number of Participants with AEs of Special Interest (AESIs) [Time Frame: Day 1 to end of study (Day 359)]; 7) GMT of mRNA-1273.214 and mRNA-1273 Against the B1.1.529 Strain [Time Frame: Up to Day 85 post-vaccination]; 8) GMT of mRNA-1273.214 and mRNA-1273 Against the Prototype Strain [Time Frame: Up to Day 85 post-vaccination]. | |
| In the report 1) Geometric mean concentration (GMC) of mRNA-1273.214 and mRNA-1273 against the BA.1 strain at Day 29 or Month 3 after study vaccine administration; 2) Ratio of GMC_mRNA-1273.214/GMC_mRNA-1273 against the BA.1 strain at Day 29 or Month 3 after study vaccine administration; 3) Geometric mean concentration (GMC) of mRNA-1273.214 and mRNA-1273 against the prototype strain at Day 29 or Month 3 after study vaccine administration; 4) Ratio of GMC_mRNA-1273.214/GMC_mRNA-1273 against the prototype strain at Day 29 or Month 3 after study vaccine administration; 5) GMC of mRNA-1273.529 and mRNA-1273 against the BA.1 strain at Day 29 or Month 3 after study vaccine administration; 6) Ratio of GMC_mRNA-1273.529/GMC_mRNA-1273 against the BA.1 strain at Day 29 or Month 3 after study vaccine administration; 7) Solicited local and systemic reactogenicity ARs during a 7-day follow up period after vaccination; 8) Unsolicited AEs during the 28-day follow-up period after vaccination; 9) SAEs, medically attended AEs (MAAEs), AEs leading to withdrawal, and AEs of special interest (AESIs) from Day 1 to end of study. | |
| Variants description | |
| Variants | |
| Description Variant name: Omicron. Direct evidence Method: prespecified analysis. Missing outcome results: 35 cases (11%) with no sequence data. | |
| Documents avalaible |
Protocol NR Statistical plan * Data-sharing stated:
Yes, once the trial is complete |
| 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 pre-print article and its supplement, the study registry was used in data extraction and risk of bias assessment. The protocol/statistical analysis plan was not available. Preliminary analysis for a study with ongoing follow-up, to the data cut-off date of August 4, 2022. There is no change from the trial registration in the intervention and control treatments. The registry reported GMT immunogenicity outcomes, however the paper reported GMC. The target sample size (n=3924) specified in the registry for parts 1 and 2 combined was not achieved (n=3548). |