Sections

Description of change and Rationale for change

Item 1

Revised in Section 1, Overview; Section 2, Background; Section ;
Section 3, Objectives and Endpoints; Section 6, Statistical
considerations; Section 9, Clinical procedures; Appendix B, Laboratory
procedures table for Groups 1 and 3 (SARS-CoV-2 seronegative
participants, main study), Appendix C, Laboratory procedures table for
Groups 2 and 4 (SARS-CoV-2 seropositive participants, main study),
Appendix D, Laboratory procedures for PBMC immunogenicity subset,
Groups 1 and 3; Appendix E, Laboratory procedures for PBMC
immunogenicity subset, Groups 2 and 4; Appendix F, Laboratory
procedures for the PBMC immunogenicity correlates (Group 1, HIV
positive, SARS-CoV-2 seronegative participants); Appendix G,
Laboratory procedures for the PBMC immunogenicity correlates (Group
2, HIV positive, SARS-CoV-2 seropositive participants); Appendix H,
Schedule of clinic procedures for Groups 1 and 3 (SARS-CoV-2
seronegative participants); Appendix I, Schedule of clinic procedures
for Groups 2 and 4 (SARS-CoV-2 seropositive participants), Appendix J,
COVID-19 symptom visits; Appendix K, Visit windows and Appendix M,
Addendum 2 to the sample informed consent form (SICF): harmonizing
protocol language with the changed study focus

The study leadership and the study sponsor are revising the current study plan to: 1)
Continue follow up only of participants who received mRNA-1273 vs mRNA-
1273.222 at Month 6 and/or who are considered to be at risk for prolonged SARSCoV-2 infections, and 2) Improve surveillance of subclinical infections.
The rational for the change in study focus is based on the fact that key pre-Month 6
study goals have been achieved (as outlined above) and that monovalent mRNA
vaccines are not likely to be commercially available moving forward.
Revisions have been made throughout the protocol to align with the changed focus of
the study. Specific sections of the protocol that have been revised are listed below.

Revised in Section 1

• Subsection ‘Study product, route of administration and regimen’ was revised
  to update number of people in America that have received the bivalent
  Moderna vaccine. Language was added to the last paragraph to provide
  information about the current study design regarding follow-up of participants
  after their Month 6 vaccination.
  • Duration per participant and estimated total study duration were updated to
  harmonize with the current study design.
  • Bioinformatico was added to the list of organizations that are a part of the
  Statistical and Data Management Center (SDMC)

Revised in Section 2, Section 9 and Appendices B, C, D, E, F, G, H, K:

• Added in Section 2.1, Rationale for Trial Concept: new paragraph # 7 with
subheading ‘Modifying the final phase of the study based on findings from
interim analyses’ to include information about the observations from interim
analysis and a succinct study plan for the post-Month 6 phase of the study.
• Revised in Section 2.1.1, Overall study design: paragraph #4 to provide
information on participant follow up after the Month 6 vaccination as per the
current study design. Deleted language in paragraph #6 specifying that
participants vaccinated at Month 6 under protocol version 5.0 will continue to
be followed. Paragraph #9 was revised to reflect the post-diagnosis schedule
for symptomatic participants as per the current study design.
• Added in Section 2.2.2, Rationale for the safety approach in this study: in
paragraph #2, provided latest information on mRNA1273.222 vaccine safety.
• Throughout Section 2, duration of participant follow up was changed from 18
months to 12 months to harmonize with the current study design.
• Section 9.4, and Section 9.6 were updated to reflect the current study design,
as explained in Section 2.
o Nasal swabs (Bullet #4) were added to the follow-up procedures
(Section 9.4).
o Figure 9-1 was updated to reflect the current study design.
o In Section 9.6, a post-diagnosis Day 56 visit was added for participants
who have a positive SARS-CoV-2 NAAT test on their Day 42 visit.
We also added language specifying the follow-up of these participants.
• The laboratory procedure tables in Appendix B, Appendix C, Appendix D,
Appendix E, Appendix F, Appendix G, Appendix J and Appendix K, were
updated to harmonize with the revised Section 9.4, and Section 9.6. New cut-off date: 04 October 2022. Updated to reflect the changes in the content of the nonclinical and clinical parts of the IB. See details below.

Updated in Section 3

Language in paragraph #1 was revised for clarity and to emphasize that the
endpoints for the first two primary objectives will be counted starting 14 days after
the last pre-M6 dose until the Month 6 dose

Revised in Section 6:

• Revised Section 6.1, Summary of statistical design, for clarity and updated
Table 6-1 to harmonize with the revised Section 6.1.

• Confirmed in section 6.3.1, Power calculations for coprimary objectives 1-4
(Efficacy), that based on data as of January 2023, we expect 4200 participants
from Groups 1-4 to receive their Month 6 vaccinations. Added language
acknowledging that the actual the sample sizes of the PLWH hybrid immunity
group who receive 1 pre-Month 6 dose and the PLWH pure vaccine group
who receive 2 pre-Month 6 doses are likely smaller than the sample sizes of
Groups 1 and 2, respectively.
• Revised table 6-2 to reflect power calculations to detect relative risk between
months 6.5 to 12.
• Deleted language in Section 6.4, Statistical analyses, to clarify that no formal
multiple-comparison adjustments will be employed for multiple safety
endpoints or multiple efficacy endpoints and there will be no exceptions to
this.
• Clarified in Section 6.4.3, Analysis of relative risk between treatment arms,
paragraph #1, considerations for the time of endpoint diagnosis (COVID-19
and severe COVID-19) for COVE based and CDC based definitions of
endpoints. Also revised language in paragraphs #5 and #6 for clarity and to
harmonize with the current focus of the study post Month 6.
• Revised in Section 6.6, Section title was changed to ‘Final analyses timing’,
to better reflect the current phase of the study. The section was also revised to
clarify final analyses of study objectives in the pre-Month 6 and the post
Month 6 stages.
• Throughout Section 6, all assessments/analyses specifying Month 18 was
updated to Month 12, to harmonize with the current study plan.

Added new Appendix M.

A new addendum to the SICF #2 was added to the existing addendum to the SICF to
provide information to the participants about the changes made to the study plan and
procedures under the current version.

Item 2

Revised in in Section 1, Overview; Section 3, Objectives and endpoints;
Section 6.4.3, Analysis of relative risk between treatment arms:
definitions to be considered for COVID-19

It has become clear that over past year that a significant number of SARS-CoV-2
infections are mildly symptomatic and therefore the symptom-driven testing as
specified in Version 6 of the protocol may be insensitive for identifying mildly
symptomatic infections. For this reason, we are adopting the CDC-derived criteria as
an additional approach for identifying cases of symptomatic COVID-19 as it allows
us to better capture mild COVID-19. The CDC criteria can be applied without
adjudication by the Endpoint Adjudication Committee (EAC). The EAC will continue to adjudicate endpoints based on the COVE criteria. Separate analyses will be done
using each approach to endpoint ascertainment.
The following sections of the protocol have been revised to reflect this:
• Removed in Section 1, under ‘Study monitoring’ that EAC will adjudicate
COVID-19 diagnoses since this will depend on criteria, and the EAC is not really
a “study monitoring” body, per se, so inclusion in this section is not appropriate.
• We have clarified in Section 3, paragraph #1 that COVID-19 endpoints will be
evaluated using both the COVE as well as the CDC-derived criteria. We have also
revised the Primary Objectives and endpoints table and the associated footnotes to
harmonize with both the definitions.
• Section 6.4.3, paragraph #1 has been revised to clarify that coprimary objectives
will be assessed separately using the two approaches for identifying cases of
symptomatic COVID-19.

Item 3

Revised in Section 2, Background; Section 3, Objectives and endpoints
and Section 6, Statistical considerations: roles of the DSMB, OG and the
EAC; and Section 11, Safety monitoring and safety review

The study is approaching its final phase and the safety of the study vaccines at this
point has been well characterized. The Oversight Group (OG) has primary
responsible for safeguarding the interests of clinical trial participants and for
enhancing the integrity of the trial; the NIAID HIV Data Safety Monitoring Board
(DSMB) may or may not continue to hold meetings.
The following sections of the protocol have been revised to represent the change in
responsibilities of these committees:
• Clarified in Section 2.1.1, Overall study design, paragraph #9 that either DSMB
or OG can make recommendations to adjust the course of the study to protect the
safety and wellbeing of participants.
• In Section 6.4.4, Safety/Tolerability analyses: clarified that DSMB will prepare
analyses of safety data for as long as it is involved in the trial.
• In Section 6.5, Operational Monitoring for Quality Trial Conduct: revised
language to clarify that the OG is primarily responsible for the integrity of the
trial conduct.
• In Section 6.7, Roles of DSMB, OG and EAC: Revised language to specify the
changes in the responsibilities of these committees.

• In Section 11.1.2, NIAID Data and Safety Monitoring Board (DSMB): clarified that
DSMB is responsible for study integrity and participant safety for as long as it is
involved in the trial.
• In Section 11.3.1, Prompt PSRT AE review: paragraph #6, clarified that in case
there is a study pause, the OG (not the DSMB) will be notified. Also clarified in
paragraph #7, that the PSRT will consult with the OG (not the DSMB), if needed,
in case of a trial pause.

Item 4

Clarified in Section 9.4, Follow-up procedures: change in antiretroviral
medication

Since there is a possibility that participants can exit the study within 4 weeks after
changing their retroviral therapy, we clarified in bullet #9 that the study site may
follow such individuals even after they exit the study.

Item 5

Clarified in Section 9.11, Early termination visit: operational guidance for
early study termination

The language in Section 9.11 was revised to clarify that the study sites should follow
operational guidance from the CoVPN3008 protocol team in the event of early study
termination for a participant as such a guidance was missing in the earlier versions.

Item 6

Clarified in Section 9.12, Pregnancy: documentation of pregnancy
outcome

Paragraph #2 in Section 9.12 was revised for clarity and to emphasize that the study
sites should try their best to remain in touch with a pregnant participant who exits the
study before pregnancy outcome is known and document the outcome in a case report
form.

Item 7

Updated in Section 11.2, 2, AE reporting: weblink for the CoVPN
Member’s site

Item 8

Clarified in Section 11.2.5, Reporting of AEs to pertinent national
regulatory authorities and Section 12, Protocol conduct: reference
documents mentioned in these sections refer to CoVPN3008 reference
documents

Item 9

Updated in Title page; Section 13, Version history and Section 16,
Literature cited: Contents of this amendment

Item 10

Corrected throughout the Protocol: Minor errors in grammar,
typography, formatting

Item 11

Updated throughout the Protocol: Section numbering and crossreferences

.

Item 12

Updated per Protocol Version 6.0, Clarification Memo 1, dated October
05, 2022