A Study to Evaluate Efficacy, Safety, and Immunogenicity of mRNA-1273 Vaccine in Adults Aged 18 Years and Older to Prevent COVID-19

• ClinicalTrials.gov Identifier: NCT04470427
• Recruitment Status: Completed
• First Posted: July 14, 2020
• Last Update Posted: January 12, 2023
• Sponsor: ModernaTX, Inc.
• Collaborators: Biomedical Advanced Research and Development Authority; National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): ModernaTX, Inc.

Tracking Information

• First Submitted Date: July 11, 2020
• First Posted Date: July 14, 2020
• Last Update Posted Date: January 12, 2023
• Actual Study Start Date: July 27, 2020
• Actual Primary Completion Date: December 29, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 12, 2022)

• Efficacy: Number of Participants with a First Occurrence of COVID-19 Starting 14 Days after Second Dose of mRNA-1273 [ Time Frame: Part A only: Day 43 (14 days after second dose) up to Day 759 (2 years after second dose) ]
• Safety: 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) ]
• Safety: Number of Participants with Solicited Local and Systemic Adverse Reactions (ARs) [ Time Frame: Part A only: Up to Day 8 (7 days after first dose) and up to Day 36 (7 days after second dose) ]
• Safety: Number of Participants with Unsolicited AEs [ Time Frame: Part A and C only: Up to Day 57 (28 days after each dose) ]
• Safety: Number of Participants with Serious AEs (SAEs) [ Time Frame: Up to Day 759 (2 years after second dose) ]

Original Primary Outcome Measures (submitted: July 11, 2020)

• 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) ]
• 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) ]
• 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) ]
• Number of Participants with Unsolicited AEs [ Time Frame: Up to Day 57 (28 days after each dose) ]

Current Secondary Outcome Measures (submitted: May 12, 2022)

• Number of Participants with a First Occurrence of Severe COVID-19 Starting 14 Days after Second Dose of mRNA-1273 or Placebo [ Time Frame: Day 43 (14 days after second dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of severe COVID-19 as predefined for the study.
• Number of Participants with a First Occurrence of Either COVID-19 or SARS-CoV-2 Infection regardless of symptomatology or Severity Starting 14 Days after Second Dose of mRNA-1273 or Placebo [ Time Frame: Day 43 (14 days after second dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of COVID-19 and SARS-CoV-2 Infection as predefined for the study.
• Number of Participants with a Secondary Case Definition of COVID-19 Starting 14 days after Second Dose of mRNA-1273 or Placebo [ Time Frame: Day 43 (14 days after second dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of secondary case definition of COVID-19 as predefined for the study.
• Number of Participants with a First Occurrence of COVID-19 Starting 14 days after First Dose of mRNA-1273 or Placebo [ Time Frame: Day 43 (14 days after first dose of the Blinded Phase) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of COVID-19 as predefined for the study.
• Number of Participants with a First Occurrence of COVID-19 Starting 14 days after Second Dose of mRNA-1273 or Placebo Regardless of Evidence of Prior SARS-CoV-2 Infection [ Time Frame: Day 43 (14 days after second dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of COVID-19 and SARS-CoV-2 infection as predefined for the study.
• Number of Participants with a First Occurrence of SARS-CoV-2 Infection in the Absence of Symptoms Defining COVID-19 Starting 14 days after Second Dose of mRNA-1273 or Placebo [ Time Frame: Day 43 (14 days after second dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of COVID-19 and SARS-CoV-2 infection as predefined for the study.
• Geometric Mean Titer (GMT) of SARS-CoV-2 Specific Neutralizing Antibody (nAb) [ Time Frame: Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759 ]
• Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 Specific nAb [ Time Frame: Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759 ]
• Quantified Levels or GMT of S Protein-Specific Binding Antibody (bAb) [ Time Frame: Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759 ]
• GMFR of S Protein Specific bAb [ Time Frame: Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759 ]
• Number of Participants With Seroresponse Against SARS-CoV-2 (Part C Only) [ Time Frame: Post-booster dose Day 29 ]
  Seroresponse is defined as a titer change from baseline (predose 1 in primary series) below the lower limit of quantitation (LLOQ) to ≥ 4 × LLOQ, or at least a 4-fold rise if baseline is ≥LLOQ.

Original Secondary Outcome Measures (submitted: July 11, 2020)

• Number of Participants with a First Occurrence of Severe 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) ]
  Clinical signs indicative of severe COVID-19 as predefined for the study.
• Number of Participants with a First Occurrence of Either COVID-19 or SARS-CoV-2 Infection regardless of symptomatology or Severity Starting 14 Days after Second Dose of mRNA-1273 or Placebo [ Time Frame: Day 29 (second dose) up to Day 759 (2 years after second dose)] ]
  Clinical signs indicative of COVID-19 and SARS-CoV-2 Infection as predefined for the study.
• Number of Participants with a Secondary Case Definition of COVID-19 Starting 14 days after Second Dose of mRNA-1273 or Placebo [ Time Frame: Day 29 (second dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of secondary case definition of COVID-19 as predefined for the study.
• Number of Participants with a First Occurrence of COVID-19 Starting 14 days after First Dose of mRNA-1273 or Placebo [ Time Frame: Day 1 (first dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of COVID-19 as predefined for the study.
• Number of Participants with a First Occurrence of COVID-19 Starting 14 days after Second Dose of mRNA-1273 or Placebo regardless of evidence of prior SARS-CoV-2 Infection [ Time Frame: Day 29 (second dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of COVID-19 and SARS-CoV-2 infection as predefined for the study.
• Number of Participants with a First Occurrence of SARS-CoV-2 Infection in the Absence of Symptoms Defining COVID-19 Starting 14 days after Second Dose of mRNA-1273 or Placebo [ Time Frame: Day 29 (second dose) up to Day 759 (2 years after second dose) ]
  Clinical signs indicative of COVID-19 and SARS-CoV-2 infection as predefined for the study.
• Geometric Mean Titer (GMT) of SARS-CoV-2 Specific Neutralizing Antibody (nAb) [ Time Frame: Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759 ]
• Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 Specific nAb [ Time Frame: Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759 ]
• Quantified Levels or GMT of S Protein-Specific Binding Antibody (bAb) [ Time Frame: Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759 ]
• GMFR of S Protein Specific bAb [ Time Frame: Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate Efficacy, Safety, and Immunogenicity of mRNA-1273 Vaccine in Adults Aged 18 Years and Older to Prevent COVID-19
• Official Title: A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older
• Brief Summary: The mRNA-1273 vaccine is being developed to prevent COVID-19, the disease resulting from Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) infection. The study is designed to primarily evaluate the efficacy, safety, and immunogenicity of mRNA-1273 to prevent COVID-19 for up to 2 years after the second dose of mRNA-1273.

Detailed Description

This is a 3-part Phase 3 study, with Part A (Blinded Phase), Part B (Open-label Observational Phase), and Part C (Booster Dose Phase). Participants in Part A are blinded to their treatment assignment, with participants receiving either mRNA-1273 vaccine or placebo. Part B of the study is designed to offer participants to be unblinded so that participants who received placebo in Part A can request 2 doses of open-label mRNA-1273 vaccine. Additionally, participants who choose to be unblinded and were only able to receive 1 dose of mRNA-1273 due to administrative reasons, can choose to receive the second dose of mRNA-1273 during Part B. In Part C, a booster dose will be provided for all eligible participants who choose to receive one.

Please access www.modernatx.com/cove-study for additional information, such as Study Overview, Participation, and Site Locations along with contact numbers for each location for the study.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Part A is observer-blind. Part B is open-label; participants can request to be unblinded by scheduling a Participant Decision clinic visit. Part C offers participants the option to receive a booster dose for those participants who received at least one dose of mRNA-1273 in the study.

Primary Purpose: Prevention

• Condition: SARS-CoV-2

Intervention

• Biological: mRNA-1273
  Sterile liquid for injection
• Biological: Placebo
  0.9% sodium chloride (normal saline) injection

Study Arms

• Experimental: mRNA-1273

  Part A (Blinded): Participants will receive 1 intramuscular (IM) injection of 100 microgram (μg) mRNA-1273 on Day 1 and on Day 29.

  Part B (Open-label): Participants who receive mRNA-1273-matching placebo during Part A and choose to be unblinded by participating in Part B, will receive 1 IM injection of 100 μg mRNA-1273 on Day 1 and Day 29. Participants who are only able to receive 1 dose of mRNA-1273 due to administrative reasons, will receive 1 IM injection of 100 μg mRNA-1273 on Day 1, if the participant chooses.

  Part C: Eligible participants in Part B who choose to receive booster dose of mRNA-1273, will receive 1 IM injection of 50 μg mRNA-1273 on Day 1.

  Interventions:

  • Biological: mRNA-1273
  • Biological: Placebo
• Placebo Comparator: Placebo
  Part A only: Participants will receive 1 IM injection of mRNA-1273-matching placebo on Day 1 and on Day 29, if the participant chooses.
  Intervention: Biological: Placebo

Publications *

• Fraiman J, Erviti J, Jones M, Greenland S, Whelan P, Kaplan RM, Doshi P. Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults. Vaccine. 2022 Sep 22;40(40):5798-5805. doi: 10.1016/j.vaccine.2022.08.036. Epub 2022 Aug 31.
• Follmann D, Janes HE, Buhule OD, Zhou H, Girard B, Marks K, Kotloff K, Desjardins M, Corey L, Neuzil KM, Miller JM, El Sahly HM, Baden LR. Antinucleocapsid Antibodies After SARS-CoV-2 Infection in the Blinded Phase of the Randomized, Placebo-Controlled mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial. Ann Intern Med. 2022 Sep;175(9):1258-1265. doi: 10.7326/M22-1300. Epub 2022 Jul 5.
• El Sahly HM, Baden LR, Essink B, Montefiori D, McDermont A, Rupp R, Lewis M, Swaminathan S, Griffin C, Fragoso V, Miller VE, Girard B, Paila YD, Deng W, Tomassini JE, Paris R, Schodel F, Das R, August A, Leav B, Miller JM, Zhou H, Pajon R; Coronavirus Efficacy (COVE) Study Group. Humoral Immunogenicity of the mRNA-1273 Vaccine in the Phase 3 Coronavirus Efficacy (COVE) Trial. J Infect Dis. 2022 Nov 11;226(10):1731-1742. doi: 10.1093/infdis/jiac188.
• Pajon R, Paila YD, Girard B, Dixon G, Kacena K, Baden LR, El Sahly HM, Essink B, Mullane KM, Frank I, Denhan D, Kerwin E, Zhao X, Ding B, Deng W, Tomassini JE, Zhou H, Leav B, Schodel F; COVE Trial Consortium. Initial analysis of viral dynamics and circulating viral variants during the mRNA-1273 Phase 3 COVE trial. Nat Med. 2022 Apr;28(4):823-830. doi: 10.1038/s41591-022-01679-5. Epub 2022 Feb 10.
• El Sahly HM, Baden LR, Essink B, Doblecki-Lewis S, Martin JM, Anderson EJ, Campbell TB, Clark J, Jackson LA, Fichtenbaum CJ, Zervos M, Rankin B, Eder F, Feldman G, Kennelly C, Han-Conrad L, Levin M, Neuzil KM, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Polakowski L, Mascola JR, Ledgerwood JE, Graham BS, August A, Clouting H, Deng W, Han S, Leav B, Manzo D, Pajon R, Schodel F, Tomassini JE, Zhou H, Miller J; COVE Study Group. Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase. N Engl J Med. 2021 Nov 4;385(19):1774-1785. doi: 10.1056/NEJMoa2113017. Epub 2021 Sep 22.
• Gilbert PB, Montefiori DC, McDermott A, Fong Y, Benkeser D, Deng W, Zhou H, Houchens CR, Martins K, Jayashankar L, Castellino F, Flach B, Lin BC, O'Connell S, McDanal C, Eaton A, Sarzotti-Kelsoe M, Lu Y, Yu C, Borate B, van der Laan LWP, Hejazi N, Huynh C, Miller J, El Sahly HM, Baden LR, Baron M, De La Cruz L, Gay C, Kalams S, Kelley CF, Kutner M, Andrasik MP, Kublin JG, Corey L, Neuzil KM, Carpp LN, Pajon R, Follmann D, Donis RO, Koup RA. Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial. medRxiv. 2021 Aug 15:2021.08.09.21261290. doi: 10.1101/2021.08.09.21261290. Preprint.
• Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021 Feb 4;384(5):403-416. doi: 10.1056/NEJMoa2035389. Epub 2020 Dec 30.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 11, 2020): 30000
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 29, 2022
• Actual Primary Completion Date: December 29, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• (Part A only) Participants 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.
• Understands and agrees to comply with the study procedures and provides written informed consent.
• Able to comply with study procedures based on the assessment of the Investigator.
• Female participants of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as surgically sterile (history of bilateral tubal ligation, bilateral oophorectomy, hysterectomy) or postmenopausal (defined as amenorrhea for ≥12 consecutive months prior to Screening without an alternative medical cause). A follicle-stimulating hormone (FSH) level may be measured at the discretion of the Investigator to confirm postmenopausal status.

• Female participants of childbearing potential may be enrolled in the study if the participant fulfills all the following criteria:

  • Has a negative pregnancy test at Screening and on the day of the first dose (Day 1, open-label Day 1, and booster dose Day 1).
  • Has 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).
  • Has agreed to continue adequate contraception through 3 months following the last dose (Day 29, open-label Day 29, and booster dose Day 1).
  • Is 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.
• (Part C Only) Is currently enrolled in Part B of the current study (mRNA-1273-P301).
• (Part C Only) Has received at least 1 dose of mRNA-1273 in the current study (mRNA-1273-P301).

Exclusion Criteria:

• Is acutely ill or febrile 72 hours prior to or at Screening or dosing (Part B and Part C). Fever is defined as a body temperature ≥38.0°Celsius/100.4°Fahrenheit. Participants meeting this criterion may be rescheduled within the relevant window periods. Afebrile participants with minor illnesses can be enrolled/dosed at the discretion of the Investigator.
• Is pregnant or breastfeeding.
• (Part A Only) Known history of SARS-CoV-2 infection.
• Prior (Part A) or concurrent (Part B and Part C) administration of non-study coronavirus (SARS-CoV, Middle East Respiratory Syndrome [MERS]-CoV) vaccine or current/planned simultaneous participation in another interventional study to prevent or treat COVID-19.
• (Part A Only) Demonstrated inability to comply with the study procedures.
• An 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 vaccine within 28 days prior to the first dose (Day 1) or plans to receive a non-study vaccine within 28 days prior to or after any dose of investigational product (IP) (except for seasonal influenza vaccine).
• (Part A only) Has participated in an interventional clinical study within 28 days prior to the day of enrollment.
• Immunosuppressive or immunodeficient state, including human immunodeficiency virus (HIV) infection, asplenia, and recurrent severe infections.
• Has received systemic immunosuppressants or immune-modifying drugs for >14 days in total within 6 months prior to IP dose administration (for corticosteroids ≥20 milligram (mg)/day of prednisone equivalent).
• Has received systemic immunoglobulins or blood products within 3 months prior to the day of IP dose administration.
• Has donated ≥450 milliliters (mL) of blood products within 28 days prior to IP dose administration.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04470427
• Other Study ID Numbers: mRNA-1273-P301; 75A50120C00034 ( Other Grant/Funding Number: BARDA )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: ModernaTX, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: ModernaTX, Inc.
• Original Study Sponsor: Same as current

Collaborators

• Biomedical Advanced Research and Development Authority
• National Institute of Allergy and Infectious Diseases (NIAID)

• Investigators: Not Provided
• PRS Account: ModernaTX, Inc.
• Verification Date: January 2023