Dose-Confirmation Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of mRNA-1273 COVID-19 Vaccine in Adults Aged 18 Years and Older

SARS-CoV-2 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04405076
• Other study ID #: mRNA-1273-P201
• Secondary ID: 75A50120C00034
• Status: Completed
• Phase: Phase 2
• Start date: May 29, 2020
• Est. completion date: October 28, 2021

Study information

• Verified date: December 2022
• Source: ModernaTX, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 660
• Est. completion date: October 28, 2021
• Est. primary completion date: October 28, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• SARS-CoV-2

Intervention

Biological:
• Biological: mRNA-1273
Sterile liquid for injection
• Placebo
0.9% sodium chloride (normal saline) injection
• mRNA-1273.351
Sterile liquid for injection

Locations

Country	Name	City	State
United States	Benchmark Research	Austin	Texas
United States	Meridian Clinical Research	Dakota Dunes	South Dakota
United States	Alliance for Multispecialty Research	Kansas City	Missouri
United States	Alliance for Multispecialty Research	Newton	Kansas
United States	Meridian Clinical Research	Norfolk	Nebraska
United States	Benchmark Research	San Angelo	Texas
United States	Meridian Clinical Research	Savannah	Georgia
United States	Trial Management Associates	Wilmington	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
ModernaTX, Inc.	Biomedical Advanced Research and Development Authority

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Solicited Local and Systemic Adverse Reactions (ARs)	Solicited ARs, including local and systemic ARs were collected in the eDiary. Local ARs included: pain at injection site, erythema (redness) at injection site, swelling/induration (hardness) at injection site, and localized axillary swelling or tenderness ipsilateral to the injection arm. Systemic ARs included: headache, fatigue, myalgia (muscle aches all over the body), arthralgia (aching in several joints), nausea/vomiting, rash, body temperature (potentially fever), and chills. All solicited ARs (local and systemic) considered causally related to injection. ARs were graded 0-4 as reviewed and confirmed by Investigator; lower score indicates lower severity and a higher score indicates greater severity. Note, not all solicited ARs were considered adverse events (AEs). The Investigator reviewed whether the solicited AR was also to be recorded as an AE. A summary of SAEs and all nonserious AEs ("Other"), regardless of causality, is located in the Reported "Adverse Events" section.	7 days post-vaccination
Primary	Number of Participants With Unsolicited AEs	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A treatment-emergent AE (TEAE) was defined as any event not present before exposure to vaccine or any event already present that worsens in intensity or frequency after exposure. Any abnormal laboratory test result (hematology, clinical chemistry, or prothrombin time [PT]/partial thromboplastin time [PTT]) or other safety assessment (for example, electrocardiogram, radiological scan, vital sign measurement), including one that worsens from baseline and is considered clinically significant in the medical and scientific judgment of the Investigator. A summary of SAEs and all nonserious AEs ("Other") reported up to the end of the study (up to Month 15), regardless of causality, is located in the Reported "Adverse Events" section.	Up to 28 days post-vaccination
Primary	Number of Participants With Medically-Attended Adverse Events (MAAEs)	An MAAE is an AE that leads to an unscheduled visit to a healthcare practitioner (HCP). A summary of SAEs and all nonserious AEs ("Other"), regardless of causality, is located in the Reported "Adverse Events" section.	Up to Month 15
Primary	Number of Participants With SAEs	An SAE was defined as any AE that resulted in death, is life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in disability/permanent damage, was a congenital anomaly/birth defect, or was an important medical event. A summary of SAEs and all nonserious AEs ("Other"), regardless of causality, is located in the Reported "Adverse Events" section.	Up to Month 15
Primary	Part A: Level of Severe Acute Respiratory Syndrome Coronavirus (SARS-COV-2)-Specific Binding Antibody (bAb) as Measured by Enzyme-Linked Immunosorbent Assay (ELISA)	The geometric mean (GM) level of VAC58 spike immunoglobulin G (IgG) antibodies, as measured by ELISA specific to the SARS-CoV-2 spike protein is reported. Antibody values reported as below the lower limit of quantification (LLOQ) were replaced by 0.5*LLOQ. Values that were greater than the upper limit of quantification (ULOQ) were converted to the ULOQ if actual values were not available. LLOQ was 1 and ULOQ was 2052. The 95% confidence intervals (CIs) were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GM value, respectively, then back transformed to the original scale for presentation.	Days 1 (Baseline), 29, 43, 57, and 209
Primary	Part B: Level of SARS-CoV-2-Specific bAb as Measured by ELISA	The GM level of VAC65 spike IgG antibodies, as measured by ELISA specific to the SARS-CoV-2 spike protein is reported. Antibody values reported as below the LLOQ were replaced by 0.5*LLOQ. Values that were greater than the ULOQ are converted to the ULOQ. LLOQ was 1 and ULOQ was 2052. The 95% CIs were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GM value, respectively, then back transformed to the original scale for presentation. The PP Set included participants with a study injection, required baseline data, had postinjection results at timepoint of primary interest for immunogenicity analysis, no major protocol deviations impacting immune response, and didn't have SARS-CoV-2.	Days 1 (Baseline) and 29
Primary	Part C: Level of SARS-CoV-2-Specific bAb as Measured by MSD	The GM level of SARS-CoV-2 protein antibody against B.1.351, as measured by MSD MULTIPLEX is reported. Antibody values reported as below the LLOQ were replaced by 0.5*LLOQ. Values that were greater than the ULOQ are converted to the ULOQ. LLOQ was 18 and ULOQ was 4200000. The 95% CIs were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GM value, respectively, then back transformed to the original scale for presentation.	Days 1 (Baseline), 8, 15, and 29
Secondary	Part A: Titer of SARS-CoV-2-Specific Neutralizing Antibody (nAb)	The GM titer (microneutralization [MN] and MN50) of serum nAb against SARS-CoV-2 as measured by live virus MN assays is reported. Antibody values reported as below the LLOQ were replaced by 0.5*LLOQ. Values that were greater than the ULOQ were converted to the ULOQ. For MN, LLOQ was 40 and ULOQ was 1280 at Days 1 (Baseline), 29, 43, and 57. For MN50, LLOQ was 91.10 and ULOQ was 2031.87 at Days 1 (Baseline), 29, 43, and 57. For MN, LLOQ was 160 and ULOQ was 1280 at Day 209. For MN50, LLOQ was 318.46 and ULOQ was 1917.83 at Day 209. The 95% CI was calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GM titer, then back transformed to the original scale for presentation.	Days 1 (Baseline), 29, 43, 57, and 209
Secondary	Part B: Titer of SARS-CoV-2-Specific nAb	The GM titer (50% inhibitory dose [ID50], 80% inhibitory dose [ID80]) of nAb against SARS-CoV-2 pseudotyped viruses as measured by pseudovirus nAb assay is reported. Antibody values reported as below the LLOQ were replaced by 0.5*LLOQ. Values that were greater than the ULOQ were converted to the ULOQ if actual values were not available. LLOQ was 18.5 and ULOQ was 45118 for IC50. LLOQ was 14.3 and ULOQ was 10232 for ID80. The 95% CI was calculated based on the t-distribution of the log-transformed values for GM titer, then back transformed to the original scale for presentation. The PP Set included participants with a study injection, required baseline data, had postinjection results at timepoint of primary interest for immunogenicity analysis, no major protocol deviations impacting immune response, and didn't have SARS-CoV-2.	Days 1 (Baseline), 29, and 181
Secondary	Part C: Titer of SARS-CoV-2-Specific nAb	The GM titer (ID50, ID80) of nAb against SARS-CoV-2 pseudotyped viruses (original strain and beta variant [B.1.351]) as measured by pseudovirus nAb assay is reported. Antibody values reported as below the LLOQ were replaced by 0.5*LLOQ. Values that were greater than the ULOQ were converted to the ULOQ if actual values were not available. For NAb ID50 Titers, LLOQ was 18.5 and ULOQ was 45118. For NAb ID80 Titers, LLOQ was 14.3 and ULOQ was 10232. For NAb ID50 Titers against B.1.351, LLOQ was 19.5 and ULOQ was 385.7. For NAb ID80 Titers against B.1.351, LLOQ was 12.5 and ULOQ was 102.2. The 95% CI was calculated based on the t-distribution of the log-transformed values for GM titer, then back transformed to the original scale for presentation.	Days 1 (Baseline), 8, 15, 29, and 181
Secondary	Part A: Percentage of Participants With Seroconversion From Baseline	Based on MN titers and MN50 titers of serum nAb against SARS-CoV-2 as measured by live virus MN assays, percentage of participants with seroconversion from baseline are reported with 2-sided 95% CI using the Clopper-Pearson method at each post-baseline timepoint. Seroconversion at a participant level was defined as a change of nAb titer from below the limit of detection (LOD) or LLOQ to equal to or above LOD or LLOQ (respectively), or a 4-times or higher titer ratio in participants with pre-existing nAb titers. Antibody values reported as below the LLOQ were replaced by 0.5*LLOQ. Values that were greater than the ULOQ were converted to the ULOQ. For MN, LLOQ was 40 and ULOQ was 1280. For MN50, LLOQ was 91.10 and ULOQ was 2031.87.	Days 29, 43, and 57
Secondary	Part B: Percentage of Participants With Seroconversion From Baseline	Based on ID50 and ID80 titers of nAb against SARS-CoV-2 pseudotyped viruses as measured by pseudovirus nAb assay, % of participants with seroconversion from baseline reported with 2-sided 95% CI using Clopper-Pearson method at each postbaseline timepoint. Seroconversion at participant level defined as change of nAb titer from below LOD or LLOQ to equal to or above LOD or LLOQ (respectively) or 4-times or higher titer ratio in participants with preexisting nAb titers. Antibody values	Days 29 and 181
Secondary	Part C: Percentage of Participants With Seroconversion From Baseline	Based on ID50 titers and ID80 titers of nAb against SARS-CoV-2 pseudotyped viruses (original strain and beta variant [B.1.351]) as measured by pseudovirus nAb assay, percentage of participants with seroconversion from baseline are reported with 2-sided 95% CI using Clopper-Pearson method at each post-baseline timepoint. Seroconversion at participant level defined as a change of nAb titer from below LOD or LLOQ =LOD or LLOQ (respectively), or a 4-times or higher titer ratio in participants with pre-existing nAb titers. Antibody values reported as below LLOQ were replaced by 0.5*LLOQ. Values >ULOQ were converted to ULOQ. NAb ID50 Titers: LLOQ was 18.5 and ULOQ was 45118. NAb ID80 Titers: LLOQ was 14.3 and ULOQ was 10232. NAb ID50 Titers against B.1.351: LLOQ was 19.5 and ULOQ was 385.7. NAb ID80 Titers against B.1.351: LLOQ was 12.5 and ULOQ was 102.2. 95% CI calculated based on t-distribution of log-transformed values for GMT, then back transformed to original scale for presentation.	Days 8, 15, 29, and 181