Moderna’s pivotal Phase 3 randomized, observer-blind, placebo-controlled efficacy trial of mRNA-1273 (Spikevax) — approximately 30,000 adults ≥18 years given two 100 µg doses 28 days apart. The COVE interim analysis published by Baden et al. (NEJM, December 2020) reported 94.1% efficacy and supported the December 2020 Emergency Use Authorization; the trial later supported the January 2022 BLA approval of Spikevax. The study expanded over time from Part A (blinded) to Part B (open-label crossover after the EUA) and Part C (booster-dose phase), which is why the later amendments grow substantially in scope.
Latest protocol we have: mrna-1273-P301-amendment-10-2022-04-07.pdf
| Category | Count | Amendments |
|---|---|---|
| Total documents in the history (Original + amendments) | 11 | |
| Direct PDFs available | 3 | Amendments 4, 6, 10 |
| Summary-only (date and rationale recorded here, no full PDF available) | 8 | Amendments 1, 2, 3, 5, 7, 8, 9; Original Protocol |
| Document | Date | Available documents | Main rationale for the amendment |
|---|---|---|---|
| Original Protocol | 15 Jun 2020 | Summary only — no full PDF of this version available | (no main-rationale paragraph in source) |
| Amendment 1 | 26 Jun 2020 | Summary only — no full PDF of this version available | The main purpose of this amendment is to provide more intensive surveillance of symptoms and severity of cases of COVID-19 after the first dose of IP. The summary of changes table provided here describes the major changes made in Amendment 1 relative to the original protocol, including the sections modified and the corresponding rationales. Minor editorial or formatting changes are not included in this summary table. |
| Amendment 2 | 31 Jul 2020 | Summary only — no full PDF of this version available | The main purpose of this amendment is to provide more intensive surveillance of symptoms and severity of cases of COVID-19 after the first dose of IP. The summary of changes table provided here describes the major changes made in Amendment 2 relative to Amendment 1, including the sections modified and the corresponding rationales. Minor editorial or formatting changes are not included in this summary table. The synopsis of Amendment 2 has been modified to correspond to changes in the body of the protocol. |
| Amendment 3 | 20 Aug 2020 | Summary only — no full PDF of this version available | The main purpose of this amendment is to make changes to the protocol in response to feedback from Center for Biologics Evaluation and Research. The summary of changes table provided here describes the major changes made in Amendment 3 relative to Amendment 2, including the sections modified and the corresponding rationales. Minor editorial or formatting changes are not included in this summary table. The synopsis of Amendment 3 has been modified to correspond to changes in the body of the protocol. |
| Amendment 4 | 30 Sep 2020 | 19745_S42_M5_protocol-mrna-1273-p301-amend-4.pdfSource ZIP19745_S42_M5_protocol-mrna-1273-p301-amend-4-trk.pdfSource ZIP19745_S42_M5_protocol-mrna-1273-p301-amend-4-trk(2103076.1).pdfSource ZIP | The main purpose of this amendment is to increase the upper limit for stratification of enrolled participants considered “at risk” at Screening to 50%. The summary of changes table provided here describes the major changes made in Amendment 4 relative to Amendment 3, including the sections modified and the corresponding rationales. The synopsis of Amendment 4 has been modified to correspond to changes in the body of the protocol. |
| Amendment 5 | 11 Nov 2020 | Summary only — no full PDF of this version available | The main purpose of this amendment is to clarify that the eDiary prompts for safety surveillance will be weekly and to add Month 19 safety call. The summary of changes table provided here describes the major changes made in Amendment 5 relative to Amendment 4, including the sections modified and the corresponding rationales. The synopsis of Amendment 5 has been modified to correspond to changes in the body of the protocol. |
| Amendment 6 | 23 Dec 2020 | mrna-1273-P301-amendment-6-2020-12-23.pdfInternet Archive | The purpose of this amendment is to inform all ongoing study participants of the availability of and eligibility criteria of any COVID-19 vaccine made available under an EUA and to offer participants who originally received placebo in this study the potential benefit of vaccination against COVID-19, given that the primary efficacy endpoint for mRNA-1273 against COVID-19 was met per the protocol-defined IA. The summary of changes table provided here describes the major changes made in Amendment 6 relative to Amendment 5, including the sections modified and the corresponding rationales. The synopsis of Amendment 6 has been modified to correspond to changes in the body of the protocol. |
| Amendment 7 | 10 Feb 2021 | Summary only — no full PDF of this version available | The purpose of this amendment is to collect safety information on suspected cases of anaphylaxis and to include participant history of facial injections or dermal fillers in the eDiary. The summary of changes table provided here describes the major changes made in Amendment 7 relative to Amendment 6, including the sections modified and the corresponding rationales. The synopsis of Amendment 7 has been modified to correspond to changes in the body of the protocol. |
| Amendment 8 | 23 Mar 2021 | Summary only — no full PDF of this version available | The purpose of this amendment is to update language around unblinding and open-label dosing in the context of the majority of participants already having completed their blinded follow-up. In addition, the amendment updates the reporting of serious COVID-19 cases. The summary of changes table provided here describes the major changes made in Amendment 8 relative to Amendment 7, including the sections modified and the corresponding rationales. As applicable, the synopsis of Amendment 8 has been modified to correspond to changes in the body of the protocol. |
| Amendment 9 | 10 Sep 2021 | Summary only — no full PDF of this version available | 1. To provide a 50 µg BD of mRNA-1273 to participants. This change is prompted by the announcement by the President of the US that, as of 20 Sep 2021, certain individuals will be eligible to receive a BD in addition to the prior receipt of a primary vaccine regimen with mRNA-1273. The interim results of an ongoing Moderna Phase 2 study (mRNA-1273-P201), in which participants who 6 to 8 months prior received 2 doses of [[PAGE 178]] ModernaTX, Inc. 07 Apr 2022 Protocol mRNA-1273-P301, Amendment 10 mRNA-1273 Confidential Page 179 50 µg or 100 µg of mRNA-1273 were administered a 50 µg booster of mRNA-1273, demonstrated enhanced immune responses compared to pre-boost levels and met the noninferiority criteria stipulated in the FDA Guidance on EUA for Vaccines to Prevent COVID-19. Additionally, no new safety signals emerged upon administration of the BD in Study mRNA-1273-P201. Based on cumulative evidence, the benefit-risk profile of a BD of mRNA-1273 is favorable, particularly in light of increasing breakthrough disease with the emergence of the Delta variant. The details of eligibility for BDs provided by the US federal government have not been specified as of the time of writing this protocol amendment. Providing the option for a BD to all federally eligible participants currently enrolled in Part B is expected to promote retention of participants in the ongoing study and thereby defend the scientific integrity of the study for the planned 2-year duration of follow-up after the completion of the primary vaccination series. 2. To provide guidance to the investigators regarding assessing and reporting AESIs, including myocarditis and pericarditis, for this study population. |
| Amendment 10 | 07 Apr 2022 | mrna-1273-P301-amendment-10-2022-04-07.pdfclinicaltrials.gov (NCT04470427) | 1. To provide guidance to the investigators in providing a booster dose to participants with breakthrough coronavirus disease 2019 infection after primary series. 2. To include immunogenicity analysis for Part C as a secondary objective of the study. |
For each amendment that ships a ‘Summary of Major Changes’ table in the source PDF, the full Section / Description / Rationale rows are reproduced below. The Original protocol typically has no change-table (nothing to compare against).
(no detailed Section / Description / Rationale table for this amendment in the source PDF)
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title page, Signature page, and header | Updated the protocol version and date. | Reflect the new version and date of the protocol. |
| Synopsis; Section 4.1, General Design; Section 8.1.3, Convalescent Period; Section 11.1, schedules of events, Table 17 | Increased the frequency of telemedicine contacts during the Convalescent Period following the Initial Illness Visit. | Improve the amount and quality of COVID-19 symptom data collected during the Convalescent Period. |
| Synopsis; Section 4.1, General Design; Section 8.1.3, Convalescent Period; Section 8.1.4, Ancillary Supplies for Participant Use; Section 11.1, schedules of events, Table 17 | Added monitoring of oxygen saturation to the Convalescent Period. | Improve surveillance for incidence of COVID-19 during the study. |
| Synopsis; Section 8.1.3, Convalescent Period; Section 8.1.4, Ancillary Supplies for Participant Use; Section 11.1, schedules of events, Table 17 | Increased the frequency of monitoring for SARS-CoV-2, using saliva as the preferred sample matrix after the Illness Visit during the Convalescent Period. | Improve the sensitivity of monitoring the time course of viral shedding during COVID-19. |
| Synopsis; Section 3, Objectives and Endpoints | Added a respiratory sample for hospitalized participants as a matrix for confirming the presence of SARS-CoV-2. | Increase the potential number of evaluable COVID-19 cases. |
| Synopsis; Section 3, Objectives and Endpoints | Broadened the definition for seroconversion at a participant level. | Included neutralizing antibody (nAb) in addition to binding antibody (bAb). |
| Section 8, Study Assessments and Procedures; Section 8.1.3, Convalescent Period; Section 8.1.4, Ancillary Supplies for Participant Use; Section 8.2.2, Use of Electronic Diaries; Section 11.1, schedules of events, Table 17 | Eliminated paper diaries, substituting an instruction card listing symptoms and a severity grading system to enhance the quality of data obtained by telemedicine contacts. | Reduce fomite transmission of SARS-CoV-2 and increase frequency of investigative staff interactions with participants during the Convalescent Period. |
| Section 8.1.2, Surveillance for COVID-19 Symptoms | Decreased the number of symptoms (to one of the 11 CDC symptoms) that would result in an Illness Visit. | Increase the likelihood of capturing all COVID-19 cases in the earliest stage of disease. |
| Section 8.2.2, Use of Electronic Diaries | Expanded the scope of eDiary prompts and data collected during the Surveillance Phase. | Increase the likelihood of capturing all COVID-19 cases in the earliest stage of disease. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | Reflect the new version and date of the protocol. |
| Section 4.1 (General Design), Section 7.2 (Discontinuation of Study Treatment), Section 8.1.1 (Efficacy Assessments Related to COVID-19 and SARS-CoV-2 Infection), Section 8.1.2 (Surveillance for COVID-19 Symptoms),Table 14 (Schedule of Events [Vaccination Phase, Day 1 – Day 57]) | Added a Day 29 NP swab prior to Dose 2. | Improve surveillance for asymptomatic infection prior to Dose 2 to assist in discriminating COVID-19 symptoms from solicited systemic reactions after vaccination. |
| Section 4.1 (General Design), Table 15 (Schedule of Events [Surveillance Phase, Day 64 – Day 394]) | Changed the clinic visit at Month 4 to a safety call. | Improve participant safety and adherence to protocol. |
| Section 4.1 (General Design), Section 8.1.2 (Surveillance for COVID-19 Symptoms), Table 14 Footnote 5 (Schedule of Events [Vaccination Phase, Day 1 – Day 57]) | Clarified symptom duration (> 48 hours) to trigger NP swab collection and investigator judgement whether to obtain an NP swab in the 7 days following vaccination due to overlap of solicited systemic symptoms and COVID-19. | Improve surveillance for cases of COVID-19. |
| Section 4.1 (General Design), Section 8.1.3 (Convalescent Period Starting with the Illness Visit), Section 8.1.4 (Ancillary Supplies for Participant Use) | Removed mention of continuous biometric monitoring. | Simplify data management and clinical operations. |
| Section 5.1 (Inclusion Criteria), Section | Removed the inclusion criterion regarding male contraception. | Requirement not generally applicable for a Phase 3 vaccine study. |
| Section 5.2 (Exclusion Criteria), Section 6.4.3 (Concomitant Medications and Vaccines that May Lead to the Elimination of a Participant from Per-Protocol Analyses) | Clarified language around influenza vaccination. | Make restrictions on influenza vaccination less restrictive than for other licensed vaccines relative to administration of investigational product. |
| Section 5.2 (Exclusion Criteria) | Removed restriction on enrollment of participants with human immunodeficiency virus (HIV) infection. | Participants on stable antiretroviral therapy are not excluded, which diversifies the participant group. |
| Section 8.3.7 (Time Period and Frequency for Collecting AE and SAE Information), Section 8.3.10 (Reporting Adverse Events) | Added expedited reporting of confirmed COVID-19 cases. | Improve surveillance for cases of COVID-19 |
| Section 8.4.2 (Data and Safety Monitoring Board) | Added an Oversight Group. | Clarify responsibility for declaring early efficacy or for taking action to stop, pause, or continue the study. |
| Section 8.4.2 (Data and Safety Monitoring Board) | Updated description of monitoring for potential harm, including details on case counting for the purpose of harm monitoring to align with a DSMB analysis plan. | Clarify description for harm monitoring, based on FDA feedback. |
| Title page, Signature page, and header | Updated the protocol version and date. | Reflect the new version and date of the protocol. |
| Synopsis; Section 4.1, General Design; Section 8.1.3, Convalescent Period; Section 11.1, schedules of events, Table 17 | Increased the frequency of telemedicine contacts during the Convalescent Period following the Initial Illness Visit. | Improve the amount and quality of COVID-19 symptom data collected during the Convalescent Period. |
| Synopsis; Section 4.1, General Design; Section 8.1.3, Convalescent Period; Section 8.1.4, Ancillary Supplies for Participant Use; Section 11.1, schedules of events, Table 17 | Added monitoring of oxygen saturation to the Convalescent Period. | Improve surveillance for incidence of COVID-19 during the study. |
| Synopsis; Section 8.1.3, Convalescent Period; Section 8.1.4, Ancillary Supplies for Participant Use; Section 11.1, schedules of events, Table 17 | Increased the frequency of monitoring for SARS-CoV-2, using saliva as the preferred sample matrix after the Illness Visit during the Convalescent Period. | Improve the sensitivity of monitoring the time course of viral shedding during COVID-19. |
| Synopsis; Section 3, Objectives and Endpoints | Added a respiratory sample for hospitalized participants as a matrix for confirming the presence of SARS-CoV-2. | Increase the potential number of evaluable COVID-19 cases. |
| Synopsis; Section 3, Objectives and Endpoints | Broadened the definition for seroconversion at a participant level. | Included neutralizing antibody (nAb) in addition to binding antibody (bAb). |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Section 5 (Study Population) | Added a sentence to describe the intent to enroll a representative sample of racial and ethnic minority participants in the study. | To enhance the diversity of the study population. |
| Section 5.2 (Exclusion Criteria) | Added clarification to exclusion criterion #11 to define the parameters based on screening CD4 count and viral load for exclusion of study participants. | To clarify the definition of controlled HIV disease in the exclusion criterion such that only participants with well-controlled HIV disease are enrolled in the study. |
| Section 5.2 (Exclusion Criteria) | Removed “topical tacrolimus” from exclusion criterion #12. | No evidence to support any systemic effect of topical tacrolimus to warrant excluding them. |
| Section 6.2.1.1 (Stratification) | Added HIV infection to the risk factors at Screening. | To stratify participants based on certain risk factors. |
| Section 8.2.3 (Demographics/Medical History) | Added collection of risk factors for complications of COVID-19. | To document the diagnosis of any risk factor for complications of COVID-19 used for stratification. |
| Section 9.3 (Sample Size Determination) | Removed redundant bullet. | To remove redundancy in the assumptions listed. |
| Section 9.5.2 (Safety Analyses) | Removed safety analysis by serostatus. | No added value for this analysis. Other subgroup analyses may be specified in the SAP, as needed. |
| Section 9.5.5 (Subgroup Analyses) | Removed the categories (white, non-white) from the Race Variable. | To allow for more refined Race categorization being collected in the eCRF. |
| Appendix 11.3 | Removed “cessation of exogenous hormonal therapy”. | To allow postmenopausal women to take these medications if needed for the treatment of the symptoms of menopause. |
| Appendix 11.3 | Removed “using hormonal contraception” from postmenopausal female with high FSH levels. | Not a standard of care for women for treatment of menopausal symptoms. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Section 6.2.1.1 (Stratification) | Increased the upper limit for stratification of enrolled participants considered “at risk” at Screening to up to 50%, from 40%. | To enhance the diversity of the study population by increasing the number of racial and ethnic minority participants in the study. as participants from these communities often have higher rates of comorbidities. |
| Section 9.5.1.1 (Efficacy Analysis on Primary Endpoint) and Section 11.4.1 (Estimands and Estimand Specifications) | Updated the description of an intercurrent event (unrelated death) and its strategy | To align with the description in the Statistical Analysis Plan. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Section 11.1 | Updated Appendix 1 (Tables 16 and 17) . | To clarify the weekly schedule for eDiary prompts through Year 1 and Year 2 of follow-up. |
| Section 11.1 | Added Month 19 Safety Call. | To clarify that participants will have continuous weekly (eDiary prompts) and monthly (safety calls) through Year 1 and Year 2 of follow-up. |
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Section 6.2.1.1 (Stratification) | Increased the upper limit for stratification of enrolled participants considered “at risk” at Screening to up to 50%, from 40%. | To enhance the diversity of the study population by increasing the number of racial and ethnic minority participants in the study. as participants from these communities often have higher rates of comorbidities. |
| Section 9.5.1.1 (Efficacy Analysis on Primary Endpoint) and Section 11.4.1 (Estimands and Estimand Specifications) | Updated the description of an intercurrent event (unrelated death) and its strategy | To align with the description in the Statistical Analysis Plan. |
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Sections 1.1 (Synopsis), 1.2 (Schema), 4.1.2 (Part B, the Open-Label Observational Phase), 6.2.8.1 (Planned Unblinding), 7.3.1 (Participant Withdrawal), and 11.1 (Schedules of Events) | Added a “Participant Decision clinic visit”. | This visit provides the opportunity for study site personnel to discuss with and offer to participants, the choice to be unblinded, as well as offering to participants who originally received placebo, the choice to receive active vaccination with mRNA-1273 and possible vaccination against COVID-19. Participants will also sign a revised informed consent form at this visit. |
| Sections 1.1 (Synopsis), 1.2 (Schema), 4.1 (General Design), 4.2 (Scientific Rationale for Study), 6.2 (Method of Randomly Assigning Participants to Treatment Groups [Part A], Blinded Phase Only), and 11.1 (Schedules of Events) | Changes to study design that split the study into a Blinded Phase and an Open-Label Observational Phase. | These changes accommodate the breaking of the blind and offering of open-label vaccination to all participants. This change also distinguishes the Open-Label Supplemental Schedule of Events (Vaccination Phase) for participants who received placebo, and who meet EUA eligibility, and request to receive active vaccine. |
| Sections 1.1 (Synopsis), 1.2 (Schema), 4.1.2 (Part B, the Open-Label Observational Phase), and 11.1 (Schedules of Events) | Added a Supplemental SoE and a Modified Supplemental SoE. | These provide paths for participants who choose to be unblinded and receive mRNA-1273, and for participants who previously received only 1 dose of blinded mRNA-1273 during the study (Blinded Phase), to transition into the Open-label Phase of the study. |
| Section 2.2.2 (Clinical Studies) | Updated status of ongoing clinical studies, including this study (mRNA-1273-P301). | The status of the 3 clinical studies (one Phase 1, one Phase 2a, and this Phase 3 study) have changed since Amendment 5. In addition, the results of the interim analyses in this study of the primary efficacy endpoint (prevention of COVID-19 infection), a major secondary endpoint (prevention of severe COVID-19), and safety and reactogenicity endpoints are now available and are provided here. These results provide the justification for offering participants the opportunity to receive active IP (mRNA-1273) and the potential benefit of vaccination against COVID-19. |
| Section 1.1 (Synopsis) and 9.5.1.3 (Long-term Efficacy Analysis) | Addition of long-term efficacy analyses. | Allows for the analysis of the long-term efficacy of mRNA-1273 in the following treatment cohorts:
|
| Section 2.3.3 (Overall Benefit/Risk Conclusion) | Updated the Benefit/Risk Assessment. | Based on the interim results from this pivotal Phase 3 study, mRNA-1273 prevents COVID-19 and severe COVID-19. The demonstrated clinical benefit of mRNA-1273 is supported by evidence of a robust immune response both in terms of binding antibodies (bAbs) and neutralizing antibodies (nAbs) as well as the induction of CD4+ T-cells with a Th-1 dominant phenotype. |
| Section 11.1 | Added footnote to Table 16. | To clarify that the eDiary Safety prompts will be triggering off on Day 61 to take into consideration the (-3 day) window allowance on Day 29. |
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Section 11.1 | Updated Appendix 1 (Tables 16 and 17) . | To clarify the weekly schedule for eDiary prompts through Year 1 and Year 2 of follow-up. |
| Section 11.1 | Added Month 19 Safety Call. | To clarify that participants will have continuous weekly (eDiary prompts) and monthly (safety calls) through Year 1 and Year 2 of follow-up. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Sections 1.1 (Synopsis), 6.2.2 (Administration of Investigational Product), 6.2.8.1 (Planned Unblinding) | Clarified that study site personnel who were blinded during the Blinded Phase will be unblinded at the participant level at the Participant Decision clinic visit. | To clarify that the site personnel is being unblinded only at the Participant Decision clinic visit. |
| Sections 1.1 (Synopsis), 4.1.2 (Part B, the Open-Label Observational Phase) | Clarified that with regard to EUA eligibility in Part B, the CDC-EUA guidance specifications will supersede eligibility criteria in the protocol. | To clarify that the CDC-EUA guidance specifications supersede protocol-specified criteria for EUA eligibility in Part B. |
| Section 4.1 (General Design) | Corrected the number of scheduled clinic visits and added mention of the participant decision visit. | To clarify the number of scheduled visits. |
| Section 4.1.2 (Part B, the Open-Label Observational Phase) | Updated text to clarify requirements for Part B subjects who are unblinded and received only 1 dose of mRNA-1273 during Part A. | Clarification of requirements for Part B subjects who received only 1 dose of mRNA-1273 during Part A. |
| Section 6.2.4 (Packaging and Labeling) | Updated to indicate that vaccine product is packaged in a 10R glass vial with a 6-dose, 5.0-mL or 10-dose, 6.3-mL fill volume. | To include IP presentation for additional supplies that may be used in Part B of the study. |
| Section 6.2.5 (Storage) | Updated to specify storage requirements for the 6-dose and 10-dose mRNA vaccine. | To include IP storage conditions for additional supplies that may be used in Part B of the study. |
| Sections 6.4.2 (Concomitant Medications and Therapies), 7.2 (Discontinuation of Study Treatment), 8.2.2 (Use of Electronic Diaries), 8.2.6 (Blood Sampling Volumes, Table 4) | Clarified requirements for Part A and Part B. | Clarification of concomitant medication, eDiary, and blood sampling procedures during Part A and Part B. |
| Section 8.2.2 (Use of Electronic Diaries), Appendix 1 (Schedule of Events, Table 17 footnote 7) | Clarified that eDiary prompts to surveil for weekly COVID-19 symptoms will be performed for all participants in Part A and Part B. Added eDiary prompt to solicit collection of participant history of facial injections or dermal fillers. | Clarification. To assure all concomitant medications are recorded. |
| Section 8.2.4 (Physical Examination) | Removed body mass index from the participant decision visit. | Clarification. |
| Section 8.2.6 (Blood Sampling Volumes) | Updated maximum planned volume of blood collection for the complete study to include a range. | Clarification. |
| Section 8.3.2 (Medically Attended Adverse Events) | Added suspected cases of anaphylaxis as an MAAE and requirement to report as an SAE. | Sponsor collecting anaphylaxis information. |
| Section 9.4 (Analysis Populations, Table 8); Synopsis | Clarified Immunogenicity Subset. | Clarification. |
| Section 9.5.1.1 (Efficacy Analysis on Primary Endpoint), Appendix 4 (Statistical Appendices, Table 23 and Table 24) | Updated intercurrent events and estimands. | Clarification of estimand. |
| Section 9.5.1.3 (Long-term Efficacy Analysis); Synopsis | Updated case count parameters. | Provide long-term efficacy analysis strategy relevant to change in study design. |
| Appendix 1 (Schedule of Events, Table 21 footnote 2, and Table 22 footnote 2) | Updated physical examination to symptom-directed physical examination and removed height and weight requirements from the Open-Label Clinic Visits. | Clarification. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Section 4.1.2 (Part B, the Open-Label Observational Phase) | States that, due to ethical and scientific concerns, all participants will be unblinded once investigational product is no longer available. In addition, the text indicates that if participants want to receive Emergency Use Authorization (EUA) vaccine outside of the study, participants will need to be withdrawn from the study. The amendment also provides directions for unblinding after Biologics License Application (BLA) database lock. | At the time of this amendment, more than 95% of the enrolled participants have completed blinded follow-up, either through being unblinded or study discontinuation. Therefore, there is no scientific value for participants to remain blinded. In addition, non-study EUA vaccines are widely available, so ethically, participants should be unblinded to ensure they can make an informed choice if they wish to receive EUA COVID-19 vaccine outside of the study. |
| Section 8.3.7 (Time Period and Frequency for collecting Adverse Events and Serious Adverse Event Information) and Section 8.3.10 (Reporting Adverse Events) | Reporting of only serious COVID-19 cases within 24 hours to Sponsor or it's designee. | Nonserious COVID-19 cases are an efficacy endpoint, so reporting to Pharmacovigilance is no longer warranted. |
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Section 1.2 (Schema); Section 4.1 (General Design); Section 4.1.3 (Part C, the Booster Dose Phase); Section 4.3 (Choice of Dose and Control Product); Section 5.1.1 (Inclusion Criteria); Section 6.2.2 (Administration of Investigational Product); Section 6.2.4 (Packaging and Labeling); Section 6.2.5 (Storage); Section 8.1.2 (Surveillance for COVID-19 Symptoms); Section 8.1.5 (Immunogenicity Assessments); Section 8.2 (Safety Assessments); Section 8.2.1 (Safety Phone Calls); Section 8.2.6 (Blood Sampling); Section 8.3.6 (Recording and Follow-up of Pregnancy); Section 8.3.7 (Recording and Follow-up of an AE and/or SAE); Section 9 (Statistical Considerations); Section 9.5.1.3 (Long-term Efficacy Analysis); Section 9.5.2.1 (Adverse Events); Section 11.1. (APPENDIX 1: Schedules of Events; Table 23) | Text updated to reflect initiation of Part C, providing for administration of an mRNA-1273 booster dose. | To promote retention of participants in the ongoing study and thereby defend the scientific integrity of the study for the planned 2-year duration of follow-up after completion of the primary vaccination series. |
| Section 2.1 (Study Rationale); Section 2.2.2 (Clinical Studies); Section 2.3.2 (Risks from Study Participation) | Updated the status of ongoing clinical research studies. | To provide context for Protocol Amendment 9. |
| Section 2.3.2 (Risks from Study Participation) | Updated to include no clinical evidence for enhanced vaccine disease from the Phase 3 clinical trial. Also updated to include very rare reports of myocarditis and pericarditis occurring after vaccination with Moderna COVID-19 vaccine. | To provide updated information to the investigators in line with updates made to the IB. |
| Section 3 (Objectives and Endpoints) | Updated to include evaluation of the safety and immunogenicity of a booster dose of mRNA-1273 as exploratory objectives. | To identify objectives related to the initiation of Part C. |
| Section 8.1.1 (Efficacy Assessments Related to COVID-19 and SARS-CoV-2 Infection) | Definition of seroconversion for participants seropositive at Baseline has been deleted. | Seroconversion in participants seropositive at Baseline was not assessed for the Part A Blinded Phase and will not be assessed for Part B or Part C. |
| Section 8.1.2 (Surveillance for COVID-19 Symptoms); Section 11.1 (Appendix 1: Schedules of Events) | Clarified that 2 NP swab samples are collected at Illness Visits. | To enhance consistency of data collection at study sites. |
| Section 8.3.3 (Adverse Events of Special Interest); Section 10 (References); Section 11.5 (Appendix 5: Adverse Events of Special Interest Terms) | Added CDC case definitions for myocarditis and pericarditis, as well as other terms for other potentially relevant adverse events of special interest. | To provide guidance to the investigators regarding assessing and reporting adverse events of special interest, including myocarditis and pericarditis, for this study population. |
| Section 8.4.4 (Independent Cardiac Event Adjudication Committee) | Added Section 8.4.4, Independent Cardiac Event Adjudication Committee. | To describe the proposed mechanism to assess risk of myocarditis and pericarditis in the study population (to address Center for Biologics Evaluation and Research [CBER] request to describe how risk of myocarditis and pericarditis will be assessed in the study population receiving mRNA-1273). |
| Section 8.8 (Exploratory Assessments and Biomarkers) | Text updated to reflect initiation of Part C of the study. | To reflect more comprehensively the current thinking on potential exploratory assessments. |
| Section 9.5.3 (Immunogenicity Analyses) | A definition of seroresponse was added. | To more clearly define the relevant antibody response. |
| Section 11.1 (Appendix 1: Schedules of Events; Table 17 and Table 18) | Adjusted the collection of eDiary data to be weekly from Day 64 through Day 759. | To ensure no gap in eDiary data collection, as they run weekly, regardless of scheduled study site visits or safety calls. |
| Section 11.1 (Appendix 1: Schedules of Events; Table 18) | Reduced the frequency of safety calls from every month after Visit 5 (Month 13) to every 2 months after Visit 5. | To reduce participant burden. COVID-19 and safety surveillance will be maintained through the continued weekly surveillance by eDiary during the second year of the Surveillance Phase. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title Page, Protocol Approval Page, Headers, Protocol Amendment Summary of Changes | Updated the protocol version and date. | To reflect the new version and date of the protocol. |
| Title Page, Protocol Approval Page | Updated Sponsor contact. | To reflect personnel change. |
| Section 1.2 (Schema) | Updated Figure 1 and Figure 2. | To reflect Part C as described elsewhere in the current protocol. |
| Section 1.1 (Synopsis), Section 2.3.2 (Risks from Study Participation), Section 2.3.3 (Overall Benefit/Risk Conclusion), Section 4.1.3 (Part C, the Booster Dose Phase) | Text updated to reflect the current benefit-risk profile of a booster dose of mRNA-1273 based on cumulative evidence. | Additional evidence informing the benefit-risk profile of booster dose from the ongoing Moderna Phase 2a study (mRNA-1273-P201) has become available since the previous amendment. |
| Section 1.1 (Synopsis), Section 2.3.2 (Risks from Study Participation), Section 4.1.3 (Part C, the Booster Dose Phase), Section 4.2 (Scientific Rationale for Study Design) | Updated sections to generally reference variants rather than a specific variant. | To encompass a broad range of emerging variants. |
| Section 1.1 (Synopsis), Section 3 (Objectives and Endpoints), Section 9.5.3 (Immunogenicity Analyses) | For Part C, immunogenicity analysis of BD vaccine response will be performed using the noninferiority tests of the 2 null hypotheses based on the 2 key secondary endpoints: Ab GMT and seroresponse rate at BD-Day 29 in Part C compared with Ab GMT and seroresponse rate at Day 57 (28 days after the second dose of the primary series of mRNA-1273). | To provide immunogenicity analysis plan relevant to the provision of a booster dose in Part C. |
| Section 1.1 (Synopsis), Section 4.1.1 (Part A, the Blinded Phase), Section 8.1.3 (Convalescent Period Starting with the Illness Visit), Section 11.1 (Appendix 1: Schedules of Events, Table 19) | Clarified that the duration of the daily telemedicine visits may extend past the 28-day Convalescent Period. | The Convalescent Period duration as presented in the Schedule of Events is 28 days; however, text was added to clarify that telemedicine visits may occur outside of this window depending on the duration of symptoms. |
| Section 1.1 (Synopsis), Section 4.1.1 (Part A, the Blinded Phase), Section 6.4.2 (Concomitant Medications and Therapies) | Occasional references to parts of the study (eg, “Part A only”) in regard to particular procedures, requirements, or prohibitions have been removed from protocol sections that are specific to the study part and/or where these apply to all parts of the study. | To remove redundancies that did not improve clarity. |
| Section 1.1 (Synopsis) Section 4.1.2 (Part B, the Open-label Observational Phase), Section 4.4 (End of Study Definition), Section 7.2 (Discontinuation of Study Treatment) | Clarified that a participant who did not receive a second dose of IP will have a study follow- up of 25 months after first dose of IP. | To address participants who may not have had the second dose of their original IP assignment following randomization. |
| Section 1.1 (Synopsis), Section 8.2 (Safety Assessments), Section 8.3.3 (Adverse Events of Special Interest), Section 9.5.2.1 (Adverse Events), Section 11.1 (Appendix 1: (Schedules of Events) | Added AESIs as an assessment for Part C (for participants who receive the BD). Removed reference to AESI in Schedule of Events tables specific for Part A and Part B. | To clarify that AESIs will be collected in Part C for participants who receive the BD. |
| Section 1.1 (Synopsis), Section 9.5.2.1 (Adverse Events) | Clarified the analysis sets used for safety analyses. | To clarify which analysis set will be used for specific parts of the study. |
| Section 4.4 (End of Study Definition) | Clarified the timing of the final visit. | To clarify when the final study visit will occur for participants who missed the second dose and for participants who entered Part C and had a BD-3 visit later than Day 759 (Month 25). |
| Section 5.1.2 (Exclusion Criteria) | Removed text specifying “Part A only” for exclusion criteria #4, #6, #11, #13, and #14; added text clarifying that exclusion criterion #10 is applicable to Part A only. | To account for the addition of Part B and Part C to the study, exclusion criteria were updated to reflect applicability of criteria to Part B and Part C. |
| Section 6.3 (Study Treatment Compliance), Section 7.2 (Discontinuation of Study Treatment), Section 7.3.1 (Participant Withdrawal) | Added participants who are withdrawn from the study due to receipt of a non-study primary series or first booster COVID-19 vaccine in addition to participants who withdraw consent. | To clarify statements to cover both types of participant withdrawal. |
| Section 6.4.3 (Concomitant Medications and Vaccines That May Lead to the Elimination of a Participant from Per-protocol Analyses) | Clarified that any non-study COVID-19 may lead to exclusion from the per-protocol analysis in addition to withdrawal from the study (for primary series or first booster only). | To remain consistent with Section 7.3.1 (Participant Withdrawal). |
| Section 7.1 (Criteria for Delay of Study Treatment) | Additional criteria for delay of study treatment added for Part C, including seasonal influenza vaccine and diagnosed COVID-19. | To allow rescheduling of IP dosing in specified situations. |
| Section 8.1.3 (Convalescent Period Starting With the Illness Visit), Section 11.1 (Appendix 1: Schedules of Events, Table 19) | Text added to allow participants who have been asymptomatic for more than 72 hours prior to Day 14 to reduce the frequency of telemedicine calls during the convalescent period. | To provide a reduced telemedicine call burden for the sites and participants when certain criteria are met. |
| Section 9.5.2 (Safety Analyses, Table 12) | Added “Part A” to the table title. | To clarify that this section applies to Part A of the study. |
| Section 9.5.4 (Exploratory Analyses in Part A) | Added “in Part A” to the section title and removed section paragraph specific to Part A, as this is now specified in the title. | To clarify that this section applies to Part A of the study. |
| Section 11.1 (Appendix 1: Schedules of Events, Table 17 and Table 18) | Duration of eDiary collection was corrected to Day 759. | The eDiary collection duration was incorrectly listed in the previous version of the schedules of events. |
| Section 11.1 (Appendix 1: Schedules of Events, Table 18) | Window for safety calls was increased from ±3 days to ±7 days. | The safety call window was increased to allow flexibility for sites and participants. |
| Section 11.1 (Appendix 1: Schedules of Events, Table 18) | Window for Day 759 Visit was changed from ±14 days to -14/+28 days. | The visit window was increased to allow flexibility for the sites and participants. |
| Section 11.1 (Appendix 1: Schedules of Events, Table 23) | Window for BD-3 Visit changed from -3/+14 to ±14 days. | The visit window was increased to allow flexibility for the sites and participants. |
| Section 11.1 (Appendix 1: Schedules of Events, Table 23) | Clarified that not all participants may receive the booster in Part C; added footnote 4 regarding sample collection details for blood for immunologic analysis; clarified that physical examinations and vital sign collection are optional for participants who chose not to receive a BD. Clarified that pregnancy tests at the BD-1 visit are for participants who receive a BD. | Text added for clarity. |
| Section 11.2.6 (Informed Consent Process) | Clarified that participants who are rescreened or rescheduled are not required to re-sign the same version of the ICF if occurring within 28 days from the previous ICF signature date. | Text added for clarity. |
| Section 11.5 (Appendix 5: Adverse Events of Special Interest Terms) | Appendix updated to clarify AESI terms. | Text edited for clarity. |