Moderna’s Phase 2 dose-confirmation study of mRNA-1273 (Spikevax) — approximately 600 adults across two age cohorts (18–54 and ≥55) randomized to placebo, 50 µg, or 100 µg of mRNA-1273 given as two injections 28 days apart. P201 provided the dose-selection rationale (100 µg) for the pivotal COVE Phase 3 trial (P301) and ran in parallel with COVE for safety/immunogenicity follow-up.
Latest protocol we have: 19745_S33_M5_protocol-mrna-1273-p201-amend-3.pdf
| Category | Count | Amendments |
|---|---|---|
| Total documents in the history (Original + amendments) | 4 | |
| Direct PDFs available | 1 | Amendment 3 |
| Summary-only (date and rationale recorded here, no full PDF available) | 3 | Amendments 1, 2; Original Protocol |
| Document | Date | Available documents | Main rationale for the amendment |
|---|---|---|---|
| Original Protocol | 22 Apr 2020 | Summary only — no full PDF of this version available | (no main-rationale paragraph in source) |
| Amendment 1 | 18 May 2020 | Summary only — no full PDF of this version available | The main purpose of this amendment was to incorporate the following modifications requested by the FDA Center for Biologics Evaluation and Research:
|
| Amendment 2 | 01 Jul 2020 | Summary only — no full PDF of this version available | The main purpose of this amendment was to change the statistical analysis plan by removing interim analyses and defining the Primary Study Analysis and End of Study Analysis. The summary of changes table 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. |
| Amendment 3 | 02 Sep 2020 | 19745_S33_M5_protocol-mrna-1273-p201-amend-3.pdfSource ZIP19745_S33_M5_protocol-mrna-1273-p201-amend-3-trk.pdfSource ZIP | The main purpose of this amendment is to clarify that data can be analyzed in multiple batches based on availability of participants who have reached the Day 57 visit. The summary of changes table 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. |
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 protocol version and date. | Revised version and date of protocol. |
| Title page, Signature page, and header | Updated the protocol title. | Revised to reflect the current purpose of the study. |
| Synopsis and Section 2.3 Exploratory Objectives | Added an exploratory objective to evaluate the effect of the mRNA-1273 vaccine on the incidence of SARS-CoV-2 infection. | Request from the Health Authority. |
| Synopsis, Section 2.3 Exploratory Objectives, Section 4.3.3 Exploratory Endpoints, Section 4.6.4 Exploratory Analyses | Revised wording for the exploratory objective/endpoint regarding spike protein-specific serum immunoglobulin class and subclass and neutralizing antibody in serum | Editorial change. |
| Synopsis, Section 3.1 Study Design, Study Flow Schema (Figure 1), Sentinel and Expansion Cohort Schema (Figure 2), Section 3.1.1 Rationale for Dose Selection, 3.4.1 Method of Assigning Participants to Dosing Groups. Dose Group Assignment (Table 1), 3.4.2 Investigational Product Administration, 4.5 Sample Size Determination | Decreased the highest dose of mRNA-1273 in the study from 250 µg to 100 µg. | Decreased based on the preliminary findings of the Phase 1 DMID study. |
| Synopsis and Section 3.1 Study Design | Deleted collection of nasopharyngeal swab samples at the Screening Visit (Day 0). | Editorial update for consistency with Schedule of Events (Table 7). |
| Synopsis and Section 3.1 Study Design | Deleted the number of visits at which participants will have blood samples collected. | Editorial update to avoid confusion as blood samples will be collected at different visits for safety and vaccine immunogenicity assessments. |
| Synopsis; Section 3.1 Study Design, Section 3.5.6 Blood Sampling Volumes (Table 3), Section 3.5.7 Safety Assessments, Section 3.5.8.6 Eliciting and Documenting Adverse Events, Section 4.3.1.2 Primary Immunogenicity Endpoint, Section 4.3.2 Secondary Endpoints, Section 4.7 Interim Analyses, Section 6.4 Clinical Study Reports, and Section 7.1 Appendix 1: Schedule of Events (Table 7) | Updated Month 7 and Month 13 visits to Day 209 and Day 394, respectively, to allow for 6-month and 12-month intervals, respectively, after the second injection on Day 29 (Month 1). | Request from the Health Authority. |
| Synopsis, Section 3.1 Study Design, and Section 7.1 Appendix 1: Schedule of Events (Table 7) | Updated the biweekly safety telephone calls from Day 211 through Day 351 to Day 223 through Day 377. | Consequent to the change made to the Day 209 Visit (Request from the Health Authority). |
| Synopsis, Section 3.1 Study Design, Section 3.1.2 Rationale for Study Design, Section 3.5.1 Assessment for SARS-CoV-2 Infection, and Section 7.1 Appendix 1: Schedule of Events (Table 7) | Updated nasal swab to nasopharyngeal swab. | Clarified the type of swab to be performed. |
| Section 3.1.1 Rationale for Dose Selection | Updated enrollment and preliminary safety data from the ongoing Phase 1 DMID study. | Updated based on the preliminary findings of the Phase 1 DMID study. |
| Section 3.2.1 Inclusion Criteria | Updated inclusion criterion #7 to exclude sperm donations through 3 months after the last injection. | Update to align with the informed consent form on refraining male participants from sperm donation through 3 months after the last injection based on IRB feedback to the ICF. |
| Section 3.3.2 Handling Withdrawal From the Study | Updated the scheduled end of study assessments at Day 394 (Month 13) to allow for a 12-month interval after the second vaccination on Day 29 (Month 1). | Request from the Health Authority. |
| Section 3.4.5 Blinding | Updated the method to maintain the blind of the dosing assignment from opaque sleeve to blinding label. | Operational change in cases for which opaque sleeves are not used. |
| Section 3.5.1 Assessment for SARS-CoV-2 Infection |
| Request from the Health Authority. |
| Section 3.5.1 Assessment for SARS-CoV-2 Infection and Section 3.5.8.2 Medically Attended Adverse Event | Deleted “or COVID-19.” | Editorial update for internal consistency. |
| Section 4.3.3 Exploratory Endpoints | Included a new exploratory endpoint to evaluate the effect of the mRNA-1273 vaccine on the incidence of SARS-CoV-2 infection. | Request from the Health Authority. |
| Section 7.1 Appendix 1: Schedule of Events (Table 7) | Deleted that Day 0 and Day 1 visits may be combined the same day. | Editorial update of template text, which did not apply to this protocol. |
| Corrected sequential footnote numbering in the schedule of events (Table 7). | Editorial update. | |
| Included a header row titled “Days Since Most Recent Vaccination.” | Update to clarify that the visits are relative to the most recent injection. |
| 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 3.1 Study Design, Section 3.5.2 Use of Electronic Diaries, Section 3.5.3 Safety Telephone Calls, Section 7.1 Appendix 1: Schedule of Events (including text, Table 7, and footnotes to Table 7) | Added eDiary questionnaires to the procedure for safety follow-up after the Day 57 visit, with completion of eDiary questionnaires alternating with safety telephone calls approximately every 2 weeks after the Day 57 visit. | Reduce the burden on study site personnel of completing safety follow-up by telephone. |
| Synopsis, Section 3.1 Study Design, Section 3.5.3 Safety Telephone Calls, Section 7.1 Appendix 1: Schedule of Events (footnote 12) | Added exposure to someone with known COVID-19 or SARS-CoV-2 infection and participant experience of COVID-19 symptoms to the list of events queried during scheduled safety telephone calls. | Improve surveillance for incidence of COVID-19 during the study. |
| Synopsis, Section 3.1 Study Design | End of Study definition was amended. | Minor clarification to define the End of Study. |
| Synopsis, Section 3.4.5 Blinding, Section 4.1 Blinding and Responsibility for Analyses, Section 4.7 Study Analyses, Section 4.7.1 Primary Study Analysis, Section 4.7.2 End of Study Analysis, Section 6.4 Clinical Study Reports | Added descriptions of the Primary Study Analysis and End of Study Analysis and respective clinical study reports, replacing descriptions of interim analyses and reports. The synopsis contains a new section. | Eliminate interim analyses in favor of a focus on the primary analysis. |
| Synopsis, Section 4.6 Statistical Methods | Stated that all analyses will be performed by treatment group overall (for the 2 cohorts combined) and for the 2 cohorts separately, unless specified otherwise. | Previous versions of the protocol had not included the overall analysis in statement of the standard scope of analysis. |
| Synopsis, Section 4.6.3 Immunogenicity Analyses | For the primary immunogenicity endpoint, geometric mean titer was changed to geometric mean. | Assays for bAb are under development. The reported values may or may not be titers; hence the protocol wording has been modified. |
| Section 3.5.1 Assessment for SARS-CoV-2 Infection | Added instructions for asymptomatic patients who have a confirmed SARS-CoV-2 infection. | To clarify the steps for the investigator to follow when a participant is confirmed to have SARS-CoV-2 infection but is asymptomatic. |
| Section 3.5.8.8 Assessment of Severity | Decoupled life-threatening and Grade 4 in the severity assessment. | To adhere to CDISC guidance and align with case report form page. |
| Section 3.5.8.8 Assessment of Severity | Added clarification on when an AE is defined as serious. | To clarify when an AE is defined as serious. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Title page, Signature page, Synopsis, and header | Updated the protocol version and date | Reflect the new version and date of the protocol. |
| Synopsis, Section 3.1 Study Design | Deleted repeated text about Safety Monitoring Committee review before expansion in Cohort 2. | Editorial removal of redundant text. |
| Synopsis, Section 3.4.5 Blinding, Section 4.1 Blinding and Responsibility for Analyses, Section 4.7.1 Primary Study Analysis | Added information about potential participant populations to be included in the primary analysis of safety and immunogenicity after completion of Day 57 procedures. | Clarification that data can be analyzed in multiple batches based on availability of participants who have reached the Day 57 visit. |
| Synopsis, Section 4.6.2 Safety Analyses | Revisions to clarify that separate summaries of Grade 3 or higher solicited ARs are not planned. | Clarification of planned safety analyses. |
| Section 3.5.2 Use of Electronic Diaries, Section 7.1 Appendix 1: Schedule of Events (Table 7) | Added clarification about site follow-up of relevant safety events from eDiary entries (includes revisions to Footnote 12). | Clarification that follow-up by telephone of relevant safety events from eDiary entries is not the same as scheduled safety follow-up telephone calls. |
| Section 7.1 Appendix 1: Schedule of Events (Table 7) | The acceptable window around the Day 29 visit has been clarified as + 7 days with no negative visit window. | Correction to reflect the minimum interval between vaccine administrations of 28 days. |
| Section 7.1 Appendix 1: Schedule of Events (Table 7) | The footnotes and footnote numbering have been updated to accommodate the footnotes that were added with Amendment 2. | Editorial clarification. |
| Section 7.1 Appendix 1: Schedule of Events (Table 7) | Footnote 4 has been revised to clarify that study days for safety follow-up are relative to Day 1 vaccine administration. | Editorial clarification. |
| Section 7.1 Appendix 1: Schedule of Events (Table 7) | Footnote 5 has been revised to explain how to handle potential visit window overlap related to Visit 8. | Editorial clarification. |
| Section 7.1 Appendix 1: Schedule of Events (Table 7) | Footnote 10 has been revised to clarify the timing of nasopharyngeal swab samples on vaccination days. | Editorial clarification. |