Clinical trial NCT04405076: Dose-Confirmation Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of mRNA-1273 COVID-19 Vaccine in Adults Aged 18 Years and Older
Official title: A Phase 2a, Randomized, Observer-Blind, Placebo Controlled, Dose-Confirmation Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of mRNA-1273 SARS-COV-2 Vaccine in Adults Aged 18 Years and Older
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: SARS-CoV-2
Keywords: mRNA-1273
mRNA-1273 vaccine
mRNA-1273.351
SARS-CoV-2
SARS-CoV-2 Vaccine
Coronavirus
Virus Diseases
Messenger RNA
COVID 19
COVID 19 Vaccine
Moderna
Lead sponsor: ModernaTX, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Biomedical Advanced Research and Development Authority
First posted: 2020-05-28
Enrollment: 660
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief summary: This clinical study will assess the safety, reactogenicity, and immunogenicity of 2 dose levels of mRNA-1273 Severe Acute Respiratory Syndrome coronavirus (SARS-COV-2) vaccine in adults 18 years of age or older.

Detailed description: This is a 3-part Phase 2a study, with Part A (Blinded Phase), Part B (Open-label Interventional Phase), and Part C (Rollover Proof of Concept).

Participants in Part A are blinded to their treatment assignment, with participants receiving either 2 active mRNA-1273 vaccine doses 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 originally received 1 or 2 doses of mRNA-1273 (50 microgram \[μg\] or 100 μg vaccine) during Part A, will have the opportunity to request to receive a single booster dose of mRNA-1273.

Part C will be a proof-of-concept rollover study to evaluate a vaccine to treat mutations of SARS-CoV2, such as the S-protein of the B.1.351 variant. Part C will include approximately 60 participants, who are currently enrolled in Moderna's Phase 3 mRNA-1273-P301 study (NCT04470427), have already been unblinded, and have previously received 2 doses of mRNA-1273 at least 6 months earlier. At enrollment into Part C of this study, their participation in mRNA-1273-P301 study will be terminated. Part C will evaluate the safety and immunogenicity of 2 dose levels (20 µg and 50 µg) of mRNA-1273.351 and mRNA-1273/mRNA-1273.351 mixture (50 µg total), given as a single booster dose.

Eligibility criteria: Key Inclusion Criteria:

Each participant must meet all of the following criteria during the screening period and at Day 1, unless noted otherwise, to be enrolled in this study:

1. Male or female, 18 years of age or older at the time of consent (Screening Visit, Day 0). For Part B, participants must have been previously enrolled in the mRNA-1273 P201 study.
2. Understands and agrees to comply with the study procedures and provides written informed consent.
3. According to the assessment of the investigator, is in good general health and can comply with study procedures.
4. Female participants of nonchildbearing potential may be enrolled in the study. Nonchildbearing 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 (Day 0) without an alternative medical cause). A follicle-stimulating hormone (FSH) level may be measured at the discretion of the investigator to confirm postmenopausal status.
5. 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 (Day 0) and on the day of the first injection (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 injection (Day 1).
   * Has agreed to continue adequate contraception through 3 months following the second injection (Day 29).
   * Is not currently breastfeeding.

   Adequate female contraception is defined as consistent and correct use of a Food and Drug Administration (FDA) approved contraceptive method in accordance with the product label. For example:
   * Barrier method (such as condoms, diaphragm, or cervical cap) used in conjunction with spermicide
   * Intrauterine device
   * Prescription hormonal contraceptive taken or administered via oral (pill), transdermal (patch), subdermal, or IM route
   * Sterilization of a female participant's monogamous male partner prior to entry into the study Note: periodic abstinence (for example, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
6. Male participants engaging in activity that could result in pregnancy of sexual partners must agree to practice adequate contraception from the time of the first injection and through 3 months after the last injection.

Adequate contraception for male participants is defined as:

* Monogamous relationship with a female partner using an intrauterine device or hormonal contraception (described above)
* Use of barrier methods and spermicide
* History of surgical sterilization
* Male participants with partners who have become pregnant prior to Screening are eligible to participate in the study.

Additional Key Inclusion Criteria for Part C

1. Participants must have been previously enrolled in the mRNA-1273-P301 study and must have received 2 doses of mRNA-1273 in Part A, has been unblinded and aware of their actual treatment in Study mRNA-1273-P301, must have been compliant in Study mRNA-1273-P301 (was not withdrawn or discontinued early), and has been at least 6 months since their second dose in Study mRNA-1273-P301 prior to enrollment in this part.

Key Exclusion Criteria:

Participants meeting any of the following criteria at the Screening Visit (Day 0) or at Day 1, unless noted otherwise, will be excluded from the study:

1. Pregnant or breastfeeding.
2. Is acutely ill or febrile 24 hours prior to or at the Screening Visit (Day 0). 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 at the discretion of the investigator.
3. Current treatment with investigational agents for prophylaxis against COVID-19.
4. Has a medical, psychiatric, or occupational condition that may pose additional risk as a result of participation, or that could interfere with safety assessments or interpretation of results according to the investigator's judgment.
5. Is a healthcare worker or a member of an emergency response team.
6. Current use of any inhaled substance (for example, tobacco or cannabis smoke, nicotine vapors).
7. History of chronic smoking (≥1 cigarette a day) within 1 year of the Screening Visit (Day 0).
8. History of illegal substance use or alcohol abuse within the past 2 years. This exclusion does not apply to historical cannabis use that was formerly illegal in the participant's state but is legal at the time of Screening.
9. Known history of hypertension, or systolic blood pressure \>150 millimeter of mercury (mmHg) in participants in Cohort 1 (≥18 to \<55 years old) or systolic blood pressure \>160 mmHg in participants in Cohort 2 (≥55 years old) at the Screening Visit (Day 0).
10. Known history of hypotension or systolic blood pressure \<85 mmHg at the Screening Visit (Day 0).
11. Diabetes mellitus
12. Diagnosis of chronic pulmonary disease (for example, chronic obstructive pulmonary disease, asthma)
13. Chronic cardiovascular disease
14. Resides in a nursing home
15. Grade 1 or higher toxicity on clinical safety laboratory testing at the Screening Visit (Day 0)
16. Current or previous diagnosis of immunocompromising condition, immune-mediated disease, or other immunosuppressive condition.
17. Received systemic immunosuppressants or immune-modifying drugs for \>14 days in total within 6 months prior to the Screening Visit (Day 0) (for corticosteroids ≥20 milligrams (mg)/day of prednisone equivalent). Topical tacrolimus is allowed if not used within 14 days prior to the Screening Visit (Day 0).
18. Anticipating the need for immunosuppressive treatment at any time during participation in the study.
19. Positive serology for hepatitis B virus surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV) type 1 or 2 antibodies identified at the Screening Visit (Day 0).
20. History of anaphylaxis, urticaria, or other significant AR requiring medical intervention after receipt of a vaccine.
21. Bleeding disorder considered a contraindication to IM injection or phlebotomy.
22. Diagnosis of malignancy within previous 10 years (excluding non-melanoma skin cancer).
23. Has received or plans to receive a licensed vaccine ≤28 days prior to the first injection (Day 1) or plans to receive a licensed vaccine within 28 days before or after any study injection. Licensed influenza vaccines may be received more than 14 days before or after any study injection.
24. Receipt of systemic immunoglobulins or blood products within 3 months prior to the Screening Visit (Day 0) or plans for receipt during the study.
25. Has donated ≥450 mL of blood products within 28 days prior to the Screening Visit (Day 0) or plans to donate blood products during the study.
26. Participated in an interventional clinical study (other than mRNA-1273 P301) within 28 days prior to the Screening Visit (Day 0) or plans to do so while participating in this study.
27. Is an immediate family member or household member of study personnel

Additional Key Exclusion Criteria for Part C

1. Is SARS-CoV-2 positive by Reverse transcription polymerase chain reaction (RT-PCR) (central or local testing) at baseline or at any time during the mRNA-1273-P301 study regardless of the presence or absence of symptoms consistent with COVID-19.
2. Had any SAE in the mRNA-1273-P301 study.

Primary outcomes:
measure: Number of Participants With Solicited Local and Systemic Adverse Reactions (ARs)
timeFrame: 7 days post-vaccination
measure: Number of Participants With Unsolicited AEs
timeFrame: Up to 28 days post-vaccination
measure: Number of Participants With Medically-Attended Adverse Events (MAAEs)
timeFrame: Up to Month 15
measure: Number of Participants With SAEs
timeFrame: Up to Month 15
measure: Part A: Level of Severe Acute Respiratory Syndrome Coronavirus (SARS-COV-2)-Specific Binding Antibody (bAb) as Measured by Enzyme-Linked Immunosorbent Assay (ELISA)
timeFrame: Days 1 (Baseline), 29, 43, 57, and 209
measure: Part B: Level of SARS-CoV-2-Specific bAb as Measured by ELISA
timeFrame: Days 1 (Baseline) and 29
measure: Part C: Level of SARS-CoV-2-Specific bAb as Measured by MSD
timeFrame: Days 1 (Baseline), 8, 15, and 29
Secondary outcomes:
measure: Part A: Titer of SARS-CoV-2-Specific Neutralizing Antibody (nAb)
timeFrame: Days 1 (Baseline), 29, 43, 57, and 209
measure: Part B: Titer of SARS-CoV-2-Specific nAb
timeFrame: Days 1 (Baseline), 29, and 181
measure: Part C: Titer of SARS-CoV-2-Specific nAb
timeFrame: Days 1 (Baseline), 8, 15, 29, and 181
measure: Part A: Percentage of Participants With Seroconversion From Baseline
timeFrame: Days 29, 43, and 57
measure: Part B: Percentage of Participants With Seroconversion From Baseline
timeFrame: Days 29 and 181
measure: Part C: Percentage of Participants With Seroconversion From Baseline
timeFrame: Days 8, 15, 29, and 181
Other outcomes:
Locations:
city: Savannah
country: United States
facility: Meridian Clinical Research
state: Georgia
city: Newton
country: United States
facility: Alliance for Multispecialty Research
state: Kansas
city: Kansas City
country: United States
facility: Alliance for Multispecialty Research
state: Missouri
city: Norfolk
country: United States
facility: Meridian Clinical Research
state: Nebraska
city: Wilmington
country: United States
facility: Trial Management Associates
state: North Carolina
city: Dakota Dunes
country: United States
facility: Meridian Clinical Research
state: South Dakota
city: Austin
country: United States
facility: Benchmark Research
state: Texas
city: San Angelo
country: United States
facility: Benchmark Research
state: Texas
Study officials:
References:
citation: Kirste I, Hortsch S, Grunert VP, Legault H, Maglinao M, Eichenlaub U, Kashlan B, Pajon R, Jochum S. Quantifying the Vaccine-Induced Humoral Immune Response to Spike-Receptor Binding Domain as a Surrogate for Neutralization Testing Following mRNA-1273 (Spikevax) Vaccination Against COVID-19. Infect Dis Ther. 2023 Jan;12(1):177-191. doi: 10.1007/s40121-022-00711-y. Epub 2022 Nov 15.
citation: Chu L, Vrbicky K, Montefiori D, Huang W, Nestorova B, Chang Y, Carfi A, Edwards DK, Oestreicher J, Legault H, Dutko FJ, Girard B, Pajon R, Miller JM, Das R, Leav B, McPhee R. Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial. Nat Med. 2022 May;28(5):1042-1049. doi: 10.1038/s41591-022-01739-w. Epub 2022 Mar 3.
citation: Choi A, Koch M, Wu K, Chu L, Ma L, Hill A, Nunna N, Huang W, Oestreicher J, Colpitts T, Bennett H, Legault H, Paila Y, Nestorova B, Ding B, Montefiori D, Pajon R, Miller JM, Leav B, Carfi A, McPhee R, Edwards DK. Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis. Nat Med. 2021 Nov;27(11):2025-2031. doi: 10.1038/s41591-021-01527-y. Epub 2021 Sep 15.
citation: Chu L, McPhee R, Huang W, Bennett H, Pajon R, Nestorova B, Leav B; mRNA-1273 Study Group. A preliminary report of a randomized controlled phase 2 trial of the safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine. Vaccine. 2021 May 12;39(20):2791-2799. doi: 10.1016/j.vaccine.2021.02.007. Epub 2021 Feb 9.