A Phase 2 Randomized, Observer-Blind, Placebo-Controlled Study to Assess the Safety, Reactogenicity, and Immunogenicity of the SARS CoV-2 Vaccine ARCT-021 in Healthy Adult Participants
Phase: PHASE2
Conditions: Covid19, SARS-CoV Infection, Corona Virus Infection
Sponsor: Arcturus Therapeutics, Inc.

CLINICAL STUDY PROTOCOL 
A PHASE 2 RANDOMIZED, OBSERVER-BLIND, PLACEBO-
CONTROLLED STUDY TO ASSESS THE SAFETY, REACTOGENICITY, 
AND IMMUNOGENICITY OF THE SARS-COV-2 VACCINE ARCT-021 IN 
HEALTHY ADULT PARTICIPANTS 
Protocol No. ARCT-021-04 
Sponsor: 
Arcturus Therapeutics, Inc. 
10628 Science Center Dr #250 
San Diego, CA 92121 
Sponsor Contact: 
 
Telephone: 
 
Safety: 
24 Hour Safety Hotline 
North America:
 
EMEA/APAC: 
 
24 Hour Safety Hotline Fax 
North America: 
 
EMEA/APAC: 
 
Version of Protocol: 
6.0 
Date of Protocol 
Amendment 5.0: 
09 March 2022 
Previous Versions: 
5.1 (Amendment 4.1), 02 August 2021 
5.0 (Amendment 4), 16 July 2021 
4.0 (Amendment 3), 17 June 2021 
3.1 (Amendment 2.1), Singapore only, 29 July 2021 
3.0 (Amendment 2), 26 February 2021 
2.1 (Amendment 1.1), 19 January 2021 
2.0 (Amendment 1), 17 January 2021 
1.0 (Original Protocol), 19 November 2020 
Compound Name(s): 
ARCT-021, ARCT-154, ARCT-165 
Study Phase: 
2 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R2): Good Clinical Practice 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Arcturus Therapeutics, Inc. This document 
contains information that is confidential, proprietary, and/or under the control of Arcturus Therapeutics, Inc. The 
information is only to be used in connection with authorized clinical studies of the investigational drug described in 
the protocol provided herewith. You may disclose the contents of this document while acting in the capacity of an 
Investigator, potential Investigator, or consultant to study personnel under your supervision and/or to an applicable 
Institutional Review Board or Independent Ethics Committee who need to know the contents for the aforementioned 
purpose and who have been advised of the confidential nature of the document. You may not disclose any of the 
information to others without written authorization from Arcturus Therapeutics, Inc. except to the extent necessary 
to obtain informed consent from those persons to whom the drug may be administered. 
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NCT #: NCT04668339

Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
2 
Confidential 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 2 Randomized, Observer-Blind, Placebo-Controlled Study to 
Assess the Safety, Reactogenicity, and Immunogenicity of the SARS 
CoV-2 Vaccine ARCT-021 in Healthy Adult Participants 
Protocol Number 
ARCT-021-04 
Protocol Date 
and Version 
Protocol Amendment 5.0 (Version 6.0), 09 March 2022 
 
Protocol accepted and approved by: 
Arcturus Therapeutics, Inc 
10628 Science Center Dr #250 
San Diego, CA 92121 
 
 
 
Date 
 
DocuSign Envelope ID: DAFB0B1B-331C-4703-9469-37DC275C6B41
3/9/2022

Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
3 
Confidential 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 2 Randomized, 
Observer-Blind, Placebo-Controlled Study to Assess the Safety, Reactogenicity, and 
Immunogenicity of the SARS-CoV-2 Vaccine ARCT-021 in Adult Participants” and the 
accompanying Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with ethical principles that have their origin in the Declaration of Helsinki, the 
International Council for Harmonisation harmonised tripartite guideline E6(R2): Good Clinical 
Practice, the Protocol Version 6.0, dated 09 March 2022, and all applicable government 
regulations. I will not make changes to the protocol before consulting with Arcturus 
Therapeutics, Inc. or implement protocol changes without independent ethics committee 
approval except to eliminate an immediate risk to participants. I agree to administer study 
treatment only to participants under my personal supervision or the supervision of a 
subinvestigator. 
I will not supply the study vaccine to any person not authorized to receive it. Confidentiality will 
be protected. Participant identity will not be disclosed to third parties or appear in any study 
reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Arcturus Therapeutics, Inc. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
4 
Confidential 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ................................................................................1 
TABLE OF CONTENTS ...............................................................................................4 
LIST OF TABLES .........................................................................................................9 
LIST OF FIGURES .......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................10 
LIST OF ABBREVIATIONS ......................................................................................30 
1 
INTRODUCTION ...........................................................................................33 
1.1 
Background ...................................................................................................33 
1.2 
Current Therapies for COVID-19 .................................................................33 
1.3 
Therapeutic Rationale for LUNAR-COV19 Vaccines in Prevention of 
COVID-19 ....................................................................................................34 
1.4 
Mechanism of Action ....................................................................................34 
1.5 
Clinical Trial Experience with ARCT-021, ARCT-154 and ARCT-165 .....36 
1.6 
Rationale for Dose Regimen Selection .........................................................38 
1.7 
Risk Benefit Assessment...............................................................................38 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................43 
2.1 
Primary Objectives and Endpoints................................................................43 
2.2 
Secondary Objectives and Endpoints............................................................44 
2.3 
Exploratory Objectives and Endpoints .........................................................44 
3 
INVESTIGATIONAL PLAN ..........................................................................47 
3.1 
Study Design .................................................................................................47 
3.1.1 
Rationale for Study Design ........................................................................48 
4 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA ...............50 
4.1 
Selection of Study Participants .....................................................................50 
4.1.1 
Inclusion Criteria .......................................................................................50 
4.1.2 
Exclusion Criteria ......................................................................................50 
4.1.3 
Screen Failures ...........................................................................................53 
4.2 
Delaying or Discontinuing Study Treatment and Participant Withdrawal 
From the Study..............................................................................................54 
4.2.1 
Delay in Study Treatment ..........................................................................54 
4.2.2 
Discontinuation of Study Vaccine (Participant) ........................................54 
4.2.3 
Withdrawal/Discontinuation From Study ..................................................55 
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Protocol ARCT-021-04, Version 6.0 
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4.2.4 
Discontinuation of Study Dosing (All Participants) ..................................57 
4.2.5 
Pausing Rules .............................................................................................57 
4.2.6 
Lost to Follow-Up ......................................................................................58 
4.2.7 
Replacements .............................................................................................58 
5 
STUDY TREATMENTS .................................................................................59 
5.1 
Method of Assigning Participants to Study Groups .....................................59 
5.2 
Treatments Administered ..............................................................................60 
5.3 
Identity of Study Vaccine .............................................................................61 
5.4 
Preparation of Study Vaccine .......................................................................61 
5.4.1 
Preparation of ARCT-021 liquid presentation for priming vaccinations: .61 
5.4.2 
LUNAR-COV19 vaccines (ARCT-021, ARCT-154, ARCT-165) 
lyophilized presentation for booster administration ..................................62 
5.5 
Management of Clinical Supplies .................................................................62 
5.5.1 
Study Vaccine Packaging and Storage ......................................................62 
5.5.2 
Study Vaccine Accountability ...................................................................62 
5.5.3 
Other Supplies for Participant Use ............................................................63 
5.6 
Overdose Management .................................................................................63 
5.7 
Medication Errors .........................................................................................63 
5.7.1 
Treatment of Medication Errors.................................................................63 
5.8 
Blinding.........................................................................................................63 
5.8.1 
Breaking the Blind .....................................................................................65 
5.9 
Compliance With Study Treatment ..............................................................66 
5.10 
Concomitant and Rescue Therapies and Procedures ....................................66 
5.10.1 
Concomitant Therapy.................................................................................66 
5.10.2 
Prohibited Concomitant Therapy ...............................................................66 
5.10.2.1 
Concomitant Procedures .........................................................................67 
5.10.3 
Rescue Medicine ........................................................................................67 
5.11 
Dose Modification ........................................................................................67 
6 
STUDY ASSESSMENTS AND PROCEDURES ...........................................69 
6.1 
Evaluation of Participants With Suspected COVID-19 ................................72 
6.2 
Efficacy Assessments....................................................................................74 
6.3 
Immunogenicity Assessments .......................................................................74 
6.4 
Safety Assessments .......................................................................................75 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
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6.4.1 
Adverse Events ..........................................................................................75 
6.4.1.1 
Definitions...............................................................................................75 
6.4.1.2 
Eliciting and Documenting Adverse Events ...........................................77 
6.4.1.3 
Reporting Adverse Events ......................................................................79 
6.4.1.4 
Follow-Up of Participants Reporting Adverse Events............................81 
6.4.2 
Reporting of Clinical Events of Special Interest........................................81 
6.4.3 
Clinical Safety Laboratory Assessments ...................................................82 
6.4.4 
Physical Examinations ...............................................................................82 
6.4.5 
Vital Signs, Body Temperature, Pulse Oximetry.......................................83 
6.5 
Pregnancy ......................................................................................................83 
6.6 
Surveillance for SARS-CoV-2 Infection ......................................................84 
7 
STATISTICAL CONSIDERATIONS.............................................................85 
7.1 
Estimands and Intercurrent Events ...............................................................85 
7.2 
Statistical Hypothesis ....................................................................................88 
7.3 
Sample Size Determination...........................................................................88 
7.4 
Analysis Sets .................................................................................................89 
7.5 
Description of Subgroups to Be Analyzed....................................................90 
7.6 
Statistical Analysis Methodology .................................................................90 
7.6.1 
General Considerations ..............................................................................90 
7.6.2 
Overview of Statistical Methods: Estimation of Estimands and Sensitivity 
Analyses .....................................................................................................91 
7.6.3 
Analysis of Primary Safety Endpoints .......................................................95 
7.6.3.1 
Main Estimation of Safety Endpoint (Estimand 1) .................................95 
7.6.3.2 
Supportive Analysis of Primary Safety Endpoint (Estimand 1) .............95 
7.6.4 
Analysis of Primary and Secondary Immunogenicity Endpoints ..............95 
7.6.4.1 
Analysis of Immunogenicity Endpoint (GMT/GMC and GMR) 
(Estimand 2) ............................................................................................95 
7.6.4.2 
Rise/Seroconversion Endpoint (Estimand 3) ..........................................96 
7.6.5 
Analysis of Exploratory Endpoints ............................................................96 
7.6.6 
Other Analyses ...........................................................................................97 
7.6.7 
Data Analyses from Re-Enrolled Participants ...........................................97 
7.7 
Handling of Missing Data .............................................................................97 
7.8 
Interim Analyses ...........................................................................................97 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
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7.9 
Independent Data Safety Monitoring Committee .........................................98 
8 
DATA QUALITY ASSURANCE ...................................................................99 
8.1 
Data Management .........................................................................................99 
8.2 
Data Disclosure ...........................................................................................100 
9 
ETHICS..........................................................................................................101 
9.1 
Independent Ethics Committee or Institutional Review Board ..................101 
9.2 
Ethical Conduct of the Study ......................................................................101 
9.3 
Participant Information and Consent ..........................................................101 
10 
INVESTIGATOR’S OBLIGATIONS ...........................................................103 
10.1 
Confidentiality ............................................................................................103 
10.2 
Data Protection............................................................................................103 
10.3 
Data Sharing................................................................................................104 
10.4 
Financial Disclosure and Obligations .........................................................104 
10.5 
Investigator Documentation ........................................................................104 
10.6 
Study Conduct .............................................................................................104 
10.7 
Adverse Events and Study Report Requirements .......................................104 
10.8 
Investigator’s Final Report .........................................................................104 
10.9 
Records Retention .......................................................................................104 
10.10 
Publications and Results Disclosures..........................................................105 
11 
STUDY MANAGEMENT ............................................................................106 
11.1 
Monitoring ..................................................................................................106 
11.1.1 
Monitoring of the Study ...........................................................................106 
11.1.2 
Inspection of Records ..............................................................................106 
11.2 
Management of Protocol Amendments and Deviations .............................106 
11.2.1 
Modification of the Protocol ....................................................................106 
11.2.2 
Protocol Deviations ..................................................................................106 
11.3 
Study Termination ......................................................................................107 
11.4 
Final Report ................................................................................................107 
12 
REFERENCES ..............................................................................................108 
13 
APPENDICES ...............................................................................................115 
13.1 
Appendix 1: Schedule of Events .................................................................116 
13.2 
Appendix 2: Clinical Laboratory Tests .......................................................122 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
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13.3 
Appendix 3: Contraceptive Guidance .........................................................123 
13.4 
Appendix 4: FDA Toxicity Grading Scales ................................................126 
13.5 
Appendix 5: Protocol Amendments ............................................................130 
13.5.1 
Protocol Amendment 1 (Version 2.0, 17 January 2021): Summary of 
Major Changes .........................................................................................130 
13.5.2 
Protocol Amendment 1.1 (Version 2.1, 19 January 2021): Summary of 
Major Changes .........................................................................................135 
13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes .........................................................................................135 
13.5.4 
Protocol Amendment 2.1 (Version 3.1, 29 July 2021, Singapore only): 
Summary of Major Changes ....................................................................143 
13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes ....................................................................................................143 
13.5.6 
Protocol Amendment 4 (Version 5.0, 16 July 2021): Summary of Major 
Changes ....................................................................................................150 
13.5.7 
Protocol Amendment 4.1 (Version 5.1, 02 August 2021): Summary of 
Major Changes .........................................................................................150 
13.5.8 
Protocol Amendment 5.0 (Version 6.0, 09 March 2022): Summary of 
Major Changes .........................................................................................152 
 
 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
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LIST OF TABLES 
Synopsis Table 1-1 
Study Group Assignments .......................................................16 
Table 1-1 
Risk Minimization Measures Included in Clinical Trials of 
LUNAR-COV19 Vaccines ..................................................................40 
Table 2-1 
Primary Objectives and Endpoints.......................................................43 
Table 2-2 
Secondary Objectives and Endpoints...................................................44 
Table 2-3 
Exploratory Objectives, and Endpoints ...............................................44 
Table 7-1 
Intercurrent Event Types......................................................................85 
Table 7-2 
Primary Safety and Immunogenicity Estimands With Rationale and 
Strategies to Address Intercurrent Events ............................................86 
Table 7-3 
Probability to Detect at Least One Adverse Event by Incidence Rate of 
Event and Sample Size.........................................................................89 
Table 7-4 
Summary of Statistical Methods and Supportive Analyses .................92 
Table 13-1 
Schedule of Events: Priming Vaccinations ........................................116 
Table 13-2 
Schedule of Events: Booster Vaccination ..........................................120 
Table 13-3 
Schedule of Clinical Laboratory Tests ...............................................122 
Table 13-4 
Toxicity Grading for Solicited Adverse Events .................................126 
Table 13-5 
Toxicity Grading for Vital Signs .......................................................127 
Table 13-6 
Toxicity Grading for Safety Laboratory Assessments .......................128 
 
LIST OF FIGURES 
Synopsis Figure 1-1 Participant Pathway in Study ARCT-021-04 ...........................15 
Synopsis Figure 1-2 Flowchart for Priming Vaccination, Re-Enrollment, and 
Booster Vaccination .............................................................................17 
Synopsis Figure 1-3. 
Summary of Key Study Procedures ...................................21 
Figure 3-1. 
ARCT-021-04 Study Design................................................................48 
Figure 6-1. 
Schematic for Unscheduled Visit Evaluations .....................................74 
 
 
 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
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PROTOCOL SYNOPSIS 
Protocol Number: ARCT-021-04 
Title: A Phase 2 Randomized, Observer-Blind, Placebo-Controlled Study to Assess the 
Safety, Reactogenicity, and Immunogenicity of the SARS-CoV-2 Vaccine ARCT-021 in 
Healthy Adult Participants 
Sponsor: Arcturus Therapeutics, Inc., 10628 Science Center Dr #250, San Diego, CA 92121 
Study Phase: 2 
Study Sites: At least 12 sites in the United States and at least 1 site in Singapore 
Indication: Prevention of disease caused by the severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2 virus) 
Study Rationale: This Phase 2 study is designed to evaluate the safety, reactogenicity, and 
immunogenicity of the ARCT-021 vaccine versus placebo administered according to 
3 different schedules for priming vaccination in 2 age groups of healthy adults. Younger 
(≥18 to <56 years) and older (≥56 years) adult participants will be evaluated for their 
responses to the ARCT-021 vaccine versus placebo following priming vaccination(s) and 
booster vaccination. Starting with Version 4.0 of the protocol, multiple booster vaccine 
candidates (ARCT-021, ARCT-154, and ARCT-165) will be evaluated in participants who 
may have previously received ARCT-021 priming vaccination. ARCT-154 and ARCT-165 
are SARS-CoV-2 vaccines that express spike protein with modifications from the D614G 
strain or the D614G and B.1.351 strains, respectively, in contrast to ARCT-021 that 
expresses spike protein from the Wuhan strain. Safety, tolerability, and immunogenicity data 
gathered in this study will characterize responses following administration of ARCT-021 
vaccine for priming and booster vaccination and will characterize responses following 
administration of ARCT-154 and ARCT-165 vaccines for booster vaccination. These data 
will be used to inform future clinical development planning for each of these investigational 
vaccines. 
ARCT-021, ARCT-154, and ARCT-165 collectively will be referred to as LUNAR®-COV19 
vaccines. 
 
 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
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Objectives and Endpoints: 
Objective(s) 
Endpoint Description 
Primary 
• 
To assess the safety and 
reactogenicity of 
ARCT-021 compared to 
placebo for priming 
vaccination 
Safety will be evaluated in all participants receiving at least 1 
administration of study vaccine (ARCT-021 or placebo) and will be 
summarized for each vaccination as number and percentage of 
participants with: 
• 
Any unsolicited adverse event (AE) initiating within 28 days 
after each study vaccine administration, by severity and 
relationship to study vaccine 
• 
Any medically attended adverse event (MAAE), new onset of 
chronic disease (NOCD), AE leading to 
discontinuation/withdrawal or serious adverse event (SAE) 
through Early Termination 
• 
Safety laboratory assessment before and 7 days after each 
study vaccine administration, by toxicity grade 
Reactogenicity will be evaluated in all participants receiving at least a 
single administration of study vaccine and will be summarized for each 
vaccination as number and percentage of participants with: 
• 
Any solicited local or systemic AE initiating within 7 days 
after each study vaccine administration, by toxicity grade 
• 
To assess the 
neutralizing antibody 
responses of ARCT-021 
compared to placebo for 
priming vaccination 
Neutralizing antibody (NAb) responses will be evaluated in all 
participants receiving at least 1 administration of study vaccine 
(ARCT-021 or placebo) 
• 
Geometric Mean Titer (GMT) measured at all time points 
• 
Geometric Mean Fold-rise from baseline (GMFR); measured at 
all time points after baseline (= Day 0) 
• 
Percentages of participants with ≥2- and 4-fold increase in titer 
from baseline (Seroconversion [SC]); measured at all time 
points after baseline 
• 
Geometric Mean Ratio (GMR) of the GMTs 
(ARCT-021/placebo) measured at all time points 
• 
To select the dose and 
schedule for use in the 
Phase 3 study in adult 
participants 
Safety and reactogenicity data after each priming vaccine administration 
and immunogenicity responses measured 28 days after each priming 
vaccination will be evaluated in younger (18 to <56 years) and older 
(≥56 years) adults 
Secondary 
• 
To assess the binding 
antibody responses of 
ARCT-021 compared to 
placebo for priming 
vaccination 
Binding antibody (BAb) responses will be evaluated in all participants 
receiving at least 1 administration of study vaccine (ARCT-021 or 
placebo) 
• 
Geometric mean concentration (GMC) and GMC ratio at all 
time points 
• 
GMFR and SC at all time points after baseline 
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09 March 2022 
 
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Objective(s) 
Endpoint Description 
Exploratory 
• 
To evaluate cell-
mediated immune (CMI) 
responses in participants 
receiving ARCT-021, 
ARCT-154 or 
ARCT-165 versus 
placebo for priming and 
booster vaccinations 
CMI responses to SARS-CoV-2 spike antigen may be measured in a 
subset of participants (CMI subset): 
• 
Cytokine-producing SARS CoV-2 Spike protein-specific T-
cells 
o 
as measured by flow cytometry and intracellular 
cytokine (Tumor necrosis factor (TNF) α, 
Interleukin-2 (IL-2), Interferon-γ (IFN- γ), IL-4, and 
IL-13) staining assay at all time points 
• 
To evaluate safety, 
reactogenicity, and 
immunogenicity 
responses in participants 
receiving ARCT 021, 
ARCT-154, ARCT-165 
versus placebo as 
booster vaccination 
given 6 months after 
priming vaccination 
Safety: 
• 
Any unsolicited AE initiating within 28 days after booster dose 
of study vaccine administration, by severity and relationship to 
study vaccine (ARCT-021, ARCT-154, ARCT-165 or placebo) 
• 
Any MAAE, NOCD, AE leading to 
discontinuation/withdrawal or SAE through Early Termination 
• 
Safety laboratory assessment prior to and 7 days after booster 
vaccine administration by toxicity grade 
Reactogenicity: 
• 
Any solicited local or systemic AE initiating within 7 days 
after booster vaccine administration, by toxicity grade 
Immunogenicity: 
• 
Binding and neutralizing antibody responses (GMFR, SC, 
GMT, GMC, BAbs/NAbs ratio) before and after booster 
administration 
• 
CMI responses before and after booster administration 
(CMI subset) 
• 
To evaluate the 
incidence of confirmed 
COVID-19 in 
participants vaccinated 
with ARCT-021, 
ARCT-154, ARCT-165 
versus placebo 
Confirmed COVID-19 will be assessed in all participants starting 7 days 
after first study vaccine (ARCT-021, ARCT-154, ARCT-165, or 
placebo) administration and will include: 
• 
Confirmation of COVID-19 symptoms 
• 
Confirmation of SARS-CoV-2 infection by reverse 
transcriptase-polymerase chain reaction (RT-PCR) 
• 
Collection of COVID-19 diagnoses made outside of study-
related procedures 
• 
To evaluate the 
incidence of 
asymptomatic 
SARS-CoV-2 infection 
in participants 
vaccinated with 
ARCT-021, ARCT-154, 
ARCT-165 versus 
placebo 
Asymptomatic SARS-CoV-2 will be assessed in all participants starting 
7 days after first study vaccine and will include: 
• 
Confirmation of SARS-CoV-2 infection by RT-PCR 
• 
Confirmation of seroconversion of SARS-CoV-2 nucleocapsid 
(N) antibody at time points after Day 14 
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Objective(s) 
Endpoint Description 
• 
To assess for vaccine-
associated enhanced 
respiratory disease 
(VAERD) following 
vaccination with 
ARCT-021, ARCT-154, 
ARCT-165 versus 
placebo 
Confirmed COVID-19 cases will be evaluated by an unblinded Data 
Safety Monitoring Board (DSMB) for frequency and severity in 
ARCT-021-, ARCT-154-, ARCT-165-, and placebo-vaccinated 
participants 
• 
To assess the 
immunogenicity 
responses to ARCT-021, 
ARCT-154, ARCT-165 
compared to placebo 
using other exploratory 
assays (eg, plaque 
reduction neutralizing 
titer [PRNT], or assays 
evaluating for responses 
to SARS-CoV-2 
variants) 
If additional assays and the corresponding blood samples are available, 
additional immune responses may be evaluated in some or all 
participants receiving at least 1 administration of study vaccine 
(ARCT-021, ARCT-154, ARCT-165 or placebo). 
• 
Immunogenicity assays and endpoints will be further defined 
in the statistical analysis plan (SAP) 
Diagnosis and Main Criteria for Inclusion and Exclusion: 
Participants will be included if they are male or female adults, ≥18 to <56 years of age 
(except ≥21 to <56 years of age in Singapore) and ≥56 years of age, as long as they do not 
have underlying conditions that place them at increased risk of severe complications of 
COVID-19, and who are medically stable such that, according to the judgment of the 
Investigator, hospitalization within the study period is not anticipated and the individual 
appears likely to be able to remain on study through the end of protocol-specified follow-up. 
Study Design: 
This is a multiregional, multicenter, Phase 2, randomized, observer-blind study designed to 
evaluate the safety, reactogenicity, and immunogenicity of the study vaccine in younger and 
older adult participants. Enrolled participants will be randomly assigned to receive either 
study vaccine ARCT-021 or placebo (sterile saline) as the priming vaccination series and 
ARCT-021, ARCT-154, ARCT-165, or placebo as the booster administration. 
Approximately 600 participants (300 younger [≥18 to <56 years of age in United States or 
≥21 to <56 years of age in Singapore] and 300 older [≥56 years of age] participants) will be 
enrolled. At Day 0, participants will be stratified by age and then randomly assigned to one 
of four groups (3 ARCT-021:1 placebo) to receive 2 doses of study vaccine and/or placebo 
(see Synopsis Table 1-1 and Synopsis Figure 1-2) separated by 28 days and, at Day 208, 
participants will be randomly assigned to ARCT-021, ARCT-154, ARCT-165, or placebo 
(for Study Groups 1, 2, 3 only) for a third (booster) dose of study vaccine given at 180 days 
after second study vaccination (Day 208). The randomization ratio of ARCT-021: 
ARCT-154 : ARCT-165 : placebo will be 1:1:1:1 for Study Groups 1, 2, 3 and the 
randomization ratio will be 1:1:1 for ARCT-021, ARCT-154, ARCT-165 (no placebo 
assignment) for any remaining participants in Study Group 4. 
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Participants who complete study procedures through Day 98 will be offered the opportunity 
to determine whether they are eligible for study re-enrollment to ensure dosing with 
ARCT-021. This provides a means of access to active investigational vaccine for those 
participants who are concerned about their ongoing risk of receiving placebo vaccine during 
a pandemic. 
After Day 98 and until Day 198, participants will be contacted to determine whether they are 
interested, if eligible, in re-enrolling in the study in order to receive active study vaccine. 
For those participants interested in receiving ARCT-021 provided by the Sponsor, an 
unblinded team member will confirm whether the participant has been assigned to Study 
Group 4 (placebo) or ARCT-021 (Study Groups 1, 2, or 3). Participants who request to re-
enroll in the study but whose treatment assignments are determined to be in Study Groups 1, 
2, or 3 will be informed they have already received ARCT-021 and will be advised to 
continue to remain on the study schedule. Participants who request to re-enroll in the study 
and whose treatment assignment was Study Group 4 will be advised they may re-enroll in the 
study. 
Participants in Study Group 4 who have not otherwise met withdrawal criteria for study 
vaccine will sign an informed consent form, will be assigned a new participant ID number, 
and will re-enter the study at Day 0. Re-enrolled participants will be randomly assigned to 
Study Groups 1, 2, and 3. 
At Day 208, all participants in Study Groups 1, 2, and 3 (including participants who have re-
enrolled in the study) will be randomly assigned to receive a single booster dose of study 
vaccine (randomly assigned as ARCT-021 : ARCT-154 : ARCT-165 : placebo  1:1:1:1). 
Study Group 4 participants who have not re-enrolled in the study to receive ARCT-021 will 
be randomly assigned to receive a single booster dose of ARCT-021, ARCT-154, or 
ARCT-165 (1:1:1 randomization) at Day 208. Study Groups are summarized in Synopsis 
Table 1-1 and a flow chart of the different pathways of study participation is shown in 
Synopsis Figure 1-1. 
 
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Synopsis Figure 1-1 Participant Pathway in Study ARCT-021-04 
 
*The last possible date for booster dose of study vaccine is 15 December 2021 and by 16 February 2022, early 
termination visits should be performed. The 16 February 2022 is a target date but may be extended up to 
two weeks for clinical evaluation, if warranted. It is expected that the final visit performed is an Early 
Termination visit but given the individual participant’s path in the study, some visits up to Day 388 may 
have been completed by some. 
Solid stars on diagram denote when doses of study vaccine may be administered. Stars with dashed outlines 
denote doses that may be withdrawn if the participant does not tolerate previous doses given. 
Study vaccine will be administered in an observer-blind fashion. Participants will be 
followed for safety and immunogenicity through at least 56 days after last vaccination (which 
may entail total participation of up to Day 396 for participants, depending on the date of 
enrollment and the timing of last vaccination). At a subset of clinical sites, all enrolled 
participants will also undergo blood sampling for evaluation of CMI responses. 
With protocol version 4.0, participants who wish to seek off-study COVID-19 vaccine will 
be allowed to continue with study participation. See Section 4.2.3. 
With protocol version 6.0, the study is terminating as of a target date of 16 February 2022. 
Final visits will revert to Early Termination visits for all participants. 
Vaccine doses will be assigned as shown in Synopsis Table 1-1 and illustrated in Synopsis 
Figure 1-2. 
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Synopsis Table 1-1 Study Group Assignments 
Stratification 
Groups 
Study 
Groups  
Priming Vaccination 
1 (Day 0) 
Randomized 1:1:1:1 
Priming 
Vaccination 2 
(Day 28) 
Booster Vaccination (Day 208) 
Booster randomization ratio: ARCT-021 : ARCT-154 : ARCT-165 : Placebo  
1:1:1:1 
Younger 
adultsa 
 
AND 
 
Older adultsb 
1 
ARCT-021 7.5 µg 
Placebo 
ARCT-021 5.0 µg 
ARCT-154 5.0 µg 
ARCT-165 5.0 µg 
Placebo 
2 
ARCT-021 5.0 µg 
ARCT-021 5.0 µg 
3 
ARCT-021 7.5 µg 
ARCT-021 7.5 µg 
4 
Placebo 
Placebo 
If not re-enrolled at Day 98-198c: Booster Vaccination (Day 208) 
Booster randomization ratio: 
ARCT-021 : ARCT-154 : ARCT-165  1:1:1 (No Placebo) 
ARCT-021 5.0 µg 
ARCT-154 5.0 µg 
ARCT-165 5.0 µg 
If re-enrolled (Day 98-198) 
Vaccination 1 (Day 0) 
Groups 1, 2, and 3 
(No Placebo) 
Randomized 1:1:1 
Vaccination 2 
(Day 28) 
Booster Vaccination 
(Day 208) 
1:1:1:1 
(Includes placebo) 
ARCT-021 7.5 µg 
Placebo 
Placebo 
ARCT-021 5.0 µg 
ARCT-154 5.0 µg 
ARCT-165 5.0 µg 
ARCT-021 5.0 µg 
ARCT-021 5.0 µg 
ARCT-021 7.5 µg 
ARCT-021 7.5 µg 
a Younger adults: 18 to <56 years of age in US and 21 to <56 years of age in Singapore 
b Older adults: ≥56 years of age 
c See Section 5.1 

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Synopsis Figure 1-2 Flowchart for Priming Vaccination, Re-Enrollment, and Booster 
Vaccination 
 
A DSMB will be in place to independently review the safety data of participants. Pausing 
Rules are also utilized in this study to reduce risk to study participants. 
Duration of Participation: 
The expected duration of participation for an individual participant is expected to be a 
maximum of 13 months for participants, inclusive of the Screening period, the maximal post-
dosing observational period (including re-enrollment, if applicable) and within the confines 
of the target Early Termination Visit date of 16 February 2022. 
Rationale for Dose Regimen Selection: 
The doses and schedules of ARCT-021 intended for evaluation are based on the evaluation of 
safety, reactogenicity and immunogenicity data from the ongoing Study ARCT-021-01, a 
Phase 1/2 dose-ranging study enrolling younger adults (21 to 55 years of age) and older 
adults (56 to 80 years of age). In this study, doses of 7.5 µg given as a single dose and 
2 doses of 5.0 µg (separated by 28 days) were well tolerated in younger and older adults and 
produced both humoral and CMI responses to the antigen encoded by the vaccine (full-
length, unmodified SARS-CoV-2 spike glycoprotein). 
The dose of booster vaccine administration to be given at Day 208 is based on the review of 
safety and immunogenicity data from the ARCT-021 clinical studies (ARCT-021-01 and the 
interim analysis data from ARCT-021-04). Based on the observation of acceptable safety and 
robust immunogenicity following single and two-dose administrations of ARCT-021, a 
5.0 µg dose is selected for evaluation of all three LUNAR-COV19 vaccine candidates in this 
study (Section 1.6). 
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The current study will also evaluate 2 priming doses of 7.5 µg ARCT-021 given at an 
interval of 28 days. This dose is supported by the results of repeat-dose (2 or 3 doses given at 
14-day intervals) studies in rabbits for safety and immunogenicity. A second administration 
of ARCT-021 within 14 days of either 20 µg or 40 µg doses of ARCT-021 in rabbits was 
associated with continued increases in anti-SARS CoV-2 IgG levels, and in both the 2-dose 
and 3-dose studies, the no observed adverse effects level (NOAEL) was assigned at the 
highest dose evaluated (40 µg) based on the safety profile. The rabbit studies are summarized 
in the Investigator’s Brochure. 
Study Assessments and Procedures: 
Overview of Procedures 
A schedule of events is provided in Appendix 1: Schedule of Events. 
Screening (up to 14 days): At Screening, individuals willing to participate in the study will 
undergo informed consent followed by an interview (to review medical history, current 
symptoms, COVID-19 exposures, medications, recent vaccinations, and availability for study 
procedures), urine test for drugs/alcohol, physical examination, measurement of vital signs 
(systolic and diastolic blood pressure, heart rate, respiratory rate, and pulse oximetry), body 
temperature, height and weight, and pregnancy testing for participants of childbearing 
potential. At the completion of Screening, the Investigator will review all data for 
determination of participant eligibility. Eligible participants will be enrolled and assigned a 
dedicated participant ID number. 
Notes: Exposure to COVID-19 is defined as a participant who has had close contact 
(within 6 feet [2 meters] for a total of 15 minutes or more) to a person with 
laboratory-confirmed COVID-19 (or clinically compatible illness) or to a person who 
has tested positive for COVID-19 (laboratory confirmed) but has not had any 
symptoms. This is irrespective of whether the person with COVID-19 or the contact 
was wearing a mask or whether the contact was wearing respiratory personal 
protective equipment (PPE). 
If, during Screening, there is uncertainty regarding past exposure to SARS-CoV-2, a 
specimen may be collected at the Investigator’s discretion, for testing for 
SARS-CoV-2 infection and/or antibody at a local laboratory. 
Visits: All enrolled participants in Study Groups 1, 2, and 3 may have up to 12 scheduled 
visits, including Screening, Dose 1 Administration (Day 0), Follow-up 1 and 2 (Day 7 and 
Day 14), Dose 2 Administration (Day 28), Follow-up 3 and 4 (Day 35 and Day 42), Follow-
up 5 (Day 56), Booster Administration (Day 208), Booster Follow-up 1 (Day 215), Booster 
Follow-up 2 (Day 236), and Early Termination Visit. 
For participants in Study Group 4 who re-enroll in the study, clinic visits representing Dose 1 
Administration (Day 0), Follow-up 1 and 2 (Day 7 and Day 14), Dose 2 Administration 
(Day 28), Follow-up 3 and 4 (Day 35 and Day 42), Follow-up 5 (Day 56) will be performed 
again, and, as such, may have up to 19 scheduled visits. Informed consent will be obtained 
again for these participants prior to re-enrollment into the study. 
 Administration Visits: At each Dose and Booster Administration visit, participants will 
undergo an interview, pregnancy testing (if the participant is a woman of childbearing 
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potential), physical examination, blood sampling for immunogenicity and safety laboratory 
assessment testing (blood sampling must occur prior to administration of study vaccine), and 
saliva sample (or, if not available, by nasal or nasal turbinate swab) for testing for 
SARS-CoV-2 virus by RT-PCR, vital signs, pulse oximetry and body temperature 
measurement prior to and after receipt of study vaccine. 
During all Administration visits (Day 0, Day 28, Day 208), all participants will be trained in 
how to measure body temperature, ruler use, how to report AEs in the Diary, what signs or 
symptoms of COVID-19 might be (Section 6.1), whom to call at the site and how quickly to 
call in the event of severe or serious AEs or signs of possible COVID-19 disease. At later 
points of contact, participants will be reminded of this training. 
Follow-up Visits: At Follow-up visits, participants will undergo an interview, vital signs, 
pulse oximetry, body temperature, blood sampling for immunogenicity, saliva for 
SARS-CoV-2 testing by RT-PCR and will be reminded of study-related procedures for data 
collection and site notification. At Follow-up visits performed 7 days after each vaccine 
administration, blood will also be drawn for safety laboratory assessments. Symptom-driven 
physical examination may be performed at all visits if warranted by the interview. 
All Screening, Dose and Booster Administration visits must be performed at the site. Follow-
up visits and unscheduled visits may be performed by telemedicine visits or in a hospital 
setting if warranted by clinical circumstances (eg, COVID-19 lockdown in the vicinity) and 
permitted by local regulations. 
Study Calls: Telephone calls will be performed one week after Follow-up Visit 2 and 
Follow-up Visit 4 and then intermittently between Follow-up Visit 5 until the Booster 
Administration (Day 208). Telephone calls will then occur every week between Booster 
Follow-up 1 and Booster Follow-up 2; then every approximately 4 weeks after Booster 
Follow-up 2 until Early Termination Visit. For participants in Study Group 4 who re-enroll in 
the study but who had not reached the milestone of Booster Administration at Day 208 by 
15 December 2021, telephone calls after Follow-up Visit 2, Follow-up Visit 4, and between 
Follow-up Visit 5 until the Booster Administration will be performed again unless these 
would fall after 16 February 2022. 
 Electronic device contact (including COVID-19 reminders) will occur at least every week 
between clinic visits. 
The purpose of this call will be to evaluate for safety and to remind the participant of the 
required assessments (Diary completion, contact the site for potential symptoms of or 
exposures to COVID 19, and reminder for participants with confirmed COVID-19 to 
complete postdiagnosis procedures). 
Unscheduled Visits: These visits will occur if warranted for the evaluation of reported 
symptoms of or exposure to COVID-19 illness or for the evaluation of AEs. 
These visits will either occur at the clinic, in the hospital (if medically unstable), or by 
telemedicine visit. 
For participants reporting symptoms suggestive of COVID-19 or exposed to COVID-19, 
visits will be accompanied by collection of a saliva or nasal swab specimen for testing. Saliva 
or nasal swab samples will be collected within 2 days (±1 day) and 5 days (±1 day) of 
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symptomatic onset/known exposure for SARS-CoV-2 testing by RT-PCR. In addition, for 
participants evaluated for COVID-19 only, a blood sample will be drawn for SARS-CoV-2 
antibody testing. 
Beyond this protocol-specified testing, participants should be referred to their treating 
primary care health professional for further evaluation and treatment of potential COVID-19. 
The Investigator should continue to follow and report the COVID-19 clinical course, 
including disease severity. The Investigator may order additional testing as clinically 
warranted for the evaluation of AEs throughout the study. These tests are subject to the 
approval by the Contract Research Organization (CRO) Medical Monitor. 
Early Termination Visit: This will occur if a participant withdraws from study participation 
or based on Sponsor decision to terminate the study (as of Protocol Version 6.0). This visit 
will either occur at the clinic, by home visit, in the hospital (if medically unstable), or by 
telemedicine visit. 
An overview of key study procedures is provided in Synopsis Figure 1-3. 
 
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Synopsis Figure 1-3. Summary of Key Study Procedures 
 
1  As of protocol version 6.0, study participation is expected to end by approximately 16 February 2022, the, the follow-up visits projected in this figure will be 
followed through to Early Term visit which is expected to fall no later than 14 days past this date. 
 

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Additional Procedural Specifics: 
Solicited AEs will be evaluated by the participant and will include measurement of body 
temperature by thermometer and injection site reaction (erythema or induration/swelling) 
measurement by ruler. Both instruments and training on how to use them will be provided by 
the site. 
An electronic Diary (eDiary) will be used to collect the following: 
• Solicited local and systemic AEs through 7 days following each study vaccination 
o Solicited local AEs: injection site erythema, injection site pain, injection site 
induration/swelling, injection site tenderness 
o Solicited systemic AEs: arthralgia, chills, diarrhea, dizziness, fatigue, fever 
(categorized by measured body temperature), headache, myalgia, 
nausea/vomiting 
o Also solicited but not categorized as AE: antipyretic and analgesic use 
following vaccination 
• Prompts for unsolicited AEs through the Early Termination. Prompts will solicit for 
all unsolicited AEs through 28 days after each vaccination and for unsolicited AEs 
categorized as SAEs, MAAEs, NOCDs, and AEs leading to 
discontinuation/withdrawal through Early Termination Visit. 
• Prompts for symptoms of or exposure to COVID-19 disease from 7 days after first 
study vaccine administration through Early Termination Visit. 
Blood sampling will be performed to collect: 
• Laboratory assessments for Screening (a list of laboratory parameters is provided in 
Appendix 2: Clinical Laboratory Tests) 
All participants: 
• Neutralizing antibody assessments for SARS-CoV-2 virus by pseudoviral 
microneutralization assay (Wuhan-Hu-1 [D614G strain]). Binding antibody 
assessments for SARS-CoV-2 including full-length spike, receptor binding domain 
(RBD) and nucleocapsid (N)-binding by Meso Scale Discover (MSD) multiplex 
assay. In some or all participants, additional exploratory antibody responses, 
including exploration of responses to SARS-CoV-2 variant strains, may also be 
evaluated if the blood and assays are available. 
CMI subset of participants: 
• CMI assessments include parametric flow cytometry for quantification and 
phenotyping of CMI responses and cytokine staining for Tumor necrosis factor (TNF) 
α, Interleukin-2 (IL-2), Interferon-γ (IFN- γ), IL-4, and IL-13. Exploratory CMI 
assessments may be evaluated if the blood samples and assays are available. 
Assessments will be performed at Days 0, 14, 28, 42, 56, 208, 215, 236, and at Early 
Termination (as applicable) in participants enrolled at centers identified with 
capabilities for isolation of peripheral blood mononuclear cells (PBMCs). For 
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participants who re-enroll into study at Day 98-198, CMI assessments will not be 
repeated during the re-enrollment study participation. 
Saliva and/or nasal swab testing will be performed as follows: 
• To measure SARS-CoV-2 virus by RT-PCR 
• To retain for additional testing of SARS-CoV-2 genetic sequencing, if warranted 
Telephone calls will be performed to collect the following: 
• To confirm Diary completion and to evaluate for unsolicited AEs (including MAAEs, 
NOCDs, SAEs, AEs leading to discontinuation/withdrawal) 
• To confirm any changes in concomitant medications 
• To evaluate for symptoms of COVID-19 disease and risks of exposure to COVID-19. 
Pausing Rules: 
Enrollment of and dosing of all enrolled participants will be paused if any of the following 
events occur in participants who have been vaccinated with ARCT-021: 
• Any SAE considered possibly, probably, or definitely related to study vaccine 
administration (as assessed by the Investigator and review of the Safety Review 
Committee [SRC]). 
• Any anaphylactic reaction 
• Any clinically apparent hypersensitivity episode that is considered at least moderate 
in severity, is considered probably or definitely related to study vaccine 
administration (as assessed by the Investigator and review of the SRC), and has the 
following features: 
o is not confined to the injection site 
o is immediate in onset (within ≤4 hours after vaccination) OR if delayed, 
involves more than one organ system. 
• Any death due to SARS-CoV-2 infection or 2 cases of severe SARS-CoV-2 infection, 
as confirmed by the DSMB, in participants randomized to receive ARCT-021, 
ARCT-154, and ARCT-165 vaccine. 
Events suspected of meeting Pausing Rule definitions will be referred to the SRC (which will 
remain blinded to individual participants’ vaccine assignments), where the case details and 
the assessment of the event causality will be assessed. Should the SRC confirm that a 
Pausing Rule has been met, investigators will be immediately (same day) instructed to pause 
dosing and regulatory authorities will be notified within 48 hours of determination that a 
pausing rule has been met. Study vaccine administrations will continue to be paused while 
the case undergoes review. This/these AE(s) and the SRC assessment will also be referred to 
the DSMB, which will review the unblinded details. After evaluation of these relevant data, 
the DSMB will make a recommendation of whether the study should be discontinued, should 
be modified prior to resumption of vaccine administrations, or should continue without 
protocol modification. This recommendation will be provided to regulatory authorities and 
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investigators within 48 hours of the DSMB recommendations and prior to resumption of 
study procedures (if applicable). 
Efficacy Assessments: 
Not applicable 
Immunogenicity Assessments: 
Immunogenicity assessments will be measured on Days 0, 14, 28, 42, 56, 208, (Day 215 for 
participants in the CMI subset only), 236, and Early Termination Visit 
SARS-CoV-2 neutralizing antibody titer will be tested using pseudoviral microneutralization 
assay. Exploratory testing may also be performed, if the assays are available. 
SARS-CoV-2 binding antibodies will be tested using the MSD Multiplex Assay, which 
measures total immunoglobulin G (IgG) against the full-length spike, RBD, and N antigens 
of the Wuhan strain SARS-CoV-2, and the full-length spike protein of SARS-CoV-2 
variants. 
T-cell subclass responses will be tested in a subset of participants by intracellular cytokine 
staining (ICS) and flow cytometry following stimulation with peptide pools from 
SARS-CoV-2 spike protein, possibly including variants, if available. Additional CMI testing 
may be performed if the assays are available. CMI testing will not be performed on 
participants re-enrolling at Day 98-198 (ie, placebo participants who re-enter study to receive 
ARCT-021 priming vaccinations). 
An additional blood sample will be drawn at specified time points (Day 28, Day 56, Day 208, 
and Day 236) to allow for the additional exploratory immunogenicity testing described 
above. 
Safety Assessments: 
Safety assessments will include monitoring and recording of solicited and unsolicited AEs, 
MAAEs, NOCDs, SAEs, AEs leading to discontinuation/withdrawal, vital signs, pulse 
oximetry, body temperature measurements, and safety laboratory assessments. 
Vital signs will be measured in a semi-supine position after 5 minutes’ rest and will include 
systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature, and pulse 
oximetry. Three readings of blood pressure and pulse will be taken, each separated by 
approximately 5 minutes. The first reading should be rejected. The second and third readings 
should be averaged to give the measurement to be recorded in the electronic case report form 
(eCRF). 
Solicited AEs (except solicitation of analgesic and antipyretic use after vaccination) and 
safety laboratory assessments will be graded for severity according to scales defined in the 
Center for Biologics Evaluation and Research’s Guidance: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(DHHS 2007). 
Analgesic and antipyretic use after vaccination will be collected as categorical responses 
(yes/no) for each of the 7 days following each study vaccination. 
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Unsolicited AEs will be graded for severity according to mild, moderate, or severe 
classification and also whether or not the AE was categorized as an SAE, an MAAE, an 
NOCD, and AEs leading to discontinuation/withdrawal and whether or not the AE was 
determined to be related to study vaccine in the judgment of the Investigator. NOCDs are 
defined as a subset of MAAEs that are specific to new onset of chronic diseases not 
otherwise suggested or suspected prior to entry into the study. 
Details of Applicable Monitoring Committee: 
Safety Review Committee: An SRC comprised of the medical monitoring teams from the 
Sponsor and the CRO will perform ongoing medical review of the blinded safety data of 
enrolled participants throughout the study. This committee may request an ad hoc meeting of 
the DSMB in the event of safety concerns. 
Independent DSMB: An independent DSMB, which will be guided by a signed charter, will 
perform ongoing review of blinded and unblinded data, including both safety and cases of 
COVID-19 at scheduled data review meetings and at 3 planned interim analyses. 
In addition to blinded and unblinded review of safety data, at each data review meeting the 
DSMB will review any confirmed COVID-19 cases amongst the participants, which may 
inform of any increased risk of vaccine associated enhanced respiratory disease. Further 
details are described in the DSMB Charter. 
At each analysis, the DSMB will review the available data and make recommendations to the 
Sponsor to continue, modify, or discontinue study enrollment (if the study is enrolling). The 
DSMB will also review safety and, if available, immunogenicity data at each interim 
analysis. 
For dose selection for Phase 3 study use, it is expected that the Sponsor will select the dose 
on the basis of review of available immunogenicity data and safety data (including DSMB 
evaluation of the benefit/risk profile). It is anticipated that if one or more vaccine groups 
have an acceptable safety and immunogenicity profile, the vaccine group with the fewest 
number of doses will be selected for future use based on the review of the Phase 2 study data. 
Study Vaccine, Dosage, and Route of Administration: 
The ARCT-021, ARCT-154, and ARCT-165 study vaccines are lipid nanoparticle formulated 
ribonucleic acid (RNA) products. The RNA comprises a replicon based upon Venezuela 
equine encephalitis virus (VEEV) in which RNA coding for the virus structural proteins has 
been replaced with RNA coding for the SARS CoV-2 full-length spike glycoprotein. 
ARCT-021 is based on the unmodified spike protein of the SARS-CoV-2 Wuhan strain. 
ARCT-154 and ARCT-165 are based on prefusion-stabilized presentations of the spike 
protein of the Wuhan strain containing the D614G mutation and variant of concern B.1.351 
SARS-CoV-2 strains, respectively. 
For LUNAR-COV19 vaccines, the nanoparticle composition includes 4 lipid excipients 
(ionizable cationic lipid, ATX-126; neutral lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine 
(DSPC); cholesterol; and polyethylene glycol-lipid conjugate (PEG2000-DMG). 
ARCT-021, given as 2 priming doses administered on Day 0 and Day 28, will use the frozen 
liquid formulation. 
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ARCT-021, ARCT-154, and ARCT-165, given as booster doses on Day 208 will each use 
lyophilized formulations. 
For a complete list of the LUNAR-COV19 vaccine components, see the Investigator’s 
Brochure (IB). The comparator (placebo) is 0.9% sterile saline. 
Each of the study vaccines will be prepared by an unblinded pharmacist and in accordance 
with the Pharmacy Manual. The ARCT-021 dose to be given to the participant will be 
determined by Study Group assignment. 
Study vaccine (ARCT-021, ARCT-154, or ARCT-165) or placebo will be administered by 
intramuscular (IM) injection to the deltoid muscle by an unblinded health care provider. 
Unblinded team members will not otherwise participate in other study-related procedures or 
assessments of the participant. 
Please note that the term “LUNAR-COV19 vaccines” refers to ARCT-021, 
ARCT-154, and ARCT-165 collectively, whereas the term “study vaccine(s)” 
includes any of the LUNAR-COV19 vaccines and/or placebo. 
The IM injection of the study vaccine will be into the deltoid muscle of the non-dominant 
arm. The participant and blinded staff members will be asked to look away while the study 
vaccine is present and is being administered. 
Epinephrine for subcutaneous injection, diphenhydramine for intravenous injection, and any 
other medications and resuscitation equipment for the emergency management of 
anaphylactic reactions must be available in close proximity to the room where the injection is 
being performed. 
Participants should be observed at the site for a minimum of 30 minutes or until clinically 
stable after each study vaccine administration. During this period of observation, vital signs 
should be checked and repeat vital signs should be taken if clinically indicated. Should a 
participant experience a severe adverse event (including but not limited to hypersensitivity or 
anaphylaxis) within 30 minutes of study vaccine administration, the participant should be 
observed until clinically stable and the CRO Medical Monitor should be notified 
immediately. Additional evaluation or testing may be performed based on discussion 
between the Medical Monitor and the Investigator, and subject to Medical Monitor approval. 
Sample Size: 
The sample size is based on clinical considerations to provide sufficient safety information 
for the analysis of the primary safety objective. With a sample size of N=75 in each 
ARCT-021 Study Group by Age Cohort or N=75 in pooled placebo recipients by Age 
Cohort, the probability of observing at least 1 AE for a given true event rate of a particular 
AE is >99.9% with a sample size of 75 participants for a given true AE rate of 10%. 
Analysis Sets: 
Intent-to-Treat (ITT) analysis set will include all participants who receive at least 1 dose of 
priming study vaccine (ARCT-021or placebo). Participants will be analyzed according to the 
study vaccine the participant was randomly assigned to at the time of priming or booster 
vaccination. 
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The safety analysis set will include all participants who receive at least 1 dose of priming 
study vaccine (ARCT-021or placebo). Participants will be analyzed according to the study 
vaccine actually received at the time of priming or booster vaccination. 
The reactogenicity analysis set (RAS) includes all participants who receive any dose of 
priming study vaccine (ARCT-021or placebo) and provide at least 1 reactogenicity diary 
report for the time period evaluated. Participants will be analyzed according to the vaccine 
received. 
The per-protocol analysis set will include all eligible randomized participants who receive 
the correct assigned dose(s) of study vaccine within the predefined SAP window, have blood 
collection within the SAP window, have valid immunogenicity results for the relevant time 
point(s), and have no other major protocol deviations expected to affect immunogenicity, as 
determined by the Sponsor Medical Monitor in a blinded manner. All participants in the per-
protocol analysis set will be analyzed according to the study vaccine that was actually 
received, in the event of a discrepancy. 
The modified intent-to-treat (mITT) analysis set includes all participants who received at 
least one dose of study vaccine and who have pre- and post-vaccination immunogenicity data 
evaluable by the assay in use with valid results for the relevant time point(s). The mITT 
analysis set will be analyzed according to vaccine assigned. 
The CMI subset includes all participants who have evaluable pre- and post-vaccination CMI 
data available. The data sets include: CD4+ T-cell responses (background subtracted), 
CD8+ T-cell responses (background subtracted), and Th1/Th2 CD4+ T-cell responses 
(background subtracted). 
The Booster Randomized analysis set consists of all participants who are randomized to a 
booster vaccination, regardless of the participant’s study treatment status in the study. 
Participants will be analyzed according to the study vaccine to which they were randomized 
for receipt of booster vaccine. 
The Booster Safety analysis set includes all participants who receive at least 1 dose of 
booster study vaccine (ARCT-021, ARCT-154, ARCT-165 or placebo) or have safety data 
collected in the period following booster administration. If a participant did not receive a 
booster dose but has safety data collected for the booster vaccination period, the participant 
will be included in the placebo booster group for summarization. Participants will be 
analyzed according to the vaccine actually received. 
The Booster Reactogenicity analysis set includes all participants who receive any dose of 
booster vaccination (ARCT-021, ARCT-154, ARCT-165 or placebo) and provide at least 1 
diary entry for the time period evaluated. Participants will be analyzed according to the 
vaccine actually received. 
Further details relating to the analysis sets are provided in the SAP. 
Statistical Methods: 
Safety Analyses: 
Numbers and percentages (with 95% confidence intervals [CI]) based on the Clopper-
Pearson method) of participants with solicited local and systemic AEs through 7 days after 
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each vaccination will be summarized by Study Group, Age Cohort and the maximum toxicity 
grade over 7 days after each vaccination. The duration of solicited local and systemic AEs 
after each vaccination will also be summarized by Study Group. 
Unsolicited AEs will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by 
Study Group, Age Cohort, as well as by severity and relationship to study vaccine. Adverse 
events through 28 days after each vaccination and all MAAEs, NOCDs, and SAEs through 
Early Termination Visit will be listed separately and summarized by Study Group and Age 
Cohort. 
Actual values, changes from baseline (where indicated), and toxicity grading for clinical 
safety laboratory assessment results will be summarized by Study Group and Age Cohort at 
each time point using descriptive statistics. 
Concomitant medications will be summarized by Study Group and Age Cohort by preferred 
drug name as coded using the World Health Organization drug dictionary. 
Additional subgroup analyses are specified in the SAP. 
Immunogenicity Analyses: 
The primary immunogenicity analyses will be performed using the mITT set evaluating 
responses measured by neutralizing antibody assay. 
For all GMC and GMT calculations (binding and neutralizing antibody responses), geometric 
means will be calculated as the mean of the assay results after making the logarithm 
transformation and then exponentiating the mean to express results on the original scale. 
Two-sided 95% CIs will be obtained by taking natural log transformations of 
concentrations/titers, calculating the 95% CI with reference to the t-distribution, and then 
exponentiating the CIs. An analysis of covariance (ANCOVA) model will be constructed at 
each post­vaccination immunogenicity visit on the log transformed titer, including the study 
treatment group and age group (≥ 18 to <56 years; ≥56 years) as fixed effects and natural 
log baseline titer as a covariate. Comparisons of ARCT-021 groups vs. placebo will be 
performed within each post-baseline visit and no adjustments for multiplicity will be carried 
out. These models will be used to estimate the geometric mean ratios with 95% CIs at each 
time point comparisons being of primary interest. 
The GMFR will be calculated as the mean of the difference of logarithmically transformed 
assay results (later time point – earlier time point) and exponentiating the mean. 
Seroconversion (SC) is defined with as ≥2-fold and also ≥4-fold GMFR. Seropositivity is 
defined as those participants with undetectable antibody responses at baseline whose 
antibody responses become detectable at time points after baseline. The number and 
percentage of participants with ≥2- and 4-fold GMFR from baseline and with seropositivity 
will be provided with 2-sided 95% CI using the Clopper-Pearson method at each post-
baseline time point. The common difference of seroconversion rate and 95% CI between 
each vaccine dose group and the placebo will be estimated in the mITT using the Cochran–
Mantel–Haenszel (CMH) method with stratification factors for each time point from Day 28 
and later timepoints as specified in the SAP. 
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Cell-mediated response for both Th1 and Th2 pathways will be assessed by measuring 
intracellular cytokine expression by flow cytometry of PBMCs isolated from whole blood 
and summarized by Study Group and Age Cohort in the CMI analysis set. Further details are 
described in the SAP. 
Exploratory analyses of antibody responses and CMI will be described in the SAP prior to 
analysis. Additional subgroup analyses are described in the SAP. 
Interim Analyses: 
Three interim analyses will be performed. 
• The first interim analysis will focus on safety and will evaluate available safety data 
for all participants who were initially enrolled as of 05 February 2021 when they have 
completed Day 7 or Early Termination visit procedures. 
• The second interim analysis will evaluate available safety and immunogenicity data 
for all participants who were initially enrolled as of 05 February 2021 when they have 
completed Day 28 or Early Termination visit procedures. 
• The third interim analysis will evaluate available safety and immunogenicity data for 
all participants when they have completed Day 56 or Early Termination visit 
procedures. 
No data base lock will be performed prior to first and second interim analyses, so it is 
assumed that the data may not be fully monitored or queried. In addition, the datasets from 
immunogenicity assessments may not contain all participants’ data. However, the data cuts 
outlined above are intended to inform additional clinical development considerations, 
including selection of ARCT-021 dose for booster administration and selection of final dose 
and schedule for ARCT-021 administration in the Phase 3 study. The data will be monitored 
prior to and the database will be locked after the third interim analysis to inform an interim 
clinical study reporting. 
All available safety and immunogenicity data will be summarized. Blinded data will be 
shared with the SRC and unblinded data will be shared with the DSMB. 
At each analysis, the DSMB will review the available data and make recommendations to the 
Sponsor to continue, modify, or discontinue study enrollment (if the study is enrolling 
participants). The DSMB will also review safety and, if available, immunogenicity data at 
each interim analysis. 
For dose selection for Phase 3 study use, it is expected that the Sponsor will select the dose 
on the basis of review of available immunogenicity data and safety data (including DSMB 
evaluation of the benefit/risk profile). It is anticipated that if one or more vaccine groups 
have an acceptable safety and immunogenicity profile, the vaccine group with the smallest 
number of doses will be selected for future use based on the review of the Phase 2 study data. 
As of protocol version 4.0, the Sponsor has selected single doses of 5 µg ARCT-021 for 
future use in Phase 3 studies. See the IB for more detail. 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACE-2 
angiotensin-converting enzyme-2 receptor 
AE 
adverse event 
AESI 
adverse event of special interest 
BAb 
binding antibody 
BMI 
body mass index 
CESI 
clinical event of special interest 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMH 
Cochran–Mantel–Haenszel 
CMI 
cell-mediated immune 
COVID-19 
Coronavirus Disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
DSMB 
Data Safety Monitoring Board 
EDC 
electronic data capture 
eCRF 
electronic case report form 
FDA 
US Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMC 
geometric mean concentration 
GMFR 
geometric mean fold-rise 
GMR 
geometric mean ratio 
GMT 
geometric mean titer 
HIV 
human immunodeficiency virus 
HCP 
healthcare provider 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
IcEv 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
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Abbreviation 
Definition 
IEC 
independent ethics committee 
IFN 
interferon 
IgG 
immunoglobulin G 
IL 
interleukin 
IM 
intramuscular 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
Intent-to-Treat 
LLOD 
lower limit of detection 
LLOQ 
lower limit of quantification 
LOD 
limit of detection 
LOQ 
limit of quantification 
LUNAR®-COV19 
LUNAR-COV19 refers collectively to vaccines ARCT-021, 
ARCT-154, and ARCT-165 
MAAE 
medically attended AE 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed-model repeated measures 
MSD 
MesoScale Discover 
NAb 
neutralizing antibody 
NOCD 
new onset of chronic disease 
PBMC 
peripheral blood mononuclear cells 
PEG2000-DMG 
polyethylene glycol-lipid conjugate-1,2-Dimyristoyl-rac-glycero-3-
methoxypolyethylene glycol-2000 
PPE 
personal protective equipment 
PRNT 
plaque reduction neutralizing titer 
RBD 
receptor binding domain 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcriptase-polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome-Coronavirus-2 
SC 
Seroconversion 
SRC 
Safety Review Committee 
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Abbreviation 
Definition 
SUSAR 
suspected unexpected serious adverse reaction 
SWFI 
sterile water for injection 
TNF 
tumor necrosis factor 
VAERD 
vaccine associated enhanced respiratory disease 
VEEV 
Venezuela equine encephalitis virus 
WHODRUG 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 
 
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1 
INTRODUCTION 
1.1 
Background 
ARCT-021 is a self-replicating RNA vaccine being developed for prevention of Coronavirus 
Disease 2019 (COVID-19), caused by SARS-CoV-2 virus. Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) is a positive strand RNA virus which causes both 
symptomatic (COVID-19) and asymptomatic infection in humans. Infection with 
SARS-CoV-2 is asymptomatic in many (Mizumoto 2020; Gudbjartsson 2020) if not most 
cases (Day 2020). Clinical manifestations are referred to as COVID-19. The most serious 
manifestation of the infection is a viral pneumonia which can progress to acute respiratory 
distress syndrome (ARDS), respiratory failure and death. Clinical symptoms relating to other 
organ systems have also been described (Zhang 2020; Zaim 2020) and, in children, a rare 
inflammatory condition resembling Kawasaki’s disease has recently been recognized 
(Verdoni 2020; Riphagen 2020; CDC 2020a; AAP 2020). Age, male sex, pregnancy, ethnic 
minority status and comorbidity, particularly chronic obstructive pulmonary disease, cancer, 
heart conditions (congestive heart failure, pulmonary hypertension, coronary artery disease), 
immunocompromise, chronic renal failure, Type 2 diabetes and obesity, are risk factors for 
more severe disease (CDC 2020b; de Lusignan 2020; Williamson 2020; Yang 2020; Zhou 
2020; Grasselli 2020). Patients with severe lung disease require ventilatory support and 
mortality rates as high as 25% to >90% have been reported in these patients (Zhou 2020; 
Richardson 2020; Auld 2020; Phua 2020), although, more recently, mortality rates may be 
decreasing as more is known about how best to manage severe disease and with treatments 
such as corticosteroids (The RECOVERY Collaborative Group 2020; Tomazini 2020) and 
remdesivir (Goldman 2020; Gilead 2020) becoming available (Horwitz 2020). 
More than 172 million cases of COVID-19 been confirmed worldwide and more than 
3.7 million people have died (WHO 2021), and the number of cases continues to rise 
globally. 
1.2 
Current Therapies for COVID-19 
COVID-19 is a complicated disease and optimal management is still evolving. As such, a 
comprehensive discussion is beyond the scope of this document. However, a number of 
treatment guidelines exist (for example: VRBPAC 2020; WHO 2020a; NIH 2020; Bhimraj 
2020). Treatment of less severe disease involves isolation and largely symptomatic 
management. Severe disease requires supplemental oxygen ± mechanical ventilation, 
prevention of thromboembolic complications and treatment of secondary infection. 
Corticosteroids have been shown to be effective (The RECOVERY Collaborative Group 
2020; Tomazini 2020) and remdesivir (Goldman 2020; Gilead 2020) has recently been 
approved in some jurisdictions. Many potential therapeutic agents are in clinical development 
(CT.gov 2020; RAPS 2020), but in most countries are currently only available within the 
context of a clinical trial. 
Since the time of this protocol’s first version (17 November 2020), three SARS-CoV-2 
vaccines (Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine, and Janssen 
COVID-19 Vaccine) have achieved emergency use authorization in the United States and 
two of these (Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine) have 
achieved emergency use authorization in Singapore (FDA 2021; Ministry of Health 
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Singapore 2021). While each of these vaccines has demonstrated promising early vaccine 
efficacy and these vaccines have been used in mass vaccination efforts, there remains a 
significant ongoing circulation of SARS-CoV-2, and vaccine rollout campaigns will take 
months or more across the globe. In this current situation of ongoing infection, lack of herd 
immunity, and incomplete vaccine rollout, there exists a new risk of evolutionary selection 
pressure on SARS-CoV-2 (Priesemann 2021). This is already illustrated in principle by the 
emergence of multiple variants, including several with increased infectivity such as B.1.1.7 
and B.1.351 (Korber 2020; Sah 2021). 
Ongoing global demand for vaccines is being fueled by the concern that the continued 
circulation of SARS-CoV-2 has led to the development of variants and may ultimately 
become endemic. With these additional challenges in mind, it will be necessary to 
characterize vaccine durability of response as well as immunogenicity against homologous 
and heterologous SARS-CoV-2 strains, and to continue mass vaccinations to limit morbidity 
and mortality associated with SARS-CoV-2 (Sah 2021). 
1.3 
Therapeutic Rationale for LUNAR-COV19 Vaccines in Prevention of COVID-19 
SARS-CoV-2 is a novel virus belonging to the β-coronavirus genus. Coronavirus host cell 
infection is mediated by the attachment of the transmembrane spike (S) glycoprotein to host 
cell receptors and subsequent fusion with host cell membranes. The S glycoprotein forms 
homotrimers protruding from the viral surface (Tortorici 2019) and can be divided into 
4 subdomains; S1, S2, transmembrane and internal domain or endodomain. The S1 domain 
contains the receptor binding domain (RBD) that allows SARS-CoV-2 to bind directly to the 
peptidase domain of the angiotensin-converting enzyme 2 receptor (ACE-2) expressed on 
epithelial cells in the lungs, heart, kidneys and gastrointestinal tract. Hence, antibodies to the 
S glycoprotein, especially the RBD, should block viral entry into cells expressing the ACE-2 
receptor and thereby prevent infection. 
Recent progress in the development and emergency authorization of SARS-CoV-2 vaccines 
suggests that the design of and vaccination with vaccines targeting the SARS-CoV-2 spike 
glycoprotein have demonstrated robust immunogenicity and high vaccine efficacy against 
COVID-19. 
1.4 
Mechanism of Action 
ARCT-021, ARCT-165, and ARCT-154 each contain Arcturus Therapeutics’ proprietary 
self-transcribing and -replicating RNA technology (STARR TechnologyTM), an RNA 
replicon construct based on the alphavirus, Venezuelan equine encephalitis virus (VEEV). 
The replicon for ARCT-021 (mRNA-2002) consists of a series of RNA nucleotides encoding 
the VEEV replicase and an RNA sequence encoding the Wuhan strain SARS-CoV-2 
S glycoprotein. The replicon for ARCT-165 (mRNA-2106) consists of a sequence of 
ribonucleotides encoding the replicase and an RNA sequence encoding the SARS-CoV-2 
S glycoprotein containing the B.1.351 variant mutations (D80A, D215G, E484K, K417N, 
N501Y, and A701V) as well as the D614G variant mutation. The replicon for ARCT-154 
(mRNA-2105) consists of a series of ribonucleotides encoding the replicase and an RNA 
sequence encoding the SARS-CoV-2 S glycoprotein containing the D614G variant mutation. 
The final drug product for all 3 vaccines includes an RNA replicon formulated with Arcturus 
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Therapeutics’ proprietary lipid nanoparticle (LNP) technology (LUNAR), including 4 lipid 
excipients. More detail relating to these vaccines is included in the IB. 
Alphaviruses are enveloped viruses with a positive-strand RNA genome. Upon infection, the 
genomic RNA serves as a template for translation of four viral nonstructural proteins that 
form replicase complexes. These complexes synthesize viral genomic and sub-genomic 
RNA, the latter of which serves as a template for translation of viral structural proteins, 
which then assemble with genomic RNA into new infectious viral particles. By replacing the 
RNA coding for the alphavirus’ structural proteins with RNA coding for a protein antigen of 
interest (in this case the SARS-CoV-2 full-length S glycoprotein) the self-replicating 
machinery of the alphavirus can be used to generate sustained expression of the antigen, 
making such alphavirus replicon constructs an attractive tool for vaccines. These replicon 
RNAs, which do not encode the complement of structural genes necessary for assembly of 
virus particles and do not contain reverse transcriptase that converts the RNA genome into 
cDNA, replicate exclusively in the cytoplasm and cannot introduce their genetic material 
into the cellular genome. A more detailed description of the mechanism of mRNA 
amplification and the biochemical functions for each of the nonstructural proteins is 
described in Rupp 2015. 
On entry into the cytoplasm, the RNA sequence coding for the replicase, encoding the four 
nonstructural proteins (nsP1 to nsP4), is translated from the mRNA construct producing only 
the replicase proteins as a single polyprotein. The RNA-dependent RNA polymerase, nsP4, is 
released from the polyprotein and, in combination with the remaining nsP123 polyprotein, 
synthesizes the complementary RNA strand of the entire mRNA, including the SARS-CoV-2 
S glycoprotein RNA and poly A tail. The remaining polyprotein is processed into nsP1, nsP2 
and nsP3 and, in combination with nsP4, transcribes only the 5´-G-methyl capped 
S glycoprotein mRNA from the 3´-5´ complementary strand of mRNA. The multiple copies 
of S glycoprotein mRNA transcript are then translated to produce full-length S glycoprotein, 
which is the vaccine antigen. Cleavage of the nsP123 polyprotein into its component 
nonstructural proteins terminates transcription of the complementary RNA (Rupp 2015). 
Remaining complementary RNA and spike glycoprotein mRNA is then degraded by 
intracellular nucleases thereby terminating production of the antigen. Tissue distribution 
studies with ARCT-021 show that the mRNA is no longer detectable in most tissues by 
15 days post dose. 
During the process of self-replication, a double-stranded RNA intermediate is produced that 
has immunostimulatory properties activating the innate immune system, ultimately 
enhancing the adaptive immune response to the expressed S glycoprotein and thereby 
behaving as an adjuvant. 
At the injection site, the LNP-formulated RNA is taken up by antigen-presenting cells and 
myocytes, the former of which traffic to regional lymph nodes where they present the 
vaccine antigen to CD4+ T cells and CD8+ T cells, resulting in their activation. Antigen can 
be detected in regional lymph nodes within hours of injection (Liang 2017; Lindsay 2019). 
IL-2 from activated CD4+ T cells is subsequently important in the terminal differentiation of 
the activated, antigen-specific CD8+ T cells (Zhang 2011). Although the immunological 
events leading to antibody responses elicited by RNA vaccines have yet to be fully 
elucidated, T follicular helper (Tfh) cells, which are a subset of CD4+ cells, are required to 
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develop germinal center responses and drive immunoglobulin class switch, affinity 
maturation, and long-term B-cell memory (Pardi 2018) and strong induction of antigen-
specific Tfh cells has been demonstrated following vaccination with mRNA vaccines 
(Lindgren 2017). 
1.5 
Clinical Trial Experience with ARCT-021, ARCT-154 and ARCT-165 
At the time of finalization of IB version 4.0, no clinical trials have been conducted with 
ARCT-154 or ARCT-165. However, ARCT-165 and ARCT-154 are based upon the similar 
LNP-formulated replicon RNA vaccine construct, ARCT-021, which has completed a Phase 
1/2 clinical trial and is currently in two Phase 2 clinical trials. The LNP used in ARCT-021 
contains the same lipids as the LNP for ARCT-165 and ARCT-154, and the RNA sequence 
of the replicase component of the replicon in ARCT-021 has 97% sequence homology with 
the replicase in ARCT-165 and ARCT-154. The principal difference in the sequences is that 
the mRNA in ARCT-021 codes for the Wuhan strain spike protein whereas the mRNA in 
ARCT-165 codes for the spike protein of the B.1.351 variant, which contains the mutations 
D80A, D215G, E484K, K417N, N501Y A701V and additionally the D614G mutation; the 
mRNA in ARCT-154 codes for the spike protein of the Wuhan-D614G variant. 
Because the principal differences between ARCT-021 and ARCT-165/ARCT-154 are 
primarily limited to the SARS-CoV-2 variant spike protein that is expressed, these changes 
only constitute a change of antigen within a platform, consistent with the “platform” 
approach described in relevant regulatory guidances (FDA 2020a; EMA 2021). As such, 
Arcturus Therapeutics is using the non-clinical tissue distribution data, Good Laboratory 
Practices toxicology data, and prior human clinical trial data generated with ARCT-021 to 
support clinical development of ARCT-165 and ARCT-154. Please refer to the IB for a 
description the results of non-clinical studies conducted with ARCT-021. ARCT-021 has 
been evaluated in a Phase 1/2 clinical trial (ARCT-021-01) in healthy adult participants in 
Singapore (completed; final report pending) an open-label extension trial (ARCT-021¬02 
which participants from ARCT-021-01 have rolled into) which is ongoing, and this study 
(ARCT-021-04) which has completed enrollment and two interim analyses and remains 
ongoing. 
ARCT-021 has been administered to more than 500 participants in these clinical trials. The 
data that are shared in this protocol are regarded as draft but inform the characterization of 
the safety and immunogenicity profile and thereby the preferred dose for use in later phase 
trials. The data from the ARCT-021-04 trial have been shared with the independent DSMB 
that has endorsed the continuation of the study without modification. 
The first-in-human study ARCT-021-01 has completed with 106 participants enrolled and 
vaccinated with either ARCT-021 (N=78) or placebo (N=28). The study was conducted in 
healthy adult participants in Singapore. At the time of IB version 4.0 finalization, the study 
report is not final but the available data are summarized in the IB. 
Analysis of the open-label extension study ARCT-021-02 has not yet been conducted. 
At the time of IB version 4.0 finalization, the present study has completed enrollment of 
579 participants. Two interim analyses have been conducted. Across the analyzed clinical 
experience to date, ARCT-021 has been generally safe and well tolerated at doses ≤7.5 µg. In 
study ARCT-021-01, the 10-µg dose tested was associated with more systemic AEs, 
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including Grade 3 events. In the clinical trials conducted thus far, no vaccine-related SAEs 
have occurred in ARCT-021-treated participants, and 8 AEs have led to discontinuation. 
Most (>90%) ARCT-021-treated participants in each study experienced at least one solicited 
AE. In each study, the majority of solicited events were Grade 1/mild or Grade 2/moderate. 
A single participant reported Grade 4 solicited events (dizziness, fatigue, nausea, chills, 
headache). 
The most common solicited AEs were injection site pain, injection site tenderness, headache, 
fatigue, myalgia, arthralgia and chills. The majority of solicited events had onset on the day 
after dosing and were no longer reported by the end of 7 days post-dose. 
In the ARCT-021-01 study, the overall incidence of solicited events was generally lower in 
older adults but in the phase 2 study, which represents the largest exposure at clinically 
relevant doses (ie, 5 µg and 7.5 µg), the incidence was similar between younger and older 
adults. 
Solicited AE reporting appears to decline slightly with second dose of ARCT-021. There 
may be a slight increase in Grade 3 solicited AE reporting following dosing with 7.5 µg 
ARCT-021 as compared with 5 µg ARCT-021. 
Unsolicited AE reporting is less frequent following ARCT-021 as compared to solicited AEs. 
The most common unsolicited AEs in both studies include headache, fatigue, injection site 
tenderness, diarrhea, elevated CPK, neutropenia, lymphopenia, urticaria and hematuria, 
which was not confirmed on microscopy. 
Overall, no trends for vaccine-related abnormalities were observed in ECGs or vital signs 
following vaccination with ARCT-021. Other safety laboratory assessments with patterns of 
interest include declining hemoglobin values (most likely due to blood sampling during trial 
participation), slight shifts in potassium values, and slight shifts in lymphocyte and 
neutrophil count. These laboratory abnormalities have been asymptomatic, and the minority 
have been reported as clinically significant changes. 
Transient, asymptomatic lymphopenia and neutropenia have been observed with other 
mRNA SARS-CoV-2 vaccines (Mulligan 2020; Sahin 2020; VRBPAC 2020), however, 
lymphopenia is thought to be a normal physiological response (innate immune-stimulation-
related redistribution of lymphocytes into lymphoid tissues) to immune stimulation from the 
vaccine (Sahin 2020, Kamphuis 2006). 
Immunogenicity results following vaccination with ARCT-021 showed a robust IgG immune 
response to the full-length SARS-CoV-2 spike glycoprotein at all doses evaluated. At doses 
≥3 µg, GMT for PRNT50 neutralizing antibody responses tested with a clinical isolate of 
SARS-CoV-2 were within the range of titers observed in convalescent plasma from 
COVID-19 patients tested in the same assay at the same laboratory. Spike-specific T-cell 
responses were observed in response to stimulation with peptides from the spike glycoprotein 
and the CD4+ response was Th1-dominant. 
The evaluation of safety data across the hundreds of participants dosed with ARCT-021 
demonstrates that the vaccine leads to mild to moderate, transient AEs following vaccination 
for the majority of individuals. Overall AE reporting may decrease with second vaccination. 
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Taken together, the favorable safety profile and clear signs of immunogenicity to the vaccine 
antigen of ARCT-021, given the fundamental similarities between the ARCT-021, 
ARCT-154, and ARCT-165 vaccines and, given the encouraging nonclinical data supporting 
immune responses to SARS-CoV-2 variants, support the continued clinical development of 
these three vaccines intended to prevent COVID-19. 
1.6 
Rationale for Dose Regimen Selection 
The doses and schedules of ARCT-021, ARCT-154, and ARCT-165 used in this study are 
based on the evaluation of both preclinical and clinical data arising from the ARCT-021 
program. As ARCT-154 and ARCT-165 include the same lipid nanoparticle formulation and 
RNA encoding for a replicon and a SARS-CoV-2 spike protein (albeit spike proteins with 
minor differences in amino acid composition), the safety and immunogenicity profile is 
expected to be informed by the experience with ARCT-021. 
The doses selected for the priming and booster vaccination series in this study are based on 
data from the following sources: 
• Study ARCT-021-01: a Phase 1/ 2 dose ranging study enrolling younger adults (21 to 
55 years of age) and older adults (56 to 80 years of age). In this study, doses of 
7.5 µg given as a single dose and 2 doses of 5.0 µg (separated by 28 days) were well 
tolerated and immunogenic in younger and older adults. 
• Repeat-dose toxicity studies in rabbits: in these studies rabbits were given 2 or 
3 doses of either 20 µg or 40 µg ARCT-021 separated by 14 days. In these dosed 
animals, ARCT-021 was associated with continued increases in anti SARS-CoV-2 
IgG levels and the NOAEL was assigned at the highest dose evaluated (40 µg) based 
on the safety profile. These data support the administration of up to 3 doses of 
ARCT-021 (including the two priming vaccination doses of 7.5 µg ARCT-021 
planned for administration to Study Group 3 of this study and a booster dose of 5 μg 
ARCT-021 planned for a subset of participants in all 4 Study Groups). 
• Based on the accumulation of data from study ARCT-021-01 (see the IB for more 
detail) and the review of the interim analysis data from this study, in protocol version 
4.0 of this study, single doses of 5 µg of ARCT-021 are selected for use for priming 
vaccination in future Phase 3 studies and single 5-μg doses of ARCT-021, 
ARCT-154, and ARCT-165 are selected for use for booster vaccination. These data 
support that single 5-µg doses of ARCT-021 demonstrated ≥4-fold seroconversion 
against SARS-CoV-2 spike protein in more than 90% participants when measured by 
MSD assay, and the reactogenicity profile of ARCT-021 was mild or moderate in the 
majority of individuals vaccinated. 
Further details on ARCT-021, ARCT-154, and ARCT-165 can be found in the Investigator’s 
Brochure. 
1.7 
Risk Benefit Assessment 
Detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ARCT-021, ARCT-154, and ARCT-165 is provided in the IB. A summary 
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of the potential risks of administration of these vaccines, together with potential mitigation 
for these risks is shown in Table 1-1. 
 
 
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Table 1-1 
Risk Minimization Measures Included in Clinical Trials of 
LUNAR-COV19 Vaccines 
Risk 
Mitigation 
Local and Systemic Reactogenicity 
• 
Vaccination via the IM route results in a 
lower rate of local reactions than 
intradermal (ID) or subcutaneous (SC) 
injection (Zhang 2015). 
• 
Aseptic cleansing of the intended 
vaccination site. 
• 
Local injection site reactions may be treated 
with acetaminophen (paracetamol), 
ibuprofen, or other NSAIDs and/or with 
topical agents (eg, ice or heat). 
• 
Solicited systemic AEs such as headache, 
fever, myalgia may be treated 
symptomatically with ibuprofen or 
acetaminophen, but administration of these 
agents within 24 hours prior to study 
vaccine administration is prohibited. 
• 
Individuals should be asked if they have a 
known history of allergy to any of the 
vaccine components prior to receiving any 
dose of ARCT-021, ARCT-154, or 
ARCT-165 vaccine. Individuals with a 
known severe allergy to any of these 
components should not be vaccinated. 
o 
ARCT-021 (frozen liquid 
formulation) includes nucleic acid 
(mRNA), four lipids (ATX-126, 
DSPC, cholesterol, PEG2000-
DMG), HEPES buffer, sucrose, 
glycerol, and sodium chloride 
o 
ARCT-021/ARCT-154/ARCT-165 
(lyophilized formulations) include 
nucleic acid (mRNA), four lipids 
(ATX-126, DSPC, cholesterol, 
PEG2000-DMG), sucrose, 
Kolliphor P188Bio, potassium 
sorbate, and sodium chloride. 
• 
Allergic AEs may be treated with 
corticosteroids, H1/H2 blockers as indicated 
and if not otherwise contraindicated. 
• 
For solicited adverse events that are 
confirmed by review by the Investigator to 
be grade 3 or higher, or for anaphylaxis or 
immediate-type hypersensitivity reactions 
of any grade (within ≤4 hours after vaccine 
administration), subsequent doses of study 
vaccine will not be administered 
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Table 1-1 
Risk Minimization Measures Included in Clinical Trials of 
LUNAR-COV19 Vaccines 
Risk 
Mitigation 
Lymphopenia and Neutropenia 
• 
There are no specific mitigations as these 
events are not preventable. However, events 
of lymphopenia and neutropenia observed 
in the first in human study ARCT-021 were 
transient and resolved spontaneously. 
Hematology (CBC) safety laboratory values 
will be collected and monitored in 
ARCT-021-04 Study. 
Vaccine-Associated Enhanced Respiratory Disease 
(VAERD) if Subsequently Infected with 
SARS-CoV-2 
• 
Vaccination of mice with ARCT-021 
produced robust neutralizing antibody 
response, CD8+T cell response and a 
balanced, Th1dominant, Th1/Th2 response 
across all doses (De Alwis 2020) 
• 
In a SARS-CoV-2 challenge study in a 
mouse model carrying the human ACE-2 
receptor (huACE-2 transgenic mouse), a 
single dose of ARCT-021 at 2 µg or 10 µg 
completely protected mice from lung 
disease and death following challenge with 
a lethal dose of SARS-CoV-2 (De Alwis 
2020) 
• 
A Th1-dominant CD4+ response was 
observed on ICS evaluation of subjects at 
the interim analysis of first-in-human study 
ARCT-021-01 
• 
Eligibility criteria for early phase studies 
exclude participants with comorbidities that 
increase risk for severe COVID-19 
• 
Participants in clinical trials will be 
followed up for at least 1-year after 
vaccination to assess long-term risk 
• 
In Arcturus Therapeutics Phase 2 and 3 
studies, an independent DSMB will assess 
the risk of VAERD 
 
Other potential risks of trial participation beyond those associated with study vaccine include 
risks relating to blood sampling and breach of confidentiality. 
Blood sampling may be associated with transient asthenia, risk of fainting, bruising, or 
infection at the blood sampling site. Risk of infection is reduced by cleansing of the skin 
prior to blood withdrawal. Risk of fainting is reduced by performing blood sampling with the 
participant in a seated position. 
As study participation involves provision of personal health information by the participant to 
the site staff, measures are in place to reduce the risk of sharing of this personal information 
with others. Measures include maintenance of personal information in secure locations (eg, 
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locked file cabinets and/or password protected electronic filing systems). Only personnel 
involved in the conduct, oversight, monitoring, or auditing of this trial will be allowed access 
to this personal information that is collected. All publications from this study will not 
disclose personal information of the participants. Study results disclosed in public locations 
such as www.clinicaltrials.gov (CT.gov 2020) will not include personal information of any 
enrolled participant. 
There may be other risks, discomforts or side effects from participation in this study that are 
currently unknown. There is no direct benefit to study participants beyond a potential benefit 
to society resulting from improved understanding of investigational vaccines to prevent 
SARS-CoV-2 virus. Vaccination with ARCT-021, ARCT-154, or ARCT-165 may or may 
not provide protection against SARS-CoV-2 infection. Vaccination with placebo is not 
expected to provide protection against SARS-CoV-2 infection. 
At the time of the planned initiation of this Phase 2 study, there remains an ongoing global 
health crisis due to outbreak of SARS-CoV-2 virus. No preventative vaccines have achieved 
full approval for widespread use. 
Arcturus Therapeutics has initiated preclinical and clinical studies with an investigational 
vaccine ARCT-021 intended to prevent SARS-CoV-2 virus. The available safety data 
gathered to date reflect that the study vaccine has been well tolerated and is immunogenic. 
Additionally, preclinical studies with ARCT-154 and ARCT-165 have demonstrated binding 
antibody and neutralizing antibody responses to the Wuhan strain and variant strains 
including B.1.1.7, P.2 and B.1.351. These data support a favorable risk/benefit profile and 
initiation of this Phase 2 clinical study. 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives and Endpoints 
The primary objective(s) and endpoints are presented in Table 2-1. For estimands, see 
Section 7.1. 
Table 2-1 
Primary Objectives and Endpoints 
Primary Objectives 
Endpoint Description 
• 
To assess the safety and reactogenicity of 
ARCT-021 compared to placebo for priming 
vaccination 
Safety will be evaluated in all participants receiving at 
least 1 administration of study vaccine (ARCT-021 or 
placebo) and will be summarized for each vaccination 
as number and percentage of participants with: 
• 
Any unsolicited adverse event (AE) initiating 
within 28 days after each study vaccine 
administration, by severity and relationship 
to study vaccine 
• 
Any medically attended adverse event 
(MAAE), new onset of chronic disease 
(NOCD), AE leading to 
discontinuation/withdrawal or serious 
adverse event (SAE) through Early 
Termination 
• 
Safety laboratory assessment before and 
7 days after each study vaccine 
administration, by toxicity grade 
Reactogenicity will be evaluated in all participants 
receiving at least a single administration of study 
vaccine and will be summarized for each vaccination 
as number and percentage of participants with: 
• 
Any solicited local or systemic AE initiating 
within 7 days after each study vaccine 
administration, by toxicity grade 
• 
To assess the neutralizing antibody responses 
of ARCT-021 compared to placebo for 
priming vaccination 
Neutralizing antibody (NAbs) responses will be 
evaluated in all participants receiving at least 1 
administration of study vaccine (ARCT-021 or 
placebo). 
• 
Geometric Mean Titer (GMT) measured at 
all time points 
• 
Geometric Mean Fold-rise from baseline 
(GMFR); measured at all time points after 
baseline (= Day 0) 
• 
Percentages of participants with ≥2- and 
4-fold increase in titer from baseline 
(Seroconversion [SC]); measured at all time 
points after baseline 
• 
GMT ratio (ARCT-021/placebo) measured at 
all time points 
• 
To select the dose and schedule for use in the 
Phase 3 study in adult participants 
Safety and reactogenicity data after each priming 
vaccine administration and immunogenicity responses 
measured 28 days after each priming vaccination will 
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Table 2-1 
Primary Objectives and Endpoints 
Primary Objectives 
Endpoint Description 
be evaluated in younger (≥18 to <56 years) and older 
(≥56 years) adults  
2.2 
Secondary Objectives and Endpoints 
The secondary objectives and endpoints are presented in Table 2-2. For estimands, see 
Section 7.1. 
Table 2-2 
Secondary Objectives and Endpoints 
Secondary Objectives 
Endpoint Description 
• 
To assess the binding antibody responses of 
ARCT-021 compared to placebo for priming 
vaccination 
Binding antibody (BAb) responses will be evaluated 
in all participants receiving at least 1 administration of 
study vaccine (ARCT-021 or placebo). 
• 
GMC and GMC ratio at all time points 
• 
GMFR and SC at all time points after 
baseline 
2.3 
Exploratory Objectives and Endpoints 
The exploratory objectives and endpoints are presented in Table 2-3. For estimands, see 
Section 7.1. 
Table 2-3 
Exploratory Objectives, and Endpoints 
Exploratory Objectives 
Endpoint Description 
• 
To evaluate cell-mediated immune (CMI) 
responses in participants receiving 
ARCT-021, ARCT-154, and ARCT-165 
versus placebo for priming vaccination 
CMI responses to SARS-CoV-2 spike antigen may be 
measured in a subset of participants (CMI subset): 
• 
Cytokine-producing SARS CoV-2 Spike 
protein-specific T-cells 
o 
as measured by flow cytometry and 
intracellular cytokine (Tumor 
necrosis factor (TNF) α, Interleukin-
2 (IL-2), Interferon-γ (IFN- γ), IL-4, 
and IL-13) staining assay at all time 
points 
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Table 2-3 
Exploratory Objectives, and Endpoints 
Exploratory Objectives 
Endpoint Description 
• 
To evaluate safety, reactogenicity, and 
immunogenicity responses in participants 
receiving ARCT-021, ARCT-154, 
ARCT-165 versus placebo booster 
vaccination given 6 months after priming 
vaccination 
Safety: 
• 
Any unsolicited AE initiating within 28 days 
after booster dose of study vaccine 
administration, by severity and relationship 
to study vaccine (ARCT-021, ARCT-154, 
ARCT-165 or placebo) 
• 
Any MAAE, NOCD, AE leading to 
discontinuation/withdrawal or SAE through 
Early Termination 
• 
Safety laboratory assessment prior to and 7 
days after booster vaccine administration, by 
toxicity grade 
Reactogenicity: 
• 
Any solicited local or systemic AE initiating 
within 7 days after booster vaccine 
administration, by toxicity grade 
Immunogenicity: 
• 
Binding and neutralizing antibody responses 
(GMFR, SC, GMC, GMT, BAbs/NAbs ratio) 
before and after booster administration 
• 
CMI responses before and after booster 
administration 
(CMI subset) 
• 
To evaluate the incidence of confirmed 
COVID-19 in participants vaccinated with 
ARCT-021, ARCT-154, ARCT-165 versus 
placebo 
Confirmed COVID-19 will be assessed in all 
participants starting 7 days after first study vaccine 
(ARCT-021, ARCT-154, ARCT-165 or placebo) 
administration and will include: 
• 
Confirmation of COVID-19 symptoms 
• 
Confirmation of SARS-CoV-2 infection by 
reverse transcriptase-polymerase chain 
reaction (RT-PCR) 
• 
Collection of COVID-19 diagnoses made 
outside of study-related procedures 
• 
To evaluate the incidence of asymptomatic 
SARS-CoV-2 infection in participants 
vaccinated with ARCT-021, ARCT-154, 
ARCT-165 versus placebo 
Asymptomatic SARS-CoV-2 will be assessed in all 
participants starting 7 days after first study vaccine 
and will include: 
• 
Confirmation of SARS-CoV-2 infection by 
RT-PCR 
• 
Confirmation of seroconversion of SARS 
CoV-2 nucleocapsid (N) antibody at time 
points after Day 14 
• 
To assess for vaccine associated enhanced 
respiratory disease (VAERD) following 
vaccination with ARCT-021, ARCT-154, 
ARCT-165 versus placebo 
Confirmed COVID-19 cases will be evaluated by an 
unblinded Data Safety Monitoring Board (DSMB) for 
frequency and severity in ARCT-021-, ARCT-154-, 
ARCT-165- and placebo-vaccinated  
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Table 2-3 
Exploratory Objectives, and Endpoints 
Exploratory Objectives 
Endpoint Description 
• 
To assess the immune responses of 
ARCT-021, ARCT-154, ARCT-165 
compared to placebo using other exploratory 
assays (eg, plaque reduction neutralizing titer 
[PRNT], or assays evaluating for responses 
to SARS-CoV-2 variants) 
If additional assays and the corresponding blood 
samples are available, additional immune antibody 
responses may be evaluated in some or all participants 
receiving at least 1 administration of study vaccine 
(ARCT-021, ARCT-154, ARCT-165 or placebo). 
• 
Immunogenicity assays and endpoints will be 
further defined in the SAP 
 
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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is a multiregional, multicenter, Phase 2, randomized, observer-blind study performed in 
younger and older adult participants. Enrolled participants will be randomly assigned to 
receive either study vaccine (ARCT-021 or placebo [0.9% sterile saline]) as the priming 
vaccination series or ARCT-021, ARCT-154, ARCT-165, or placebo as the booster 
administration. This study will evaluate the safety, reactogenicity, and immunogenicity of the 
study vaccine in younger and older adult participants. 
Approximately 600 participants will be stratified by age group (300 each in younger (≥18 to 
<56 years of age or ≥21 to <56 years of age if in Singapore) and older (≥56 years of age). At 
Day 0, participants will be stratified by age and then randomly assigned (ARCT-021:placebo 
in a ratio of 3:1) to receive 2 doses of study vaccine separated by 28 days and at Day 208, 
participants will be randomly assigned to ARCT-021, ARCT-154, ARCT-165, or placebo 
(for Study Groups 1, 2, 3 only) for a third (booster) dose of study vaccine given at 180 days 
after second study vaccination (Day 208). The randomization ratio of ARCT-021, 
ARCT-154, ARCT-165, placebo will be 1:1:1:1 for Study Groups 1, 2, 3 and the 
randomization ratio will be 1:1:1 for ARCT-021, ARCT-154, ARCT-165 (no placebo 
assignment) for any remaining participants in Study Group 4. 
Participants who complete study procedures through Day 98 will be offered the opportunity 
to determine whether they are eligible for study re-enrollment to ensure dosing with 
ARCT-021. Participants may also to seek an approved COVID-19 vaccine, if available 
locally and recommended by local authorities. 
Study vaccine will be administered in an observer-blind fashion. 
With Protocol Version 6.0, the last study vaccine doses are intended for administration by 
15 December 2021 and participants will be followed for safety and immunogenicity through 
at least 56 days after last vaccination. The last study visit will be an Early Termination visit 
rather than Final Visit. 
The total study participation for each participant would be described as follows: 
• Total participation of up to Day 353 for participants who did not enroll and who 
received booster vaccine; 
• Total participation of up to Day 396 for participants who did not re-enroll and who 
did not receive booster vaccine; 
• Total participation of up to Day 264 after re-enrollment. 
At a subset of clinical sites, all enrolled participants will also undergo blood sampling for 
evaluation of CMI responses. 
The overall design is shown in Figure 3-1. 
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Figure 3-1. 
ARCT-021-04 Study Design 
 
 
*For Group 4 participants who are eligible to re-enroll into the study following Day 98, the randomization for 
re-enrollment will be 1:1:1 between Study Groups 1, 2, 3 only (receiving ARCT-021 vaccine). 
3.1.1 
Rationale for Study Design 
This Phase 2 study is designed to evaluate the safety and immunogenicity of the ARCT-021 
vaccine administered according to 3 different schedules for priming vaccination and to 
explore one of three vaccines (ARCT-021, ARCT-154, and ARCT-165) versus placebo given 
as a single dose for booster vaccination in 2 age groups of healthy adults. Younger (≥18 to 
<56 years) and older (≥56 years) adult participants will be evaluated for their responses to the 
ARCT-021 vaccine versus placebo. Safety, reactogenicity, and immunogenicity data 
gathered following the priming vaccination series will be used to select a dose schedule of 
ARCT-021 that will be used in the next clinical trial in adults. In addition, durability of 
immune response and the impact of booster dose administration will be investigated within 
this study design. 
The rationale for re-randomization is based on consideration for participants in the study who 
are assigned to the placebo group in a study under execution in the midst of a global health 
crisis. Allowing re-enrollment provides these participants access to active study vaccine (ie, 
ARCT-021) designed to reduce the risk of COVID-19 disease, should this be aligned with 
the presiding health authority’s perspective and with the participant’s perception of personal 
risk. Targeting earliest re-entry after Day 98 allows for approximately 4 months of safety 
comparison in these participants to provide a meaningful comparator group to those 
participants assigned to ARCT-021 at the start of the study. 
Starting with Version 4.0 of the protocol, multiple booster vaccine candidates will be 
evaluated in participants who may have previously received ARCT-021 priming vaccination. 
2
Younger Adults
(≥21 to <56 years: Singapore; 
≥18 to <56 years: US)
Older Adults
(≥ 56 years)
͂300 parƟcipants
͂300 parƟcipants
First Priming 
VaccinaƟon:
Day 0
Second Priming 
VaccinaƟon:
Day 28
Group 1:
Placebo
Group 2:
5 µg 
ARCT-021
Group 3:
7.5 µg 
ARCT-021
IniƟal
RandomizaƟon 
3:1*
Booster
VaccinaƟon:
Day 208
Group 4:
Placebo
Group 1:
7.5 µg 
ARCT-021
Group 2:
5 µg 
ARCT-021
Group 3:
7.5 µg 
ARCT-021
Group 1:
Placebo
Group 2:
5 µg 
ARCT-021
Group 3:
7.5 µg 
ARCT-021
Group 4:
Placebo
Group 4:
Placebo
Group 1:
7.5 µg 
ARCT-021
Group 2:
5 µg 
ARCT-021
Group 3:
7.5 µg 
ARCT-021
Group 4:
Placebo
RandomizaƟon 
1:1:1:1
RandomizaƟon 
1:1:1
RandomizaƟon 
1:1:1
RandomizaƟon 
1:1:1:1
ARCT
021 5 µg
ARCT
154 5 µg
ARCT
165 5 µg
ARCT
021 5 µg
ARCT
154 5 µg
ARCT
165 5 µg
ARCT
021 5 µg
ARCT
154 5 µg
ARCT
165 5 µg
Placebo
ARCT
021 5 µg
ARCT
154 5 µg
ARCT
165 5 µg
Placebo
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ARCT-165 and ARCT-154 are SARS-CoV-2 vaccines that express spike protein from the 
B.1.351 and D614G strains in contrast to ARCT-021 that expresses spike protein from the 
Wuhan strain. Safety, tolerability, and immunogenicity data gathered in this study will 
characterize responses following administration of ARCT-021 vaccine for priming and 
booster vaccination and will characterize responses following administration of ARCT-154 
and ARCT-165 vaccines for booster vaccination. These data will be used to inform future 
clinical development planning for each of these investigational vaccines. 
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4 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA 
4.1 
Selection of Study Participants 
Approximately 600 participants will be enrolled in Singapore and the United States. 
Participants will be assigned to study vaccine only if they meet all of the inclusion criteria 
and none of the exclusion criteria. 
Participants who withdraw from the study after initial randomization will not be replaced. 
4.1.1 
Inclusion Criteria 
Each participant must meet all of the following criteria to be enrolled in this study: 
Consent and Compliance 
1. Individuals or legally authorized representatives must freely provide consent to study 
participation as described in Section 9.3. 
2. Individuals must agree to comply with all study visits and procedures (including 
blood and saliva or nasal swab sampling, Diary completion, receipt of telephone calls 
from the site). 
3. Individuals must be willing and able to adhere to the prohibitions and restrictions 
specified in this protocol. 
4. Individuals who are sexually active in relationship(s) of childbearing potential must 
be willing to adhere to contraceptive requirements as specified in Appendix 3: 
Contraceptive Guidance. 
Age and Gender 
5. Individuals who are adult male or female ≥18 to <56 years of age (except in 
Singapore where adults are ≥21 to <56 years of age) or ≥56 years of age at the time of 
signing of the informed consent. 
Type of Participant 
6. Individuals who are medically stable such that, according to the judgment of the 
Investigator, hospitalization within the study period is not anticipated and the 
individual appears likely to be able to remain on study through the end of protocol 
specified follow-up. 
4.1.2 
Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from the study: 
Medical Conditions 
1. Individuals with a history of laboratory-confirmed SARS-CoV-2 infection or 
clinically diagnosed COVID-19 disease. 
2. Individuals at high risk for severe COVID-19, including those with any of the 
following risk factors: 
a. Individuals with a history of malignancy EXCEPT: 
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i. Malignancy with low potential risk for recurrence after curative 
treatment (eg, history of childhood leukemia) or metastasis (for 
example, indolent prostate cancer) in the opinion of the Investigator 
ii. Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease 
iii. Adequately treated uterine cervical carcinoma in situ without evidence 
of disease 
iv. Localized prostate cancer 
b. Chronic kidney disease Stage 3 or worse defined as estimated glomerular 
filtration rate <60 mL/min/1.73 m2) 
c. Chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis 
d. Cardiovascular conditions INCLUDING: 
i. Hypertension uncontrolled for age according to the Eighth Joint 
ii. National Committee guidelines (James 2014) 
iii. Congestive heart failure by New York Heart Association classification 
≥2 (Dolgin 1994) 
iv. Recent (within 6 months prior to first study vaccination) exacerbation 
of coronary artery disease as manifested by cardiac intervention, 
addition of new cardiac medications for control of symptoms, or 
unstable angina 
v. Cardiomyopathy 
vi. Pulmonary hypertension 
e. Immunocompromised state from solid organ transplant 
f. Obesity (body mass index ≥30 kg/m2) 
g. Sickle cell disease or other hemoglobinopathies 
h. Has smoked within the past 1 year. This includes vaping, tobacco, and 
marijuana products. 
i. Type 2 diabetes mellitus with glycosylated hemoglobin ≥8% within the past 2 
months 
3. Individuals with severe and/or uncontrolled cardiovascular disease, respiratory 
disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, and 
neurological illness, as judged by the Investigator (mild/moderate well-controlled 
comorbidities are allowed). 
Diagnostic Tests 
4. Individuals with a positive test for human immunodeficiency virus (HIV), hepatitis B 
surface antigen, or hepatitis C virus antibodies (HCV Abs) at Screening. 
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Medical Conditions 
5. Individuals with a history of hypersensitivity or severe allergic reaction (ie, 
anaphylaxis, generalized urticaria, angioedema, or other significant reaction) to any 
licensed or investigational vaccine. 
6. Individuals with a history of autoimmune disease or an active autoimmune disease 
requiring therapeutic intervention, including but not limited to: systemic or cutaneous 
lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré 
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia 
purpura, glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal 
arteritis), psoriasis, and insulin-dependent diabetes mellitus (type 1). 
7. Individuals with significant infection or other acute illness, including body 
temperature >100.4°F (>38.0°C) on the day prior to or day of randomization (See 
also: Section 4.2.1). 
8. Individuals with medical or psychiatric condition or laboratory abnormality that may 
increase the risk of study participation or, in the Investigator’s judgment, make the 
individual inappropriate to enroll into the study. 
9. Individuals with a recent (within 1 year) history of, or current drug or alcohol abuse 
or positive drug/alcohol test at Screening (except marijuana, where legal or analytes 
that reflect routine use of prescribed medications, as determined by Investigator 
review and documentation). 
10. Individuals with a positive or indeterminate pregnancy test or who are known to be 
pregnant at the time of Screening. 
11. Individuals who are breastfeeding or plans to breastfeed from the time of study 
enrollment through 60 days after the last study vaccination. 
12. Individuals who are intending to become pregnant within 60 days of last study 
vaccination. 
13. Individuals with confirmed or suspected immunosuppressive or immunodeficient 
state, including asplenia. 
14. Individuals with bleeding diatheses or conditions associated with prolonged bleeding 
that would, in the opinion of the Investigator, contraindicate intramuscular injection. 
15. Individuals with any other significant disease, disorder, or finding that may 
significantly increase the risk to the participant because of participation in the study, 
affect the ability of the participant to participate in the study, or impair interpretation 
of the study data as determined by the Investigator or Sponsor. 
Prior/Concomitant Therapy 
16. Individuals who have previously received investigational; emergency/investigational 
use-authorized, or approved coronavirus (SARS-CoV, MERS-CoV, SARS-CoV-2) 
vaccine or treatments or who have current or future plans to receive SARS-CoV-2 
vaccine or to participate in another interventional study to prevent or treat 
COVID-19. 
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17. Individuals who have received investigational or non-registered product (drug or 
vaccine) other than the study vaccine within 30 days or 5 half-lives of investigational 
drug/vaccine, whichever is longer, preceding the first dose of study vaccine. 
18. Individuals who have received blood/plasma products or immunoglobulin, within 
60 days before study vaccine administration or who anticipate receipt of these 
products during study participation. 
19. Individuals who have received systemic immunosuppressants (including cytotoxic 
agents) or immune-modifying drugs for >14 days in total within 6 months prior to 
Screening (for corticosteroids ≥20 mg/day of prednisone equivalent) or who are 
anticipated to require immunosuppressant treatment during study participation. 
a. Topical tacrolimus is allowed if not used within 14 days prior to Screening 
and not anticipated to be required during study participation. 
b. Intra-articular, intrabursal, inhaled, intranasal, or topical (skin or eyes) 
corticosteroids are allowed. 
20. Individuals with previous participation in other studies involving study intervention 
containing lipid nanoparticles or VEEV-derived vaccine. 
Other Exclusions 
21. Individuals who are Investigator site staff members, employees of Arcturus 
Therapeutics or the Clinical Research Organization directly involved in the conduct 
of the study, or site staff members otherwise supervised by the Investigator or 
immediate family members of any of the previously mentioned individuals. 
Prior/Concomitant Therapy - Continued 
The following criterion was separated from Exclusion Criterion #19 in Protocol Amendment 
2 (26 February 2021). 
22. Has received or plans to receive a licensed, live replicating vaccine within 28 days 
prior to first study vaccination or a licensed inactivated or non-replicating vaccine 
within 14 days prior to first study vaccination. Please also refer to Section 5.10.2.1 for 
on-study vaccine considerations. 
4.1.3 
Screen Failures 
Screen failures are individuals who do not meet one or more inclusion criteria or meet at least 
1 of the exclusion criteria. Repeat safety laboratory testing at Screening will not be permitted, 
unless Screening assessments are repeated due to lapse of the 14-day screening visit window. 
A fever the day before screening does not result in a screening failure, but it would result in a 
delay of vaccine administration (Section 4.2.1). Individuals who have signs of significant 
infection and/or fever must not be randomized until resolution/stabilization of the illness 
and/or absence of fever for 48 hours. Any individual who fails to recover according to these 
preconditions should be marked as a screen failure. Any individual who meets these 
conditions of recovery and who is otherwise eligible for study participation may be 
randomized to receive study vaccine. 
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In the event the screening visit window lapses, participants should be re-consented and the 
following procedures/ assessments performed: an interview (to re-review medical history, 
current symptoms, COVID-19 exposures, medications, recent vaccinations, and to assess 
continued availability for study procedures), urine test for drugs/alcohol, physical 
examination, measurement of vital signs (systolic and diastolic blood pressure, heart rate, 
respiratory rate, and pulse oximetry), body temperature, height and weight, and pregnancy 
testing for participants of childbearing potential. 
4.2 
Delaying or Discontinuing Study Treatment and Participant Withdrawal From 
the Study 
4.2.1 
Delay in Study Treatment 
Body temperature must be measured, and the participant asked about recent antipyretic or 
analgesic use prior to each administration of study vaccine. 
The following events constitute criteria for delay of study vaccination and the window of 
delay specified forthwith: 
• Acute moderate or severe infection with or without fever at the time of dosing (delay: 
until afebrile for 48 hours and clinically recovered according to Investigator 
judgment) 
o Participants with minor illness and without fever may be vaccinated if deemed 
appropriate according to Investigator judgment 
• Fever without signs of acute illness, defined as body temperature ≥38.0°C (100.4°F) 
(delay: until afebrile for 48 hours) 
o Use of antipyretics or analgesics within 24 hours (delay: at least 24 hours) 
Vaccination may be performed once these criteria are no longer met and this 
will not constitute a protocol deviation. 
4.2.2 
Discontinuation of Study Vaccine (Participant) 
Additional administrations of study vaccine are absolutely contraindicated for any of the 
following reasons: 
• Grade 3 solicited AEs (as confirmed by Investigator review), severe anaphylaxis, 
severe related (possibly, probably, or definitely) unsolicited AEs, or immediate type 
hypersensitivity (≤ 4 hours after injection) following the administration of the study 
vaccine. 
• Any SAE judged to be related (possibly, probably, or definitely) to vaccine. 
• Pregnancy in a female participant. 
• Any clinically significant medical condition that, in the opinion of the Investigator, 
poses an additional risk to the participant if he/she continues to participate in the 
study. 
• New information becomes available that makes further participation unsafe. 
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A participant should not receive subsequent administrations of study vaccine for any of the 
following additional reasons: 
• Participant receives an off-study COVID-19 vaccine 
• Participant is lost to follow-up. 
• As deemed necessary by the Investigator for non-compliance or other reasons. This 
may include previously undisclosed or new conditions that meet exclusion criteria. 
• Termination of the trial. 
If any of these events occur during the study, then the participant must not receive additional 
doses of study vaccine. Furthermore, the participant will be encouraged to continue study 
participation for safety and immunogenicity evaluations through the Early Termination Visit 
after the first vaccination. 
4.2.3 
Withdrawal/Discontinuation From Study 
Participants are free to withdraw from participation in the study at any time upon request, 
without any consequence. 
A participant will be discontinued from the study if any of the following occur prior to first 
administration of study vaccine: 
• The participant requests to discontinue study participation. 
• Study vaccine is not administered. 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study may include the following: 
• Refused further follow-up. 
• Lost to follow-up. 
• Death. 
• Study terminated by the Sponsor. 
• AEs. 
• Participant request. 
• Investigator request. 
• Protocol deviation. 
• Opportunity to receive an approved COVID-19 vaccine (with protocol version 4.0 
participants who wish to seek off-study COVID-19 vaccine will be allowed to 
continue with study participation). 
If a participant approaches the site requesting to receive off-study COVID-19 vaccine, the 
participant should be counseled and reminded of the study design allowing greater possibility 
of access to active study vaccine at either Day 98 or additional study vaccine at Day 208 
(booster administration). The participant should be encouraged to demonstrate evidence of a 
scheduled appointment to receive off-study COVID-19 vaccine. If after counseling and 
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confirmation of the appointment, a study participant maintains his/her interest in receiving 
off-study vaccine, he/she will be advised that the Sponsor and the site will not provide the 
off-study vaccine, the participant is advised to preferably schedule off-study vaccine at least 
28 days after last dose of study vaccine, and the participant will not be eligible to receive 
additional doses of study vaccine. However, the participant is invited to continue study 
procedures through to Early Termination Visit. 
For any participant terminating the study sooner than 60 days after last study vaccine 
administration, the following guidelines should be observed: 
• The participant should also be reminded about use of highly effective contraception 
until 60 days following last study vaccine exposure. 
• Any pregnancy occurring during this window should be reported to the Sponsor as 
soon as feasible. 
• Should the PI/Site become aware at any time of any death or pregnancy occurring in 
these subjects it should be reported to Sponsor. 
The following guidance applies for participants who choose to receive authorized COVID-19 
vaccine: 
• After early termination visit procedures and data entry by the site, participants may be 
unblinded. 
• If the participant received ARCT-021, the participant is advised to wait 4 weeks since 
last study vaccination before seeking licensed vaccine. 
• Should a former participant experience any severe or serious or concerning adverse 
events following receipt of the approved COVID-19 vaccine, they should notify the 
site. These events would be collected as post-study AEs. The participant should also 
report these adverse events to the vaccine provider. 
The Investigator must capture the reason for withdrawal in the case report form (CRF) for all 
participants. 
If a participant withdraws consent to receive booster vaccine administration but chooses to 
remain in the study, he/she would continue study procedures through Day 388 wherein the 
participant would exit the study after Early Termination Visit procedures are performed. 
If a participant withdraws altogether from the study, he/she may request destruction of any 
remaining samples taken and not tested, and the Investigator must document any such 
requests in the site study records and notify the Sponsor or CRO accordingly. 
If a participant withdraws consent and specifies no further contact with him/her or persons 
previously authorized by the participant to provide this information, this should be 
documented by the Investigator in the study source documents. In the event that vital status 
(whether the participant is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law. 
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4.2.4 
Discontinuation of Study Dosing (All Participants) 
The DSMB, based on their review of the blinded or unblinded safety data (including 
assessment for potential VAERD) will recommend whether the study should terminate, 
proceed unmodified, or proceed but with changes to the protocol. 
With Protocol Version 6.0 Arcturus Therapeutics has taken the decision to discontinue study 
vaccinations as of 15 December 2021 and to target 16 February 2022 as the last visit for 
study participants. 
The end of the study (EOS) is defined as the date on which the last participant completes the 
last study visit (including the EOS visit and any additional long-term follow-up). Any 
additional long-term follow-up that is required for monitoring of the resolution of an AE or 
finding may be appended to the clinical study report (CSR). 
4.2.5 
Pausing Rules 
Enrollment of and dosing of all enrolled participants will be paused if any of the following 
events occur in participants who have been vaccinated with ARCT-021, ARCT-154, or 
ARCT-165: 
• Any SAE considered possibly, probably, or definitely related to study vaccine 
administration (as assessed by the Investigator and review of the SRC) 
• Any anaphylactic reaction 
• Any clinically apparent hypersensitivity episode that is considered at least moderate 
in severity, is considered probably or definitely related to study vaccine 
administration (as assessed by the Investigator and review of the SRC) and has the 
following features: 
o is not confined to the injection site 
o is immediate in onset (within ≤4 hours after vaccination) OR if delayed, 
involves more than one organ system. 
• Any death due to SARS-CoV-2 infection or 2 cases of severe SARS-CoV-2 infection, 
as confirmed by DSMB, in participants randomized to receive 
ARCT-021/ARCT-154/ARCT-165 vaccine 
Events meeting Pausing Rule definitions will be referred to the SRC (which will remain 
blinded to the individual participants’ vaccine assignments), where the case details and the 
assessment of the event causality will be assessed. Should the SRC confirm that a Pausing 
Rule was met, investigators will be immediately (same day) instructed to pause dosing and 
regulatory authorities will be notified within 48 hours of determination that a pausing rule 
has been met. Study vaccine administrations will continue to be paused while the case 
undergoes review. This/these AE(s) and the SRC assessment will also be referred to the 
DSMB, which will review the unblinded details. After evaluation of these relevant data, the 
DSMB will make a recommendation of whether the study should be discontinued, should be 
modified prior to resumption of vaccine administrations, or should continue without protocol 
modification. This recommendation will be provided to regulatory authorities and 
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investigators within 48 hours of the DSMB recommendations and prior to resumption of 
study procedures (if applicable). 
4.2.6 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled 
visits or is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
If the participant continues to be unreachable, he/she will be considered to have withdrawn 
from the study. 
4.2.7 
Replacements 
Participants who withdraw from the study after randomization will not be replaced. 
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5 
STUDY TREATMENTS 
5.1 
Method of Assigning Participants to Study Groups 
Assignment of participants to Study Groups will proceed through the use of an interactive 
response technology (IRT) system. The site personnel (study coordinator or specified 
designee) will be required to enter or select information including but not limited to the 
password, the protocol number, participant age and the participant code (a unique number 
identifying the participant). The site personnel will then be provided with a vaccine 
assignment and randomization number. The IRT system will provide a confirmation report 
containing the participant code, randomization number, and study intervention allocation 
assigned. The confirmation report must be stored in the site’s files. 
Additional guidance relating to study vaccine assignment is included in the Investigator Site 
File. 
The Study Group assignments are summarized in Synopsis Table 1-1. Participants enrolled in 
this study (N=600) will be stratified by age (younger, older; N=300 in each age group). 
Within each age group, the participants will be randomly assigned to receive ARCT-021 or 
placebo for the primary vaccination (3:1 randomization ratio), which will consist of 
2 injections separated by 28 days (Day 0 and Day 28). At Day 208, participants will be 
randomly assigned to ARCT-021, ARCT-154, ARCT-165, or (for Study Groups 1, 2, 3 only) 
placebo for a third (booster) dose of study vaccine given 180 days after second study 
vaccination (ie, on Day 208). The randomization ratio of ARCT-021, ARCT-154, 
ARCT-165, and placebo will be 1:1:1:1 for Study Groups 1, 2, 3, and the randomization ratio 
of ARCT-021, ARCT-154, and ARCT-165 will be 1:1:1 (no placebo assignment) for any 
remaining participants in Study Group 4. 
Participants who complete study procedures through Day 98 will be offered the opportunity 
to determine whether they are eligible for study re-enrollment to ensure dosing with 
ARCT-021. 
After Day 98 and until Day 198, participants will be contacted to determine whether they are 
interested, if eligible, in re-enrolling in the study in order to receive active study vaccine. 
For those participants interested in receiving ARCT-021 provided by the Sponsor, an 
unblinded team member will confirm whether the participant has been assigned to Study 
Group 4 (placebo) or ARCT-021 (Study Groups 1, 2, or 3). Participants who request to re-
enroll in the study but whose treatment assignments are determined to be in Study Groups 1, 
2, and 3 will be informed they have already received ARCT-021 and will be advised to 
continue to remain on the study schedule. 
Participants who intend to exit the study to seek approved COVID-19 vaccine will be 
allowed, after the approval of protocol version 4.0, to receive these vaccines. See 
Section 4.2.3 for additional guidance. 
Participants in Study Group 4 who have not otherwise met withdrawal criteria for study 
vaccine will sign a consent form, will undergo Early Termination Visit, will be assigned a 
new participant ID number, and will re-enter the study at Day 0. Re-enrolled participants will 
be randomly assigned to Study Groups 1, 2, and 3. 
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Study vaccine will be administered in an observer-blind fashion. Participants will be 
followed for safety and immunogenicity through 570 days after first vaccination. 
Participation in the study past Day 388 is optional for participants enrolled in the United 
States. For participants enrolled in Singapore, participation through the Early Termination 
Visit is expected. At a subset of clinical sites, all enrolled participants will also undergo 
blood sampling for evaluation of CMI responses. 
Vaccine doses will be assigned as shown in Synopsis Table 1-1 and illustrated in Synopsis 
Figure 1-2. 
5.2 
Treatments Administered 
As this is an Observer Blind study, the preparation and administration of study vaccines 
(ARCT-021, ARCT-154, ARCT-165, or placebo) are to be performed only by unblinded 
staff members. The participant will be asked to look away while the study vaccine is present 
and is being administered. Blinded staff members are not to be present in the room at the 
time when study vaccines are prepared and administered. 
The study vaccine will be prepared for injection as a single 0.5-mL dose for each participant 
based on the randomization assignment and as detailed in the Pharmacy Manual. 
The IM injection should be into the deltoid muscle in the non-dominant arm, unless visibility 
of the intended vaccination site is obscured by tattooing or skin abnormalities, a pre-existing 
injury, or unless the participant expresses a preference to vaccinate the alternate arm. 
Unblinded personnel (Section 5.8) who will not participate in any other aspect of the study, 
will perform study vaccine accountability (Section 5.5.2), preparation (Section 5.4), and 
administration. The investigator will designate unblinded medically qualified personnel (not 
involved in assessments of study endpoints) to administer the vaccine according to the 
procedures stipulated in this protocol and Pharmacy Manual. 
Study-specific training will be provided. 
At each visit when study vaccine is administered, participants will be monitored for a 
minimum of 30 minutes or until clinically stable after administration. Assessments will 
include vital sign measurements and monitoring for local or systemic reactions. 
The study site will be appropriately staffed with individuals with basic CPR 
training/certification. 
Either on site resuscitation equipment and personnel or appropriate protocols for the rapid 
transport of participant to a resuscitation area/facility are required. 
Should a participant experience a severe adverse event (including but not limited to 
hypersensitivity or anaphylaxis) immediately following study vaccine administration, the 
participant should be observed until clinically stable and the CRO Medical Monitor should 
be notified immediately (Section 6.4.1.3.1). Additional evaluation or testing may be 
performed based on discussion between the Medical Monitor and the Investigator, and 
subject to Medical Monitor approval. 
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5.3 
Identity of Study Vaccine 
Each of the study vaccines, ie, ARCT-021, ARCT-154, and ARCT-165, is a lipid-
nanoparticle-formulated RNA product. The RNA comprises a replicon based upon VEEV 
virus in which RNA coding for the virus structural proteins has been replaced with RNA 
coding for the SARS-CoV-2 full-length spike glycoprotein. ARCT-021 is based on the spike 
protein of the SARS-CoV-2 Wuhan strain, ARCT-154 is based on the spike protein of the 
Wuhan strain containing the D614G mutation, and ARCT-165 is based on the spike protein 
of the variant of concern B.1.351 SARS-CoV-2 strain. 
For each of these LUNAR-COV19 vaccines, the nanoparticle composition includes 4 lipid 
excipients (ionizable cationic lipid, ATX-126; neutral lipid, 1,2-distearoyl-sn-glycero-3-
phosphocholine (DSPC); cholesterol; and polyethylene glycol-lipid conjugate, PEG2000-
DMG). Liquid ARCT-021 is dispersed in HEPES buffer, pH 
 and 2 cryoprotectants 
(sucrose and glycerol) as well as sodium chloride. Lyophilized ARCT-021, ARCT-154, and 
ARCT-165 are dispersed in Tris buffer, pH 
 and 3 lyo-protectants (sucrose, potassium 
sorbate and Kolliphor P188 Bio) as well as sodium chloride. 
Liquid ARCT-021, for the initial 2 doses on Day 0 and Day 28, is presented as a sterile, 
frozen, aqueous formulation with 0.2 mg/mL of mRNA 2002 and as a 1 mL fill 
(0.2 mg/1 mL) in 2-mL Type I glass vials. ARCT-021 is a white to off-white liquid when 
thawed with a nominal 
 and osmolality of approximately 
 mOsm/kg. 
For booster dose administration of ARCT-021, ARCT-154, ARCT-165, the drug product is 
presented as a lyophilized, sterile formulation in a multi-dose Type I glass vial. For 
lyophilized drug product, upon reconstitution with 0.9% sodium chloride injection, it is a 
clear, opalescent liquid with a nominal 
 and an osmolality of approximately 
 mOsm/kg. 
Storage and handling instructions for all study vaccines are described in the Pharmacy 
Manual. 
The comparator (placebo) vaccine for this study is 0.9% sterile saline and will be provided to 
the site by the Sponsor. 
Sterile water for injection (SWFI) and sterile saline for dilution of the liquid (frozen) 
ARCT-021 product and sterile saline for reconstitution of the lyophilized LUNAR-COV19 
booster doses will also be provided to the site by the Sponsor. SWFI is only for use with the 
frozen liquid formulation given as a priming vaccine. It is not used for the formulation 
of the lyophilized vaccine. 
ARCT-021, ARCT-154, and ARCT-165 characteristics are provided in the IB. 
5.4 
Preparation of Study Vaccine 
Please refer to the Pharmacy Manual provided by the Sponsor or designee for more detailed 
instructions for study vaccine preparation. 
5.4.1 
Preparation of ARCT-021 liquid presentation for priming vaccinations: 
ARCT-021 for priming vaccination (Day 0, Day 28) is supplied as a concentrated single-
use vial containing frozen liquid. Upon withdrawal of the concentrated vaccine from the 
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original vial and dilution in a new sterile vial, this second vial will be used for administration 
of doses to those participants assigned to the same study group only. All doses of study 
vaccine must be administered within 6 hours of first puncture of the ARCT-021 study 
vaccine vial. The final volume of ARCT-021 for IM administration is 0.5 mL. See the 
Pharmacy Manual for further considerations. 
5.4.2 
LUNAR-COV19 vaccines (ARCT-021, ARCT-154, ARCT-165) lyophilized 
presentation for booster administration 
ARCT-021, ARCT-154, ARCT-165 for booster vaccination (Day 208) are each supplied as 
a single-use, multiple dose vial containing lyophilized powder. Prior to use, sterile saline 
(0.9%) is added to the study vaccine vial for reconstitution. This reconstituted solution is 
intended for preparation of multiple syringes for administration but all doses of study vaccine 
must be administered within 6 hours of first puncture of the study vaccine vial. 
The final volume of ARCT-021, ARCT-154, and ARCT-165 for booster IM administration is 
0.5 mL. See the Pharmacy Manual for further considerations. 
5.5 
Management of Clinical Supplies 
5.5.1 
Study Vaccine Packaging and Storage 
The Sponsor will provide the Investigator with packaged LUNAR-COV19 drug product 
containers labeled in accordance with specific country regulatory requirements. Syringes, 
vials, sterile saline, sterile water and needles will also be provided to the site by the Sponsor. 
Doses of lyophilized study vaccines (ARCT-021, ARCT-154, and ARCT-165) must be 
stored in separately marked areas of the freezer from vials of frozen liquid ARCT-021 
and must be stored separately marked areas of the freezer from each other. 
The study staff is required to document the receipt, dispensing, and return/destruction 
LUNAR-COV19 supplies provided by the Sponsor. The site must destroy or return all 
unused vials of LUNAR-COV19 to the Sponsor or designee for destruction. Used or thawed 
vials of LUNAR-COV19 should be destroyed by the site or delegate after drug accountability 
has been done by the unblinded study monitor. 
5.5.2 
Study Vaccine Accountability 
The Investigator will maintain accurate records of receipt of all study vaccines, including 
dates of receipt. In addition, accurate records will be kept regarding when and how much 
study vaccine is administered to each participant in the study. Only participants enrolled in 
the study may receive any study vaccine and only authorized site personnel may supply or 
administer the study vaccine. Reasons for departure from the expected dispensing regimen 
must also be recorded. At the completion of the study, to satisfy regulatory requirements 
regarding drug accountability, all study vaccines will be reconciled and destroyed according 
to applicable regulations. Further guidance and information for the final disposition of 
unused study vaccines are provided in the Pharmacy Manual. 
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5.5.3 
Other Supplies for Participant Use 
Study sites will distribute Sponsor-provided rulers and thermometers for participants to 
measure injection site erythema and induration/swelling reactions and body temperature, 
respectively. The measurements will be captured in the Diary. If participants do not have or 
do not wish to use a personal phone as a diary, enrolled participants may be provided a 
device for electronic diary use by the Sponsor/delegate. 
Participants will be provided a Home Test Kit if the participant reports possible COVID-19 
symptoms or risk of exposure to SARS-CoV-2, and the participant cannot come into the 
clinic for evaluation. Within this kit, there will be an instruction card, a pulse oximeter for 
measuring oxygen saturation, and saliva collection tubes with instructions on how to return 
samples to the site. 
5.6 
Overdose Management 
Study vaccine (LUNAR-COV19 vaccines or placebo) errors (including overdose, underdose, 
and administration errors) must be documented as protocol deviations. A brief description 
should be provided in the deviation, including whether the participant was symptomatic (list 
symptoms) or asymptomatic, and whether the event was accidental or intentional. 
Dosing details should be captured on the Dosing CRF. 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of study treatment is not itself an 
adverse event, but it may result in an adverse event. If the participant receives a dose of study 
vaccine (LUNAR-COV19 vaccines or placebo) that exceeds protocol specifications and the 
participant is symptomatic, then the symptom(s) should be documented as an AE and be 
reported per Section 6.4.1.3. 
5.7 
Medication Errors 
Should an overdose or administration error occur, the Investigator or designee should refer to 
the Guidance for the Investigator section of the Investigator’s Brochure and contact the 
Sponsor or designee within 24 hours. 
5.7.1 
Treatment of Medication Errors 
There are no known treatments for potential overdose of study vaccine. Unless there is a user 
error leading to failure to administer any volume of study vaccine, "catch-up" vaccine 
administrations will not be performed. 
5.8 
Blinding 
The study is blinded to study site staff, participants and the sponsor up to Day 98 and again 
from Day 208 (administration of the booster) up to Early Termination. Between Day 98 and 
Day 208 a partial unblinding occurs as follows: 
Between Day 98 and Day 198, certain site staff may become unblinded to some participants’ 
treatment assignment to determine eligibility for re-enrollment (Section 5.1). At this point, 
these site staff will be partially unblinded in that they would know whether the participants in 
question received active study vaccine or placebo during the initial priming vaccinations, but 
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they would not know the actual vaccine dose or schedule. With the act of re-enrolling in the 
study or team members with access to the IRT, partial unblinding of a participant’s priming 
vaccination might also occur. 
At Day 208, participants are re-randomized to booster vaccination, which will be 
administered in a blinded fashion. Therefore, the booster vaccine assignment would be 
blinded until the final study analysis (except in cases of medical emergency). 
The blinded site and CRO staff, the Sponsor team providing direct oversight of the study, and 
the SRC will remain blinded to individual participant vaccine assignments for the duration of 
the study. The identification of Sponsor team members and blinding status will be 
documented in an unblinding memo. 
Steps to ensure data integrity during the period of unblinding are described in Section 5.8.1. 
The following measures are taken to maintain the blind during the blinded periods of the 
study: 
The study vaccines will be administered in an observer-blind fashion. 
Each of the study vaccines will be prepared by an unblinded pharmacist and in accordance 
with the Pharmacy Manual. 
Unblinded personnel (of limited number) will be assigned to vaccine accountability 
procedures and will prepare study vaccine for all participants. These personnel will have no 
study functions other than study vaccine management, documentation, accountability, 
preparation, and administration. They will not be involved in participant evaluations and will 
not reveal the identity of study vaccine to either the participant or the blinded study site 
personnel involved in the conduct of the study unless this information is necessary in the case 
of an emergency. 
• Unblinded health care providers will administer the study vaccine. They will not be 
involved in assessments of any study endpoints. 
• Unblinded site monitors, not involved in other aspects of monitoring, will be assigned 
as the study vaccine accountability monitors. They will have responsibilities to ensure 
that sites are following all proper study vaccine accountability, preparation, and 
administration procedures. 
• An unblinded statistical and programming team will perform the pre-planned interim 
analyses. 
• Team members at the CRO and the Sponsor who are unblinded to individual and 
group treatment assignments are also documented in the files of each respective party. 
• A DSMB will review the interim data to safeguard the interests of clinical study 
participants and to help ensure the integrity of the study. The DSMB will review 
unblinded statistical outputs and interim analysis results, provided by the unblinded 
statistician, and make recommendations to the Sponsor. 
In order to maintain an observer-blind design, investigators, site staff, participants, and CRO 
staff with oversight of study conduct will remain blinded to vaccine assignments for the 
study duration. 
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The dosing assignment will be concealed by having the unblinded personnel prepare the 
study vaccine in a secure location not accessible or visible to blinded study staff members. 
Prepared syringes will be protected from view by the application of a label, as there is a 
slight difference in appearance between prepared ARCT-021 and saline. Only designated 
unblinded site staff will perform the injection of prepared study vaccine. Once the injection is 
completed, only the blinded study staff will perform further assessments and interact with the 
participants. Access to the randomization code will be strictly controlled at the pharmacy. All 
other site staff performing study-related assessments will be blinded for the duration of the 
study. 
5.8.1 
Breaking the Blind 
An individual participant’s study vaccine assignment will not be unblinded to the 
Investigator or other blinded study site staff until the end of the study unless: 1) awareness of 
the vaccine assignment is relevant to the care of study participant or 2) the participant 
requests re-entry into the study after Day 98 (and prior to Day 198) to receive ARCT-021. In 
the event that the blind needs to be broken because of a medical emergency, the Investigator 
may unblind an individual participant’s treatment allocation. After Day 98 and until Day 198, 
participants will be contacted to determine whether they are interested, if eligible, in re-
enrolling in the study in order to receive active study vaccine. An unblinded team member 
will confirm whether the participant has been assigned to Study Group 4. Participants in 
Study Groups 1, 2, and 3 will continue to remain on the study schedule. It is acknowledged 
these participants may be aware of having received ARCT-021 vaccine if the request to re-
enroll is made and this is declined by the site. However, the participants in Study Group 1, 2, 
and 3 will not be informed of the specific study group assignment. In addition, it is expected 
that the administration of subsequent study vaccine at Day 208 will be performed in an 
observer blind manner. 
Participants in Study Group 4 who have not otherwise met withdrawal criteria for study 
vaccine will be assigned a new participant ID number and will re-enter the study at Day 0. 
Re-enrolled participants will be randomly assigned to Study Groups 1, 2, and 3 and will 
receive study vaccine in an observer-blind manner. The actual ARCT-021 Study Group 
vaccine assignment will not otherwise be revealed to the participant or blinded team 
members until after study unblinding. 
To summarize, treatment assignment will be unblinded for participants who experience a 
medical emergency when knowing the treatment received is needed for clinical management. 
For participants who re-enroll in the study, treatment will be unblinded as to whether they 
received active study vaccine versus placebo for the initial priming vaccinations. Participants 
who decide to continue in the study to receive the Day 208 booster vaccination will remain 
blinded. 
To the extent possible, before emergency unblinding, the Investigator should contact the 
CRO Medical Monitor to discuss the medical emergency and the reason for revealing the 
actual treatment received by that participant. 
The study vaccine assignment will be unblinded through IRT. Reasons for unblinding must 
be clearly explained and justified in the electronic case report form (eCRF). The date on 
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which the code was broken together with the identity of the person responsible must also be 
documented. 
5.9 
Compliance With Study Treatment 
When participants are dosed at the site, they will receive the study vaccine directly from the 
designated unblinded health care professional, under medical supervision. The date and time 
of each dose administered in the clinic will be recorded in the source documents and 
recorded in the eCRF. The receipt of study vaccine and study participant identification will 
be confirmed at the time of dosing by a member of the study site personnel other than the 
person administering the study vaccine. 
5.10 
Concomitant and Rescue Therapies and Procedures 
The use of concomitant therapies or procedures defined in the following section must be 
recorded on the participant’s eCRF. Adverse events associated with administration of these 
therapies or procedures must also be documented on the appropriate eCRF. 
5.10.1 
Concomitant Therapy 
Study site staff must question the participant regarding any medications taken and 
vaccinations received by the participant and record the following information in the eCRF: 
• All non-study vaccinations administered within the period starting 28 days before the 
first dose of study vaccine. 
• All concomitant medications taken through 28 days after each dose of study vaccines. 
• All non-study vaccinations received at any point in the study. 
• Any concomitant medications used to prevent or treat COVID-19. 
• Any concomitant medications relevant to or for the treatment of an SAE, an NOCD, 
an MAAE, or an AE leading to discontinuation/withdrawal. 
• Participant will be asked in the Diary if they have taken any antipyretic or analgesic 
to treat or prevent fever or pain within 7 days after each study vaccine administration, 
including the day of dosing. Reported antipyretic or analgesic medications should be 
recorded in the source document by the site staff during the study visits or via other 
participant interactions (eg, telephone calls). 
5.10.2 
Prohibited Concomitant Therapy 
The use of the following concomitant medications and/or vaccines will not require 
withdrawal of the participant from the study but may determine a participant’s eligibility to 
receive a second dose or evaluability in the per-protocol analysis: 
• Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period. Off-study COVID-19 vaccine, if received, will 
lead to suspension of further administrations of study vaccine. However with protocol 
version 4.0, the participant may continue study participation. 
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• A non-study live, attenuated vaccine administered during the period from 28 days 
before through 28 days after each dose of study vaccine or any approved inactivated 
or recombinant vaccine that was administered within 14 days before or after any dose 
of study. 
• Immunoglobulins and/or any blood products administered during the study period 
(except for treatment of COVID-19). 
• Medications that suppress the immune system, including corticosteroids administered 
at doses of 20 mg prednisone equivalent/day or higher, with the exception of 
medications used in the treatment of COVID-19. 
If a participant receives/takes a prohibited vaccine or drug therapy, the Investigator and the 
CRO's Medical Monitor will make a joint decision about continuing or withholding further 
dosing from the participant based on the time the medication was administered, the drug’s 
pharmacology and pharmacokinetics, and whether use of the medication will compromise the 
participant’s safety or the interpretation of data. It is the Investigator’s responsibility to 
ensure that details regarding the concomitant medications are adequately recorded in the 
eCRF. 
All medication and interventions necessary for the appropriate care for the study participant, 
particularly to treat COVID-19, should be administered and appropriately documented along 
with the adverse event. 
• All concomitant medications must be recorded in the eCRF until 28 days after each 
dose of study vaccine. Thereafter, only non-study vaccinations received at any point 
in the study and concomitant medications associated with an SAE or MAAE or for 
treatment of COVID-19 will be entered in the eCRF. 
5.10.2.1 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (eg, surgery/biopsy, physical 
therapy) or diagnostic assessment (eg, blood gas measurement, bacterial cultures) performed 
between signing of the informed consent document and the participant’s last protocol 
specified study visit. 
All concomitant procedures must be recorded in the eCRF until 28 days after the last dose of 
study vaccine. Thereafter, only concomitant procedures associated with an SAE, MAAE, or 
evaluation of COVID-19 cases will be entered in the eCRF. 
5.10.3 
Rescue Medicine 
Epinephrine for subcutaneous injection, diphenhydramine for intravenous injection, and any 
other medications and resuscitation equipment for the emergency management of 
anaphylactic reactions must be available in close proximity in the room where the 
vaccination is administered. 
5.11 
Dose Modification 
No dose modifications will be allowed. However, at Day 98 participants may request to re-
enroll into the study. Participants assigned to the placebo group (Study Group 4), will be 
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allowed to re-enter the study and will be randomly assigned to one of the three ARCT-021-
containing groups (Study Groups 1, 2, and 3). 
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6 
STUDY ASSESSMENTS AND PROCEDURES 
Before any study procedures are performed, all potential participants will sign an informed 
consent form (ICF). Additional procedural details related to the ICF are provided in 
Section 9.3. 
A schedule of events is provided in Appendix 1: Schedule of Events. 
Overview of Procedures 
Screening (up to 14 days): At Screening, individuals willing to participate in the study will 
undergo informed consent followed by an interview (to review medical history, current 
symptoms, COVID-19 exposures, medications, recent vaccinations, and availability for study 
procedures), urine drug/alcohol test, physical examination, blood sampling, and measurement 
of vital signs (heart rate, blood pressure, and respiratory rate), body temperature, height and 
weight, and pregnancy testing for participants of childbearing potential. At the completion of 
Screening, the Investigator will review all data for determination of participant eligibility. 
Eligible participants will be enrolled and assigned a dedicated participant ID number. 
Note: Exposure to COVID-19 is defined as a participant who has had close contact 
(within 6 feet [2 meters] for a total of 15 minutes or more) to a person with 
laboratory-confirmed COVID-19 (or clinically compatible illness) or to a person who 
has tested positive for COVID-19 (laboratory confirmed) but has not had any 
symptoms. This is irrespective of whether the person with COVID-19 or the contact 
was wearing a mask or whether the contact was wearing respiratory personal 
protective equipment (PPE). 
If there is uncertainty regarding past exposure to SARS-CoV-2, a specimen can be 
collected at the Investigator’s discretion for testing for SARS-CoV-2 by RT-PCR at a 
local laboratory. 
Visits: All enrolled participants may have up to 12 scheduled visits, including Screening, 
Dose 1 Administration (Day 0), Follow-up 1 (Day 7), Follow-up 2 (Day 14), Dose 2 
Administration (Day 28), Follow up 3 (Day 35), Follow-up 4 (Day 42), Follow-up 5 (Day 
56), Booster Administration (Day 208), Booster Follow-up 1 (Day 215), Booster Follow-up 2 
(Day 236), and Early Termination Visit. Visit windows are provided in the Schedule of 
Events (Appendix 1: Schedule of Events). 
For participants in Study Group 4 who re-enroll in the study, clinic visits representing Dose 1 
Administration (Day 0), Follow-up 1 and 2 (Day 7 and Day 14), Dose 2 Administration 
(Day 28), Follow up 3 and 4 (Day 35 and Day 42), Follow-up 5 (Day 56) will be performed 
again, and, as such, may have up to 19 scheduled visits. Informed consent will be obtained 
again for these participants prior to re-enrollment into the study. 
Unscheduled visits will occur if warranted for the evaluation of AEs or possible COVID-19 
illness. 
Administration Visits: At each Dose and Booster Administration visit, participants will 
undergo an interview, pregnancy testing (if the participant is a woman of childbearing 
potential), physical examination, blood sampling for immunogenicity and safety laboratory 
assessment testing (blood sampling must occur prior to administration of study vaccine), and 
saliva sample (or, if not available, by nasal or nasal turbinate swab) for testing for 
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SARS-CoV-2 virus by RT-PCR, vital signs, pulse oximetry and body temperature 
measurement prior to and after receipt of study vaccine. 
During all Administration visits (Day 0, Day 28, and Day 208), all participants will be 
trained in how to measure body temperature, ruler use, how to report AEs in the Diary, what 
signs or symptoms of COVID-19 might be (Section 6.1), whom to call at the site and how 
quickly to call in the event of severe or serious AEs or signs of possible COVID-19 disease. 
At all later points of contact, participants will be reminded of this training. 
Follow-up Visits: At follow-up visits, participants will undergo an interview, vital signs, 
pulse oximetry, body temperature, blood sampling for immunogenicity and safety laboratory 
assessments, saliva for SARS-CoV-2 testing, and will be reminded of study-related 
procedures for data collection and site notification. At Follow-up visits performed 7 days 
after vaccine administration, blood will also be drawn for safety laboratory assessments. 
Symptom-directed physical examination may be performed at all visits if warranted by the 
interview. 
All Screening and Administration visits must be performed at the site. Follow-up visits and 
Unscheduled visits may be performed by telemedicine visits, or in a hospital setting, if 
warranted by clinical circumstances (eg, COVID-19 lockdown in the vicinity) and permitted 
by local regulations. 
Study Calls: Telephone calls will be performed one week after Follow-up Visit 2 and 
Follow-up Visit 4 and then between Follow-up 5 until the booster administration (Day 208) 
on the days shown in the Schedule of Events (Appendix 1: Schedule of Events) Telephone 
calls will then occur every week between Booster Follow-up 1 and Booster Follow-up 2; then 
every 4 weeks after Booster Follow-up 2 until the Early Termination Visit For participants in 
Study Group 4 who re-enroll in the study, telephone calls after Follow-up Visit 2, Follow-up 
Visit 4, and between Follow-up Visit 5 until the Booster Administration will be performed 
again unless these would fall after 16 February 2022. 
Electronic device contact (including COVID-19 reminders) will occur at least every week 
between clinic visits. 
The purpose of this call will be to evaluate for safety and to remind the participant of the 
required assessments (Diary completion, contact the site for potential symptoms of or 
exposure to COVID 19, and reminder for participants with confirmed COVID-19 to 
complete post diagnosis procedures [Section 6.1]). 
Unscheduled Visits: These visits will occur if warranted for the evaluation of reported 
symptoms of or exposure to COVID-19 illness (Section 6.1) or for the evaluation of AEs 
These visits will either occur at the clinic, by visit in the hospital (if medically unstable), or 
by telemedicine visit. 
For participants reporting symptoms suggestive of COVID-19 or exposed to COVID-19, 
visits will be accompanied by collection of a saliva or nasal swab specimen for testing. Saliva 
or nasal swab samples will be collected within 48 hours of symptomatic onset/known 
exposure for SARS-CoV-2 testing by RT-PCR. Blood sampling for SARS-CoV-2 antibodies 
will also be performed, if feasible. Blood sampling for SARS-CoV-2 antibodies will not be 
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performed for participants who have an unscheduled visit for evaluation of an AE that is 
unrelated to COVID-19. 
Beyond this protocol-specified testing, participants should be appropriately evaluated and 
treated for potential COVID-19 diagnosis and care. This may include locally run testing to 
confirm the COVID-19 diagnosis and/or to exclude other potential respiratory pathogens. 
Early Termination Visit: This visit will occur if a participant withdraws from study 
participation or based or based on Sponsor decision to terminate the study (as of Protocol 
Version 6.0). This visit will either occur at the clinic, by home visit, in the hospital (if 
medically unstable), or by telemedicine visit. 
An overview of key study procedures is shown in Synopsis Figure 1-3. 
Additional procedural specifics 
Solicited AEs will be evaluated by the participant and will include measurement of body 
temperature by thermometer and injection site reaction measurement by ruler. Both 
instruments and training on how to use them will be provided by the site. 
An electronic Diary (eDiary), either the participant’s own phone or a device provided by the 
Sponsor/delegate) will be used to collect the following: 
• Solicited local and systemic AEs through 7 days following each study vaccination. 
Should these AEs continue past 7 days after each study vaccination, continued 
collection of these events until resolution will also occur in the Diary. 
• Prompts for unsolicited AEs through the Early Termination Visit. Prompts will solicit 
for all unsolicited AEs through 28 days after last priming and booster vaccinations 
and for unsolicited AEs categorized as AEs leading to discontinuation/withdrawal, 
MAAEs, NOCDs, and SAEs through the Early Termination Visit. 
• Prompts for symptoms of COVID-19 disease through the Early Termination Visit. 
Blood sampling will be performed to collect the following: 
• Laboratory assessments for Screening (a list of laboratory parameters is provided in 
Appendix 2: Clinical Laboratory Tests). 
• All participants: Antibody assessments for neutralizing antibodies and SARS-CoV-2 
virus binding antibodies including full-length spike antibody, RBD and N antibody 
multiplex assay 
Subset of participants: CMI assessments by flow cytometry and cytokine staining. The 
analysis plan will be described in further detail in the SAP. 
Saliva and/or nasal swab testing will be performed as follows: 
• To measure SARS-CoV-2 virus by RT-PCR 
• To retain for additional testing of genetic sequencing, if warranted 
Telephone calls will be performed to collect the following: 
• To confirm Diary completion and to evaluate for unsolicited AEs (including MAAEs, 
NOCDs, SAEs, AEs leading to discontinuation/withdrawal) 
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• To confirm any changes in concomitant medications 
To evaluate for symptoms of COVID-19 disease and risks of exposure to COVID-19 
(Section 6.6). 
6.1 
Evaluation of Participants With Suspected COVID-19 
If a participant experiences any of the following potential symptom of COVID-19 
(irrespective of perceived etiology or clinical significance), he or she is instructed to contact 
the site immediately: fever, chills, cough, shortness of breath or difficulty breathing, fatigue, 
muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny 
nose, nausea or vomiting, and diarrhea. 
If the symptoms are confirmed, an Unscheduled Visit should occur. An exception to this rule 
is if the potential symptoms of COVID-19 are observed within 7 days following first study 
vaccine administration. Individuals with COVID-19 diagnosed prior to 7 days after first 
study vaccination will not be required to attend for an unscheduled visit but will be followed 
clinically for resolution/stabilization in accordance with local practice. 
As shown in Figure 6-1, for all other participants evaluated on the basis of clinical symptoms 
or risk of exposure as assessed at least 7 days after first vaccination, the Unscheduled Visit 
will be performed at the site (preferred) or via telemedicine visit within 48 hours of symptom 
onset or identified exposure, and saliva (or nasal swab or nasal turbinate swab) will be 
collected for testing for SARS-CoV-2 by RT-PCR. Repeat sample collection for 
SARS-CoV-2 should be performed within 120 hours of onset of symptoms if symptoms 
persist and the first SARS-CoV-2 test was negative. In addition to the saliva/nasal swab 
collection, visit procedures will include interview, physical examination, vital signs, pulse 
oximetry and body temperature measurement, and blood sampling for testing of N antibody 
to SARS-CoV-2. In the event the visit is performed via telemedicine, the physical 
examination, vital signs, and blood sampling for testing of N antibody to SARS-CoV-2 will 
not be required. Participants will be provided with a pulse oximeter, which, along with the 
previously provided thermometer, will be used to perform daily measurements. Please note: 
samples of blood (for binding antibody test for nucleocapsid) and saliva (for RT-PCR 
testing) sent to the central laboratory are not regarded as diagnostic tests. Therefore, if 
clinical suspicion of COVID-19/SARS-CoV-2 exposure exists, local laboratory testing 
should be performed and/or arrange with a primary care provider as clinically warranted to 
appropriately manage the care of the participant. 
An Unscheduled Visit should also be performed for any participant who reports potential 
exposure to COVID-19. This visit should be performed within 48 to 120 hours of the 
suspected exposure to COVID-19. 
Exposure to COVID-19 is defined as a participant who has had close contact (within 6 feet 
[2 meters] for a total of 15 minutes or more) to a person with laboratory-confirmed COVID-
19 (or clinically compatible illness) or to a person who has tested positive for COVID-19 
(laboratory confirmed) but has not had any symptoms. 
Note: This is irrespective of whether the person with COVID-19 or the contact was wearing a 
mask or whether the contact was wearing respiratory PPE. 
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An unscheduled clinic visit does not substitute for a participant’s routine medical care. 
Therefore, participants should be encouraged to seek evaluation and care, if appropriate, 
from their usual provider. 
Participants with confirmed COVID-19 should receive treatments/medications according to 
the standard of care. 
The first Unscheduled Visit performed for the evaluation of COVID-19 symptoms or 
exposure starts the beginning of the COVID-19 surveillance period. Starting the day after the 
Unscheduled Visit, the participant will be contacted daily by telephone or by telemedicine 
visits until: 
• An asymptomatic participant who has been exposed to COVID-19 has a negative 
RT-PCR test result 
• A participant with symptoms of COVID-19 and a positive RT-PCR clinically 
recovers or 14 days have passed since onset of symptoms. For participants with 
ongoing illness 14 days later, the COVID-19 event will be followed to resolution and 
the frequency of calls and unscheduled visits will be based on clinical discretion. 
• A symptomatic participant has two negative test (RT-PCR) results 
• Should a participant who was exposed to COVID-19, whose RT-PCR test is negative 
go on to develop symptoms suggestive of COVID-19 within the next 14 days, the 
participant should have another Unscheduled Visit and receive repeat RT-PCR 
testing. If COVID-19 is confirmed, the participant will undergo the follow-up 
described above. 
During daily check calls to the participant, the participant will be asked to verbally report the 
presence and severity of COVID-19-associated AEs, their highest body temperature and 
lowest oxygen saturation for that day, and the Investigator will determine if medical attention 
is required due to worsening of COVID-19 symptoms. 
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Figure 6-1. 
Schematic for Unscheduled Visit Evaluations 
 
 
*If the Unscheduled Visit is not held in person, this procedure is not performed. 
**If symptoms persist at 14 days, follow-up calls/visits to confirm clinical resolution are based on clinical 
discretion. 
6.2 
Efficacy Assessments 
Not applicable. 
6.3 
Immunogenicity Assessments 
Blood sampling for immunogenicity testing will be drawn according to the schedule of 
events (Appendix 1: Schedule of Events). In addition, at Days 28, 56, 208, and Day 236, an 
additional tube of blood will be drawn for purposes of immunogenicity exploratory testing. 
SARS-CoV-2 neutralizing antibody titer will be tested using pseudoviral microneutralization 
assay (Wuhan-Hu-1, D614G strain), and, if available, PRNT assay. If assays are available, 
additional strain-specific neutralizing antibody testing may be performed. The details of the 
assay and endpoints will be specified in the SAP prior to the time of the analysis. Please note: 
the protocol refers to geometric mean titer as the units of this assay throughout but the assay 
readout is a geometric mean concentration. 
SARS-CoV-2 binding antibodies will be tested using an MSD multiplex assay for full-length 
spike, RBD and N antigens. If available, the MSD assay will include analysis of 
SARS-CoV-2 variant strains. The details of the assay and endpoints will be specified in the 
SAP prior to the time of the analysis. 
CMI subset of participants: 
CMI responses will be evaluated using parametric flow cytometry for quantification and 
phenotyping and cytokine staining for TNF-α, IL-2, IFN- γ, IL-4, and IL-13. Assessments 
will be performed at Days 0, 14, 28, 42, 56, 208, 215, 236, and Early Termination (if 
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applicable) in participants enrolled at centers identified with capabilities for isolation of 
peripheral blood mononuclear cells (PBMCs). 
CMI testing will not be performed on participants re-enrolling at Day 98-198 (ie, placebo 
participants who re-enter study to receive ARCT-021 priming vaccinations). 
Additional details relating to the analysis of immunogenicity assessments will be described in 
the SAP. 
6.4 
Safety Assessments 
Safety assessments will include monitoring and recording of solicited and unsolicited AEs, 
MAAEs, NOCDs, AEs leading to discontinuation/withdrawal, SAEs, vital signs, pulse 
oximetry, body temperature measurements, and safety laboratory assessments. 
6.4.1 
Adverse Events 
6.4.1.1 
Definitions 
6.4.1.1.1 
Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to the study vaccine or their clinical significance. AE 
collection will begin after the signing of informed consent; however, AEs that occur prior to 
the administration of first dose of study vaccine (ie, non-treatment-emergent AEs) will be 
listed separately in the CSR. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of medicinal 
(investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An adverse event can therefore be any of the following: 
• Any unfavorable and unintended sign (including a clinically significantly abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
• Recurrence of an intermittent medical condition (eg, headache) not present at baseline 
• Any clinically significant deterioration in a laboratory value or other clinical test (eg, 
electrocardiogram, x-ray) that is associated with symptoms or leads to a change in 
study treatment or concomitant treatment or discontinuation from Study Drug 
• Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to administration of study vaccine (eg, Screening invasive procedures 
such as biopsies) 
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• Any solicited AE that lasts longer than 7 days after vaccination or that meets the 
definition of AE leading to discontinuation/withdrawal, MAAE, NOCD, or SAE will 
be captured in addition as an unsolicited AE 
6.4.1.1.2 
Serious Adverse Events 
An SAE is defined as any event that 
• 
results in death 
• 
is immediately life threatening 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
6.4.1.1.3 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected adverse drug reaction (SUSAR) is any SAE wherein a causal 
relationship to study vaccine is at least reasonably possible and wherein the nature or severity 
of the AE is not consistent with the Reference Safety Information in the ARCT-021 
Investigator's Brochure. 
6.4.1.1.4 
Medically Attended Adverse Events and New Onset of Chronic Disease 
An MAAE is an AE that leads to an Unscheduled Visit (including a telemedicine visit) with a 
healthcare provider (HCP, eg, nurse, nurse practitioner, physician's assistant, physician). This 
would include visits to a study site for unscheduled assessments (eg, rash assessment, 
abnormal laboratory follow-up, COVID-19 and visits to HCPs external to the study site (eg, 
urgent care, primary care physician). Investigators will review unsolicited AEs for the 
occurrence of any MAAEs. All MAAEs must be fully reported on the AE page of the eCRF. 
Under the category of MAAE, additional events reflected as the NOCD may be described. 
An NOCD is defined as any AE representing a new diagnosis of a chronic medical condition 
that was not present or suspected prior to enrollment. 
6.4.1.1.5 
Adverse Events Leading to Discontinuation/Withdrawal 
Any AE that leads to discontinuation of the vaccine (Section 4.2.2) and/or withdrawal from 
the study (Section 4.2.3) will be regarded as an AE leading to discontinuation/withdrawal. 
Investigators will review reasons for discontinuation/withdrawal report this on the 
appropriate eCRF page (AE eCRF for AEs leading to withdrawal of the study vaccine and 
Study Termination eCRF for reason for study discontinuation). 
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6.4.1.1.6 
Adverse Event of Special Interest 
An adverse event of special interest (AESI), including both serious or non-serious events, is 
one of scientific and medical concern specific to the Sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the Investigator to the Sponsor could be 
appropriate. 
Adverse events of special interest, if defined in the study protocol or associated documents, 
are required to be reported by the Investigator to the Sponsor immediately, no more than 
24 hours after the Investigator’s first knowledge of the event. 
No AESIs are specified for this study. 
6.4.1.1.7 
Clinical Events of Special Interest 
Clinical Events of Special Interest (CESI) are events relating to the detection of disease 
(SARS-CoV-2) activity relevant to the study vaccine. These events are analyzed separately 
from safety data; however, if the CESI demonstrates untoward signs or symptoms that, in the 
opinion of the Investigator, suggest the events are more likely related to study vaccine rather 
than to SARS-CoV-2, these signs/symptoms will be reported as AEs. 
To be considered as a CESI of COVID-19 the following case definition adapted from the CBER 
Guidance: Development and Licensure of Vaccines to Prevent COVID-19 (DHHS 2020) must 
be met: 
• The participant must have experienced at least 1 of the following systemic symptoms: 
fever (≥38ºC), chills, myalgia, headache, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea, fatigue, new olfactory and taste disorder(s), cough, 
shortness of breath, or difficulty breathing OR 
• Clinical or radiographical evidence of pneumonia; AND 
• The participant must have at least 1 test positive for SARS-CoV-2 by RT-PCR. 
To be considered as a CESI of asymptomatic SARS-CoV-2 infection, a participant who 
demonstrates none of the COVID-19 symptoms described above but who tests positive for 
SARS-CoV-2 on PCR test or anti-nucleocapsid antibody test (if nucleocapsid antibody 
negative prior to entry into the study) will be counted. 
6.4.1.2 
Eliciting and Documenting Adverse Events 
Adverse events will be assessed from the time the participant signs the informed consent 
form until exit from the study (Early Termination Visit). 
If the Investigator learns of any SAE, including a death, at any time after a participant has 
been discharged from the study, and he/she considers the event to be reasonably related to the 
study vaccine or study participation, the Investigator must promptly notify the Sponsor. 
At every study visit, participants will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. Any and all new changes to the participant’s 
health (including exacerbation of underlying disease) is regarded as an unsolicited AE. 
Participants will also be asked to complete a Diary for at least 7 days after each 
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administration of study vaccine. The Diary will collect participant responses relating to 
solicited AEs. 
In addition to participant observations, AEs identified from any study data (eg, clinically 
significant changes in safety laboratory assessments, physical examination findings, vital 
signs, or pulse oximetry) or identified from review of other documents (eg, participant Diary) 
that are relevant to participant safety will be documented on the AE page in the eCRF. 
All solicited AEs through 7 days after study vaccine administration will be summarized. 
Continuing solicited AEs after 7 days will be captured as unsolicited AEs and followed until 
stabilization/resolution. All unsolicited AEs through 28 days after study vaccine 
administration will be summarized. 
Unsolicited AEs that meet the protocol definition of MAAE, NOCD, SAE, or AEs leading to 
withdrawal/discontinuation will be captured for the duration of study participation. 
6.4.1.2.1 
Assessment of Severity 
The severity, or intensity, of an unsolicited AE refers to the extent to which an AE affects the 
participant’s daily activities. The intensity of the unsolicited AE will be rated as mild, 
moderate, or severe using the following criteria: 
Mild: 
These events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
OR 
 
An event usually transient in nature and generally not interfering with normal 
activities. 
Moderate: 
These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
normal functioning. 
OR 
 
An AE that is sufficiently discomforting to interfere with normal activities. 
Severe: 
These events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually 
incapacitating. 
OR 
 
An AE that is incapacitating and prevents normal activities. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity. Adverse events characterized as intermittent 
do not require documentation of onset and duration of each episode. 
Solicited local and systemic AEs will be categorized for severity by application of the DHHS 
Toxicity Grading Scale (Appendix 4: FDA Toxicity Grading Scales). 
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6.4.1.2.2 
Assessment of Causality 
The Investigator’s assessment of an unsolicited AE’s relationship to the study vaccine is part 
of the documentation process, but it is not a factor in determining what is or is not reported in 
the study. If there is any doubt as to whether a clinical observation is an AE, the event should 
be reported. 
Solicited AEs are, by definition, regarded as related to study vaccine. Therefore, causality is 
not assessed. 
The relationship or association of the study vaccine in causing or contributing to the AE will 
be characterized using the following classification and criteria: 
Unrelated: 
There is no association between the study vaccine and the reported event. 
 
Possible: 
Treatment with the study vaccine caused or contributed to the AE, ie, the event 
follows a reasonable temporal sequence from the time of vaccine administration 
or follows a known response pattern to the study vaccine but could also have 
been produced by other factors. 
 
Probable: 
A reasonable temporal sequence of the event with vaccine administration exists 
and, based upon the known pharmacological action of the drug, known or 
previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the Investigator’s clinical experience, the association of the event with 
the study vaccine seems likely. The event disappears or decreases on cessation 
or reduction of the dose of study vaccine. 
 
Definite: 
A definite causal relationship exists between vaccine administration and the 
AE, and other conditions (concurrent illness, progression/expression of disease 
state, or concurrent medication reaction) do not appear to explain the event. The 
event reappears or worsens if the study vaccine is readministered. 
6.4.1.3 
Reporting Adverse Events 
All unsolicited AEs reported or observed during the study will be recorded on the AE page in 
the eCRF. Information to be collected includes the following: 
• 
drug treatment 
• 
dose 
• 
event term 
• 
time of onset 
• 
investigator-specified assessment of severity and relationship to the study vaccine 
• 
time of resolution of the event 
• 
seriousness 
• 
any required treatment or evaluations 
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• 
outcome 
• 
whether the AE met the protocol definition of MAAE, NOCD 
• 
whether the AE led to study vaccine withdrawal 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs (solicited and unsolicited) will be followed to adequate resolution. MedDRA will be 
used to code all unsolicited AEs. 
Any medical condition that is present at the time that the participant is screened or prior to 
first dose administration but does not deteriorate should be reported as medical history rather 
than as an AE. However, if this medical condition deteriorates at any time during the study 
after first dose administration, it should be recorded as an AE. 
6.4.1.3.1 
Reporting Serious Adverse Events 
Any AE (solicited or unsolicited) that meets SAE criteria (Section 6.4.1.1) must be reported 
to the CRO Safety Line immediately (ie, within 24 hours) after site personnel first learn of 
the event. The Investigator will be requested to complete and transmit to the Sponsor or 
designee the SAE information using the AE eCRF in electronic data capture (EDC), or a 
paper form should the electronic system not be available. The following contact information 
is to be used for SAE reporting: 
24 Hour Safety Hotline: 
North America: 
 
EMEA/APAC: 
 
24 Hour Safety Hotline Fax: North America: 
 
EMEA/APAC: 
 
The Sponsor is required to notify national regulatory agencies and (in conjunction with the 
Investigator) local regulatory authorities about the safety of a study vaccine under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review 
Board/Independent Ethics Committee (IRB/IEC), and investigators. 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information from the Sponsor will review and then file it as appropriate and 
will notify the IRB/IEC, if appropriate according to local requirements. 
6.4.1.3.2 
Reporting Suspected Unexpected Serious Adverse Reactions 
The Sponsor or designee will promptly evaluate all SUSARs against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
investigators, IRBs/IECs, and applicable health authorities based on applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor or designee will assess 
the expectedness of these events using the ARCT-021 Investigator's Brochure 
The Sponsor will compare the severity of each SUSAR and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
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Reporting requirements will also be based on the Investigator's assessment of causality and 
seriousness, with allowance for upgrading (but not downgrading) by the Sponsor as needed. 
6.4.1.3.3 
Exceptions 
Because CESI events are typically associated with the disease under study, they will not be 
reported as SUSARs even though the event may meet the definition of a SAE. These events 
will be recorded on the CESI eCRF page in the participant’s eCRF. 
6.4.1.4 
Follow-Up of Participants Reporting Adverse Events 
All AEs must be reported on the appropriate page in the eCRF and followed to satisfactory 
resolution, until the Investigator deems the event to be chronic or not clinically significant, 
the event is considered to be stable, or the participant is lost to follow-up. 
For any participant terminating study participation at any time, any ongoing adverse events at 
the time of study withdrawal should be followed until resolution or stabilization (unless 
consent is withdrawn). Any vaccine-related serious adverse event that occurs after study 
withdrawal should be reported to the Sponsor as soon as possible. 
6.4.2 
Reporting of Clinical Events of Special Interest 
Any case of confirmed COVID-19 or asymptomatic SARS-CoV-2 infection will be regarded 
as a CESI (Section 6.4.1.1.7) and must be reported within 24 hours of Investigator 
notification to the Sponsor or designee during the study. Whilst the participant is enrolled in 
the study this will be performed by completion of a CESI eCRF. Surveillance for COVID-19 
and asymptomatic SARS-CoV-2 should be performed through the Early Termination Visit. 
The reporting instructions, including the fax number and email address for submitting paper 
forms can be found in the Investigator Site File for the study. 
All CESIs will be reviewed by the Sponsor/designee to determine if the case definition of 
severe COVID-19 is met. This definition is as follows: 
• Any virologically confirmed SARS-CoV-2 infection AND any of the following: 
o Signs of severe systemic illness: respiratory rate ≥ 30 per minute, heart rate 
≥ 125 per minute, and/or SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 
<300 mm Hg 
o Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or extracorporeal membrane oxygenation 
[ECMO]) 
o Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood 
pressure <60 mm Hg, or requiring vasopressors) 
o Significant acute renal, hepatic, or neurologic dysfunction 
o Admission to an Intensive Care Unit (ICU) 
o Death 
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6.4.3 
Clinical Safety Laboratory Assessments 
Any abnormal laboratory test results (hematology or clinical chemistry) or other safety 
assessments (eg, vital sign measurements) assessed as clinically significant in the medical 
and scientific judgment of the Investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition, are not to be reported as AEs or SAEs. 
AEs of clinically significant abnormal laboratory values should be graded using the 
unsolicited AE severity ratings (Section 6.4.1.2.1). 
The Investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study. If the laboratory reports are not 
transferred electronically, the values must be filed with the source information (including 
reference ranges). In most cases, clinically significant abnormal laboratory findings are those 
that are not associated with the underlying disease, unless judged by the Investigator to be 
more severe than expected for the participant's condition. 
Repeat safety laboratory testing at Screening will not be permitted unless the result is 
uninterpretable, or Screening assessments are repeated due to lapse of the 14-day screening 
visit window. 
All safety laboratory assessments performed at Day 0 and later visits and with results 
considered clinically significant abnormal should be repeated until the values return to 
normal or baseline or are no longer considered clinically significant by the Investigator. If 
such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified, and the Sponsor notified. 
All safety laboratory assessments, as defined in Appendix 2: Clinical Laboratory Tests, must 
be conducted in accordance with the Laboratory Manual and the Schedule of Events 
(Appendix 1: Schedule of Events). If laboratory values from nonprotocol-specified 
laboratory assessments performed at the institution’s local laboratory require a change in 
participant management or are considered clinically significant by the Investigator (eg, SAE 
or AE or dose modification), the results must be recorded in the eCRF. 
6.4.4 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the general 
status of the participant, the skin of the intended vaccine administration site, cardiovascular, 
respiratory, lymph nodes, gastrointestinal, and neurological systems. Height and weight will 
also be measured and recorded. A directed physical examination will include, at a minimum, 
assessments of the skin of the intended/actual vaccine administration site, lymph nodes, 
and/or any organ systems relevant to symptoms or AEs reported by the participant. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Should the participant develop unsolicited AEs (eg, rash) that are visible on 
physical examination and should the participant provide consent, photos of the involved 
area(s) may be taken in order to facilitate the medical review. The photos must be prepared in 
a way to obscure the participant’s identity. 
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6.4.5 
Vital Signs, Body Temperature, Pulse Oximetry 
Vital signs will be measured in a semi-supine position after 5 minutes’ rest and will include 
systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature, and pulse 
oximetry. Three readings of blood pressure and pulse will be taken, each separated by 
approximately 5 minutes. The first reading should be rejected. The second and third readings 
should be averaged to give the measurement to be recorded in the eCRF. 
After each study vaccine administration, vital signs should be checked, and repeat vital signs 
should be taken if clinically indicated. 
6.5 
Pregnancy 
If a participant becomes pregnant or a pregnancy is suspected, or if a male participant 
believes his sexual partner has become pregnant during the study participation (through the 
Early Termination Visit) or within 60 days of last study vaccine administration (for those 
participants who terminate the study early), then the site staff must be informed immediately. 
The pregnancy will be reported using a paper Pregnancy Notification Form and collected in 
the safety database. The Pregnancy Notification Form, which should be faxed or emailed to 
the Sponsor or designee. Follow-up information including delivery or termination should be 
reported within 24 hours. Pregnancy reporting instructions, including the fax number and 
email address for submitting paper forms can be found in the Investigator Site File for the 
study. 
Female participants: If a suspected pregnancy occurs while on the study in a female 
participant that has received ARCT-021, a pregnancy test will be performed. If the pregnancy 
test is positive, the participant will be encouraged to complete all study procedures except 
receipt of additional doses of study vaccine. 
If it informs a decision relating to pursuit of additional care or vaccination, the vaccine 
assignment of the participant may be unblinded according to the judgment of the 
Investigator. If the pregnancy results in the birth of a child, the site and Sponsor may require 
access to the mother and infant’s medical records to obtain additional information relevant to 
the pregnancy progress and outcome. A longer follow-up may be required if a newborn child 
experiences a medical condition. Follow-up will be performed to the extent permitted by the 
applicable regulations and privacy considerations; eg, pregnancy ICF may be required. 
Male participants: In the event that that the female partner of a male participant that has 
received ARCT-021 becomes pregnant, the progress of the pregnancy of the male 
participant’s partner should be followed until the outcome of the pregnancy is known (ie, 
delivery, elective termination, or spontaneous abortion). If the pregnancy results in the birth 
of a child, the Study Center and Sponsor may follow-up with the mother and may request 
access to the mother and infant’s medical records to obtain additional information relevant to 
the pregnancy progress and outcome. A longer follow-up may be required if a newborn child 
experiences a medical condition. Follow-up will be performed to the extent permitted by the 
applicable regulations and privacy considerations; eg, partner informed consent form may be 
required. 
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6.6 
Surveillance for SARS-CoV-2 Infection 
In concert with the collection of AEs, at each visit and the follow-up telephone calls 
participant will be interviewed for potential symptoms of COVID-19 disease, recent 
diagnosis of SARS-CoV-2 infection, and for potential exposure to COVID-19. A guide will 
be used for this process (see Investigator Site File). 
Potential symptoms of COVID-19 disease include (at a minimum): fever or chills, cough, 
shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss 
of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea. 
Participants should be reminded to contact the site within 24 hours if experiencing COVID 
19 like symptoms or if exposed to a confirmed COVID-19 case. 
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7 
STATISTICAL CONSIDERATIONS 
This section summarizes the planned statistical analysis strategy and procedures for the 
study. The details of statistical analysis will be provided in the SAP, which will be finalized 
before the first interim analysis. If, after the study has begun, but prior to any unblinding, 
changes are made to primary and/or key secondary objectives/hypotheses, or the statistical 
methods related to those hypotheses, then the protocol will be amended (consistent with 
International Council for Harmonisation [ICH] Guideline E9). Changes to other secondary or 
exploratory analyses made after the protocol has been finalized, along with an explanation as 
to when and why they occurred, will be listed in the SAP or CSR for the study. Ad hoc 
exploratory analyses, if any, will be clearly identified in the CSR. 
Data collected after ARCT-021 vaccinations for those participants who originally are 
randomized to the placebo group (Study Group 4) and who are re-enrolled to receive 
ARCT-021 will be summarized and presented by dose group in statistical table/listing 
separately from those participants who complete the study as originally randomized. 
7.1 
Estimands and Intercurrent Events 
Possible intercurrent events are presented in Table 7-1. 
Table 7-1 
Intercurrent Event Types 
Label 
Intercurrent Event (IcEv)Type 
IcEv1 (Death) 
Death due to any cause (including pneumonia) other than COVID-19.  
IcEv2 (Missed dose) 
Does not receive the second or booster vaccinations at Day 28 and Day 
208, respectively. 
IcEv3 (Immune-modifying) 
Use of immune-modifying drugs or non-study vaccines which interfere 
with immunogenicity.  
IcEv4 (Early infection) 
Antigens or antibodies indicating exposure to SARS-CoV-2 prior to 
vaccination or early infection before Day 7. (This IcEv is particularly 
relevant to assessing immunogenicity.) 
IcEv5 (Study infection) 
Develops COVID-19 or asymptomatic SARS-CoV-2 infection on or after 
Day 7. (This IcEv is particularly relevant to immunogenicity and CESI 
events.) 
 
Attributes for the primary safety and immunogenicity estimands with strategies for 
intercurrent events (IcEvs) are presented in Table 7-2. 
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Table 7-2 
Primary Safety and Immunogenicity Estimands With Rationale and 
Strategies to Address Intercurrent Events 
Estimand Label 
Estimand 1 (Safety) 
Estimand Description 
Count and percentage of vaccinated healthy adults who would develop 
MAAEs, NOCDs, SAEs, AEs leading to discontinuation/withdrawal, 
solicited AEs, and unsolicited AEs: 
These will be evaluated after each dose of study vaccine by priming 
vaccine study group (Group 1, 2, 3, and 4) and by booster vaccine 
received (ARCT-021, ARCT-154, ARCT-165, or placebo). A treatment 
policy strategy is used for assessing safety irrespective of an early 
infection within 7 days after the first vaccination or an infection during 
the study or missed subsequent vaccination. Infections and death are 
included in the endpoint (composite strategy). 
Target Population 
Participants receiving at least 1 dose of study vaccine (as defined by 
eligibility criteria). 
Endpoint 
Occurrence of MAAEs, NOCDs, AEs leading to 
discontinuation/withdrawal, SAEs, solicited, or unsolicited AEs: 
• 
Solicited AEs within 7 days of each vaccination (by Toxicity 
Grade, Appendix 13.4): Day 7, Day 35, Day 215 
• 
Unsolicited AEs within 28 days of each vaccination (by 
mild/moderate/severe severity): Day 28, Day 56, Day 236 
• 
MAAEs, NOCDs, SAEs, AEs leading to 
discontinuation/withdrawal from Vaccination 1 to Prior to 
Vaccination 2, Vaccination 2 to Prior to Booster 
Vaccination, Overall Prior to Booster Vaccination, and Post-
booster Vaccination  
Treatment Conditions 
Placebo or 5.0 µg or 7.5 µg ARCT-021 administered on Day 0, Day 28; 
placebo, ARCT-021, ARCT-154, or ARCT-165 administered on Day 208.  
Population-Level Summary 
Percentage of vaccinated participants (who would develop each type of 
AE). 
Intercurrent Event Strategy   
IcEv1 (Death) 
Composite strategy 
IcEv2 (Missed dose) 
Treatment policy strategy 
IcEv3 (Immune-modifying) 
Treatment policy strategy 
IcEv4 (Early infection) 
Treatment policy strategy 
IcEv4 (Study infection) 
Composite strategy 
Rationale for Strategies 
Deaths and symptomatic infections during study would contribute as part 
of the endpoint (ie, included as MAAEs, SAEs, NOCDs, AEs leading to 
discontinuation/withdrawal, solicited AEs or unsolicited AEs) as per 
normal practice. A treatment policy strategy is used for assessing safety 
irrespective of early infection and missed additional (second, booster) 
study vaccinations. 
 
 
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Estimand Label 
Estimand 2 (Geometric Mean Titers/Concentrations) 
Estimand Description 
The GMT of NAbs (primary) and GMC of BAbs (secondary) against 
SARS-CoV-2 up to Early Termination after first vaccination with 
ARCT-021 of each group (5.0, 7.5 µg, or placebo) and with/without 
booster dose in healthy adults. 
Interest will lie in comparing the GMT/GMC of each dosing regimen to 
placebo based on the Geometric Mean Ratio (GMR). 
The hypothetical strategy is used to estimate antibody levels had all 
scheduled vaccinations been received, and without subsequent 
SARS-CoV-2 infection or influence from immune-modifying drugs or 
non-study vaccines. The principal stratum strategy excludes those with 
active or early SARS-CoV-2 infection within 7 days after the first study 
vaccine administration. 
Analysis Population 
Vaccinated healthy adults (as defined by eligibility criteria) without active 
or early SARS-CoV-2 infection (infection within 7 days after the first 
vaccination). 
Endpoint 
Total NAbs (primary) and BAbs (secondary) specific for the 
SARS-CoV-2 measured pre- and post-priming vaccine administration (on 
Day 0, 14, 28, 42, 56, and 208) and following booster vaccine 
administration (Day 236, Early Termination). 
Treatment Conditions 
Placebo or 5.0 µg or 7.5 µg ARCT-021 administered on Day 0, Day 28; 
placebo, ARCT-021, ARCT-154, or ARCT-165 administered on Day 208.  
Population-Level Summary 
The GMT, GMC and GMR of comparisons of interest at each time point. 
GMR will compare responses in placebo-, ARCT-021-, ARCT-154-, and 
ARCT-165-vaccinated groups at relevant timepoints. For additional 
considerations on population-level summary see the SAP. 
Intercurrent Event Strategy   
IcEv1 (Death) 
Hypothetical strategy 
IcEv2 (Missed dose) 
Hypothetical strategy 
IcEv3 (Immune-modifying) 
Hypothetical strategy 
IcEv4 (Early infection) 
Principal stratum strategy 
IcEv5 (Study infection) 
Hypothetical strategy 
Rationale for Strategies 
Hypothetical strategy is used to understand antibody levels achieved 
through receiving scheduled vaccination, without subsequent 
SARS-CoV-2 infection and without any influence from immune-
modifying drugs or non-study vaccines. In estimation, the hypothetical 
uses a statistical model on the mITT (excluding data points following 
intercurrent events and not complete removal of all data for the 
participant). 
 
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Estimand Label 
Estimand 3 (Rise/Seroconversion) 
Estimand Description 
Percentage of participants with at least 2- and 4-fold increase in antibody 
responses from baseline (seroconversion) in NAbs (primary) and BAbs 
(secondary) at each time point from Day 14 to Early Termination. 
The hypothetical strategy is used to estimate antibody levels had all 
scheduled vaccinations been received, and without subsequent 
SARS-CoV-2 infection or influence from immune-modifying drugs or 
non-study vaccines. The principal stratum strategy excludes those with 
active or prior SARS-CoV-2 infection at first vaccination. 
Target Population 
Vaccinated healthy adults (as defined by eligibility criteria) without active 
or early SARS-CoV-2 infection within 7 days after first vaccination. 
Endpoint 
GMFR and seroconversion against SARSCoV-2 NAbs (primary) and 
BAbs (secondary) measured pre- and post-priming vaccine administration 
(on Day 0, 14, 28, 42, 56, and 208) and following booster vaccine 
administration (Day 236, Early Termination). 
Treatment Conditions 
Placebo or 5.0 µg or 7.5 µg ARCT-021 administered on Day 0, Day 28; 
placebo, ARCT-021, ARCT-154, or ARCT-165 administered on Day 208.  
Population-Level Summary 
The GMFR and ≥2- and 4-fold seroconversion (SC) at each time point.  
Intercurrent Event Strategy   
IcEv1 (Death) 
Hypothetical strategy 
IcEv2 (Missed dose) 
Hypothetical strategy 
IcEv3 (Immune-modifying) 
Hypothetical strategy 
IcEv4 (Early infection) 
Principal stratum strategy 
IcEv5 (Study infection) 
Hypothetical strategy 
Rationale for Strategies 
Hypothetical strategy is used to understand seroconversion achieved 
through receiving scheduled vaccination, without subsequent 
SARS-CoV-2 infection and without any influence from immune-
modifying drugs or non-study vaccines. In estimation, the hypothetical 
uses a statistical model on the mITT (excluding data points following 
intercurrent events and not complete removal of all data for the 
participant). 
 
7.2 
Statistical Hypothesis 
There is no hypothesis testing in the phase 2 study; where statistical methods are applied, the 
emphasis will be on estimation with 95% CIs. 
7.3 
Sample Size Determination 
The sample size is based on clinical considerations to provide sufficient safety information 
for the analysis of the primary safety objective. With 75 participants randomly assigned to 
each priming vaccination dose group but with as few as 25 participants randomly assigned to 
individual booster vaccine groups Table 7-3 presents estimated probability to detect at least 
one adverse event at various incidence rates by possible sample size in this study. The 
estimated probability was calculated using a formula as below. 
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p = 1 – (1 – R)N 
where R = incidence rate and N = sample size. 
If the incidence rate of an adverse event is 1%, the probability to detect one event in 
75 vaccinated participants is 52.9%, and the probability of detecting one event in 
25 vaccinated participants is 22.2%; however, this probability will be 95.1% in a sample size 
of 300 in each Age Cohort. See more details and scenarios in the table below. 
Table 7-3 
Probability to Detect at Least One Adverse Event by Incidence Rate of 
Event and Sample Size 
Rate (%) 
N=25  
N=75 
N=150 
N=225 
N=300 
0.01 
0.002497002 
0.007472 
0.014889 
0.02225 
0.029556 
0.1 
0.024702287 
0.072291 
0.139357 
0.201574 
0.259293 
1.0 
0.222178641 
0.529413 
0.778548 
0.895788 
0.950959 
2.0 
0.39653527 
0.780236 
0.951704 
0.989386 
0.997667 
5.0 
0.722610427 
0.978656 
>0.999 
>0.999 
>0.999 
10.0 
0.928210201 
>0.999 
>0.999 
>0.999 
>0.999 
The study plans to randomize 75 participants to each Study Group within each Age Cohort. 
Assuming a geometric coefficient of variance (CoV) of 180% (SD of 1.2 on loge scale), a 
sample size of 75:75 will provide a >99% power to detect 2-fold increase in antibody titers in 
ARCT-021 Study Groups versus placebo Study Groups. These power analyses were 
performed using PASS Version 15 software. 
7.4 
Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
Intent-to-Treat (ITT) analysis set: includes all participants who receive at least 1 dose of 
priming study vaccine (ARCT-021 or placebo). Participants will be analyzed according to the 
vaccine the participant was randomly assigned to. 
Safety analysis set: includes all participants who receive at least 1 dose of priming study 
vaccine (ARCT-021 or placebo). Participants will be analyzed according to the vaccine 
received at time of priming or booster vaccination. 
Reactogenicity analysis set (RAS): includes all participants who receive any dose of 
priming study vaccine (ARCT-021 or placebo) and provide at least 1 reactogenicity diary 
report for the time period evaluated. Participants will be analyzed according to the vaccine 
received. 
Per-protocol analysis set: includes all eligible randomized participants who receive the 
correct assigned dose(s) of assigned study vaccine within the predefined SAP window, have 
blood collection within the SAP window, have valid immunogenicity results for the relevant 
time point(s), and have no other major protocol deviations expected to affect 
immunogenicity, as determined by the Sponsor Medical Monitor in a blinded manner. All 
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participants in the per-protocol analysis set will be analyzed according to what study vaccine 
that was received. 
Modified intent-to-treat (mITT) analysis set: includes all participants who received at least 
one dose of study vaccine and who have pre- and post-vaccination immunogenicity data 
evaluable by the assay in use with valid results for the relevant time point(s). The mITT 
analysis set will be analyzed according to vaccine assigned. 
CMI subset: includes all participants who have evaluable pre- and post-vaccination CMI 
data available. The data sets include: CD4+ T-cell responses (background subtracted), 
CD8+ T-cell responses (background subtracted), and Th1/Th2 CD4+ T-cell responses 
(background subtracted). 
Booster Randomized analysis set: consists of all participants who are randomized to a 
booster vaccination, regardless of the participant’s study treatment status in the study. 
Participants will be analyzed according to the study vaccine to which they were randomized 
for receipt of booster vaccine. 
Booster Safety analysis set: includes all participants who receive at least 1 dose of booster 
study vaccine (ARCT-021, ARCT-154, ARCT-165 or placebo) or have safety data collected 
in the period following booster administration. If a participant did not receive a booster dose 
but has safety data collected for the booster vaccination period, the participant will be 
included in the placebo booster group for summarization. Participants will be analyzed 
according to the vaccine actually received. 
Booster Reactogenicity analysis set: includes all participants who receive any dose of 
booster vaccination (ARCT-021, ARCT-154, ARCT-165 or placebo) and provide at least 
1 diary entry for the time period evaluated. Participants will be analyzed according to the 
vaccine actually received. 
7.5 
Description of Subgroups to Be Analyzed 
In this study, randomization grouping is based on Age Cohort. Additional subgroup analyses 
include: participants with and without SARS-CoV-2 participant analysis by gender, by age 
(≥18 to <56 and ≥ 56 years), and by country. Additional subgroup analyses may be specified 
in the SAP. 
7.6 
Statistical Analysis Methodology 
Details of the statistical analyses, methods, and data conventions will be described in the 
SAP. Statistical analysis will be performed using SAS software Version 9.4 or later. 
Continuous variables will be summarized using the mean, standard deviation, median, 
minimum value, and maximum value. Categorical variables will be summarized using 
frequency counts and percentages. Data will be listed in data listings. 
7.6.1 
General Considerations 
For this study, statistical analysis will be descriptive, and 2-sided 95% CI will be provided 
whenever applicable. No formal multiple comparison adjustments will be employed for 
multiple safety, immunogenicity, or exploratory endpoints. Nominal confidence intervals will 
be computed for immunogenicity data analyses without controlling for multiplicity. 
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7.6.2 
Overview of Statistical Methods: Estimation of Estimands and Sensitivity 
Analyses 
A summary of the statistical methods and sensitivity analyses is presented in Table 7-4. 
Placebo participants will be pooled across dose groups summaries. 
 
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Table 7-4 
Summary of Statistical Methods and Supportive Analyses 
Estimand 
Label 
Estimand Description 
Main Estimation 
Supportive Analysis 
 
 
Analysis 
Set 
Imputation/ 
Data/ Censoring 
Rules 
Analysis Model/Method 
 
Estimand 1 
(Primary) 
Percentage of vaccinated 
healthy adults who: 
• 
report solicited AEs 
within the specified 
timeframe 
• 
 develop unsolicited 
AEs including 
MAAEs, etc, within 
the specified 
timeframe. 
A treatment policy strategy is 
used for assessing safety 
irrespective of a current (or 
prior) infection at time of first 
vaccination or missed second 
vaccination. See Table 7-2 for 
full definition. 
RAS 
(solicited 
AEs) 
SAS 
(unsolicit
ed AEs) 
Infections and 
death (if they 
meet the AE and 
time window 
criteria) are 
included in the 
endpoint 
(composite 
strategy). 
Summaries of number of participants 
(%) with solicited AEs (by toxicity 
grade), safety laboratory assessments 
(by toxicity grade), unsolicited AEs 
(by severity and relatedness to study 
vaccine), MAAEs, NOCDs, SAEs, 
and AEs leading to 
discontinuation/withdrawal will be 
presented. The Clopper-Pearson 95% 
CIs will be presented for the 
incidence rate of these events. See 
Section 7.6.3.1 and the SAP for 
further details. 
Supportive: Analysis will be 
performed for a number of different 
time intervals, specifically: 
• Solicited AEs: within 7 days of 
first vaccination and also within 
7 days after each vaccination 
• Safety laboratory assessments 
7 days before and after each 
vaccination 
• Unsolicited AEs: within 28 days 
of each vaccination (Days 28, 56, 
236) 
• All unsolicited AEs, MAAEs, 
NOCDs, SAEs, AEs leading to 
discontinuation/withdrawal up to 
by time period after the first 
vaccination 
• Additional supportive analyses 
are defined in the SAP 

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Table 7-4 
Summary of Statistical Methods and Supportive Analyses 
Estimand 
Label 
Estimand Description 
Main Estimation 
Supportive Analysis 
 
 
Analysis 
Set 
Imputation/ 
Data/ Censoring 
Rules 
Analysis Model/Method 
 
Estimand 2 
The GMT of total NAbs 
(primary) and GMC of BAbs 
(secondary) titers against 
SARS-CoV-2 from Day 14 up 
to Early Termination after 
initial priming vaccination 
with ARCT-021 and booster 
vaccinations (ARCT-021, 
ARCT-154, and ARCT-165) 
(exploratory) of each dose in 
healthy adults. Interest will lie 
in comparing the GMC of 
each dosing regimen to 
placebo (GMR). 
The hypothetical strategy is 
used to estimate antibody 
levels had both scheduled 
vaccinations been received, 
and without any influence 
from immune-modifying 
drugs or non-study vaccines, 
or subsequent SARS-CoV-2 
infection. See Table 7-2 for 
further details. 
mITT 
Values below the 
limit of 
quantification 
(LOQ) or limit of 
detection (LOD) 
will be replaced 
by LOQ/2 and 
LOD/2, 
respectively. 
Total NAbs and BAbs levels will be 
summarized with descriptive 
statistics, including boxplots (on log 
scale versus time) by time point: 
Days 14, 28, 42, 56, 208, 236, Early 
Termination. GMTs with 
corresponding 95% CI will be 
provided at each time point. The 95% 
CIs will be calculated based on the t-
distribution of the log-transformed 
values then back transformed to the 
original scale. GMFRs with 
corresponding 95% CI will be 
provided at each post-baseline 
timepoint over baseline. The 95% CIs 
will be calculated based on the t-
distribution of the log-transformed 
values then back transformed to the 
original scale.  
Supportive: For the priming 
vaccination period ANCOVA will 
be fitted to the natural log 
transformed antibody titers and 
antibody concentrations measured 
against SARS-CoV-2 with terms for 
treatment group, age group and 
natural log baseline titer by each 
post-vaccination immunogenicity 
visit. The geometric least squares 
mean (GLSM) and corresponding 
2-sided 95% CI for each treatment 
group will be provided by visit. 
Geometric mean ratio (GMR), 
estimated by the ratio of GLSM, 
and the corresponding 95% CI will 
be provided to assess the difference 
between ARCT-021 vs. placebo 
groups at each visit. 
Descriptive statistics, GMT/GMFRs 
based on t-distribution will be 
presented by the following analysis 
subgroups: age group, gender and 
country. ANCOVA models will be 
presented by gender and country.  

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Table 7-4 
Summary of Statistical Methods and Supportive Analyses 
Estimand 
Label 
Estimand Description 
Main Estimation 
Supportive Analysis 
 
 
Analysis 
Set 
Imputation/ 
Data/ Censoring 
Rules 
Analysis Model/Method 
 
Estimand 3 
Percentage of participants 
with at least 2- and 4-fold 
increase in antibody responses 
from baseline 
(seroconversion) in NAbs 
(primary) and BAbs 
(secondary) at each time point 
from Day 14 to Early 
Termination after initial 
priming vaccination with 
ARCT-021 (for each dose and 
placebo), and booster 
vaccinations (ARCT-021, 
ARCT-154, and ARCT-165) 
(exploratory) in healthy 
adults. 
Same hypothetical/principal 
stratum strategies and vaccine 
groups as for Estimand 2.  
mITT 
Titer values 
below the LOQ or 
LOD will be 
replaced by 
LOQ/2 and 
LOD/2, 
respectively, prior 
to calculation of 
fold changes and 
seroconversion. 
The number and percentage of 
participants with ≥ 2- and 4- fold 
increase from baseline will be 
provided with 2-sided 95% CI using 
the Clopper-Pearson method at each 
post-baseline timepoint: Days 14, 28, 
42, 56, 208, 236, Early Termination. 
The number and percentage of 
participants with seropositivity at a 
participant level (defined as a 
detectable level above LLOQ) will be 
provided with 2-sided 95% CI using 
the Clopper-Pearson method at each 
post-baseline timepoint. 
Supportive: Similar tabulations will 
be done for the following analysis 
subgroups: age group, gender and 
country. For the priming 
vaccination period: the common 
difference of seropositivity and 
seroconversion rates and 95% CIs 
between each vaccine dose group 
and the placebo will be estimated 
using the Cochran–Mantel–
Haenszel (CMH) method with age 
group as stratification factor for 
each time point.  
 

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7.6.3 
Analysis of Primary Safety Endpoints 
7.6.3.1 
Main Estimation of Safety Endpoint (Estimand 1) 
Summaries of the number of participants (%) with solicited AEs, unsolicited AEs, MAAEs, 
SAEs, and AEs leading to discontinuation/withdrawal will be presented. Unsolicited events 
will be presented overall and also with a focus on those related to vaccine administration. All 
summaries will be evaluated by study group as well as vaccine administration (first dose, 
second dose, booster dose). 
The Clopper-Pearson 95% CIs will be presented for the incidence rate of unsolicited AEs, 
SAEs, MAAEs, NOCDs, and AEs leading to discontinuation/withdrawal, as well as those 
that are considered related (possibly, probably, or definitely) to study vaccine. 
7.6.3.2 
Supportive Analysis of Primary Safety Endpoint (Estimand 1) 
Analysis of safety, as described in Section 7.6.3.1, will be performed for a number of 
different time intervals, specifically the following: 
• Within 7 days after each vaccination 
• Up to 28 days after each vaccination (Day 28, Day 56, Day 236) 
• At specified time periods: Vaccination 1 to Prior to Vaccination 2, Vaccination 2 to 
Prior to Booster Vaccination, Overall Prior to Booster Vaccination, and Post-booster 
Vaccination 
The number and percentage of participants with any solicited AEs (local injection site and 
systemic events) and safety laboratory assessments before and after each vaccination will be 
reported, including summaries by grade (Appendix 4: FDA Toxicity Grading Scales). The 
incidence rate for solicited AEs will be presented with 2 sided 95% CIs using the Clopper-
Pearson method. 
7.6.4 
Analysis of Primary and Secondary Immunogenicity Endpoints 
7.6.4.1 
Analysis of Immunogenicity Endpoint (GMT/GMC and GMR) (Estimand 2) 
The primary immunogenicity analyses will be performed using the mITT set evaluating 
responses measured by neutralizing antibody assay. Secondary immunogenicity analyses will 
be performed using the mat set evaluating responses measured by binding antibody assays. 
Total NAbs and BAbs titers will be summarized using descriptive statistics (number of 
subjects (n), median, minimum and maximum) by each time point: Baseline, Days 14, 28, 42, 
56, 208, 236, Early Termination. Geometric mean titers (GMT) with corresponding 95% CIs 
will be provided. The 95% CIs will be calculated based on the t-distribution of the log-
transformed values then back transformed to the original scale for presentation. GMTs and 
corresponding 95% CIs will be plotted at each timepoint. GMFRs with corresponding 
95% CIs will be provided at each post-baseline timepoint over baseline. The 95% CIs will be 
calculated based on the t-distribution of the log-transformed values then back transformed to 
the original scale for presentation. GMFRs and corresponding 95% CIs will also be plotted at 
each timepoint. Analyses will be repeated by subgroups as follows: gender, age group 
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(≥18 to <56 and ≥56 years) and country. Scatter plots of NAbs and BAbs titers at specific 
time points will be presented. 
For the priming vaccination period an analysis of covariance model (ANCOVA) will be 
fitted to the natural log transformed neutralizing antibody titers measured against SARS CoV 
2 with terms for treatment group, age group (≥18 to <56 and ≥ 56 years) (stratification factor 
at randomization) and natural log baseline titer by each post-vaccination immunogenicity 
visit. The geometric least squares mean (GLSM) and corresponding 2-sided 95% CI for each 
treatment group will be provided by visit. Geometric mean ratio (GMR), estimated by the 
ratio of GLSM, and the corresponding 95% CI will be provided to assess the difference 
between ARCT-021 vs. placebo groups at each visit. No adjustments for multiplicity will be 
carried out. ANCOVA analyses will be repeated by the following subgroups: gender and 
country. 
The above summaries and analyses will be present for binding antibody concentrations as 
well. 
7.6.4.2 
Rise/Seroconversion Endpoint (Estimand 3) 
Seroconversion with ≥ 2- and 4- fold increase from baseline: The number and percentage of 
participants with 2- and 4- fold GMFR from baseline will be provided with 2-sided 95% CI 
using the Clopper-Pearson method at each post-baseline time point. 
The common difference of seroconversion rate and 95% CI between each vaccine dose group 
and the placebo will be estimated using CMH method with stratification factors for each time 
point from Day 14 to Day 208 for the mITT. The definition of seroconversion may depend 
on assay-specific performance characteristics and the final definition of seroconversion due 
to vaccination will be documented in the SAP. 
Seropositivity at a participant level: is defined as a change of NAb titer from below the LOD 
or Lower Limits of Quantification (LLOQ) to equal to or above LOD or LLOQ 
(respectively), or a 4-times or higher log-transformed titer ratio in participants with pre-
existing NAb titers. Seropositivity rates will be provided with 2-sided 95% CI using the 
Clopper-Pearson method at each post-baseline time point. 
7.6.5 
Analysis of Exploratory Endpoints 
Statistical analyses of exploratory endpoints will be descriptive over time point by vaccine 
group in the mITT set, unless otherwise specified. These endpoints include the following: 
• Descriptive statistics of GMT in cases of confirmed COVID-19, confirmed severe 
COVID-19, and asymptomatic SARS-CoV-2 infection over time point by the vaccine 
group. 
• CMI responses to SARS-CoV-2 may be measured in a subset of participants. 
Quantity, phenotype, and percentage of cytokine-producing SARS-CoV-2 spike 
protein-specific T cells, as measured by flow cytometry/intracellular cytokine staining 
assay (Days 0, 14, 28, 42, 56, 208, 236, and Early Termination). 
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• The durability of immune response following vaccination with ARCT-021 versus 
placebo will be evaluated in binding, neutralizing antibody responses and CMI 
responses up to Day 236 after first vaccination. 
7.6.6 
Other Analyses 
Summary statistical analyses will be provided for demographics, medical history, physical 
examination, social history, and risk factor variables at baseline, as well as vital signs, 
clinical laboratory tests, etc. 
7.6.7 
Data Analyses from Re-Enrolled Participants 
All safety data collected after active vaccination from Study Group 4 participants who are re-
enrolled into Study Groups 1, 2, or 3 (ARCT-021-exposed study groups) will be summarized 
and presented by dose group and overall separately from those participants who complete the 
study as originally randomized. Participant level data will be displayed in listings, separately 
from data in originally randomized. 
Immunogenicity data collected after active vaccination from Study Group 4 participants who 
are re-enrolled into Study Groups 1, 2, or 3 (ARCT 021-exposed study groups) will be listed. 
This data may be summarized and presented by dose group and overall separately from those 
participants who complete the study as originally randomized. If summarized, it will be 
reported in an addendum to the CSR. 
7.7 
Handling of Missing Data 
Details regarding handling of missing endpoints and diary data for the evaluation of solicited 
AEs and patient-reported outcomes data for exploratory endpoints will be described in the 
SAP. 
7.8 
Interim Analyses 
Five interim analyses will be performed. 
• The first interim analysis will focus on safety and will evaluate available safety data 
for all participants who were initially enrolled as of 05 February 2021 when they have 
completed Day 7 or Early Termination visit procedures. 
• The second interim analysis will evaluate available safety and immunogenicity data 
for all participants who were initially enrolled as of 05 February 2021 when they have 
completed Day 28 or Early Termination visit procedures. 
• The third interim analysis will evaluate available safety and immunogenicity data for 
all participants after they have completed Day 56 or Early Termination visit 
procedures. 
At each of these interim analyses, the datasets from immunogenicity assessments may not 
contain all participants’ data. However, the data cuts outlined above are intended to inform 
additional clinical development considerations, including selection of ARCT-021 dose for 
booster administration and selection of final dose and schedule for ARCT-021 administration 
in the Phase 3 study. The data will be monitored prior to and the database will be locked 
prior to the third interim analyses to inform interim clinical study reporting. 
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All available safety and immunogenicity data will be summarized. Blinded data will be 
shared with the SRC and unblinded data will be shared with the DSMB. 
The ARCT-021 dose for future Phase 3 studies is a single dose of 5 µg ARCT-021 and is 
based on review of available immunogenicity and safety data in the clinical development of 
ARCT-021 to date. The recommendation for ARCT-021 dose and schedule for Phase 3 and 
the data that informed this recommendation will be shared with the relevant regulatory 
authorities prior to initiation of the Phase 3 study. 
The study will remain blinded to site staff overseeing study assessments, blinded CRO 
personnel, and (with the exception of group unblinding) the Sponsor until the time of final 
analysis. 
Additional details regarding the interim analyses will be found in the SAP. 
7.9 
Independent Data Safety Monitoring Committee 
An independent DSMB, which will be guided by a signed charter, will perform ongoing 
review of blinded and unblinded data, including both safety and cases of COVID-19 at 
scheduled data review meetings and at 3 planned interim analyses. The DSMB composition 
will include (at a minimum) 4 physicians with participant matter expertise relating to 
vaccines and/or COVID-19 and an independent biostatistician. 
Scheduled reviews by the DSMB will include the review of safety data, including the option 
to review unblinded safety data. Unscheduled (ad hoc) meetings will occur promptly (ideally 
within 2 business days) in the event of any AE(s) suspected of triggering a Pausing Rule 
(Section 4.2.5). Further details relating to the analysis of safety data are described in the 
DSMB Charter. 
At each analysis, the DSMB will review the available data and make recommendations to the 
Sponsor relating to the recommendation to continue, modify, discontinue study enrollment (if 
the study is enrolling), or discontinue the study. The DSMB will also review safety and, if 
available, immunogenicity data at each interim analysis. 
If the DSMB votes to discontinue the study for safety reasons health authorities will be 
notified within 48 hours of this determination. 
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8 
DATA QUALITY ASSURANCE 
This study will be conducted according to the ICH E6(R2) risk and quality processes 
described in the applicable procedural documents. The quality management approach to be 
implemented in this study will be documented and will comply with the current ICH 
guidance on quality and risk management. The Sponsor assumes accountability for actions 
delegated to other individuals (eg, the CRO). 
The critical endpoints for this study are immunogenicity and safety. To ensure data integrity 
for these endpoints during the period from Day 98 to Day 208 when certain study site staff 
may become unblinded to some study participants treatment assignment (Section 5.8), the 
following measures are included in the study: 
• Immunogenicity: these assessments are based on laboratory evaluations and are 
therefore unbiased and objective 
• Safety: the sponsor team responsible for oversight of the study, the drug safety 
physician and the SRC will remain blinded to individual participants’ study vaccine 
assignment throughout the study to ensure unbiased assessment of safety endpoints 
and DSMB interactions. 
8.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the Investigator agrees 
to maintain adequate case histories for the participants treated as part of the research under 
this protocol. The Investigator agrees to maintain accurate CRFs (electronic and paper, where 
relevant) and source documentation as part of the case histories. These source documents 
may include laboratory reports. 
All CRF information is to be filled in. If an item is not available or is not applicable, this fact 
should be indicated. Blank spaces should not be present unless otherwise directed. If paper 
CRFs are used, a correction should be made by striking through the incorrect entry with a 
single line and the corrected information should be entered adjacent to the deleted item. The 
correction must be initialed and dated by the person making the correction. 
Each completed paper CRF must be reviewed, signed, and dated by the Investigator in a 
timely manner. The completed paper CRF will not be collected by clinical monitors but will 
be stored in the Investigator’s files. 
For electronic CRFs, investigative site personnel will enter participant data into the Medidata 
EDC system. The analysis data sets will be a combination of these data and data from other 
sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable CRO standards 
and data cleaning procedures to ensure the integrity of the data, eg, removing errors and 
inconsistencies in the data. Adverse event terms will be coded using MedDRA, an internal 
validated medical dictionary, and concomitant medications will be coded using WHODRUG. 
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8.2 
Data Disclosure 
The Sponsor will publicly disclose clinical study results through posting the results of studies 
on www.clinicaltrials.gov (CT.gov 2020) and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results will be reported in an objective, accurate, balanced, and complete 
manner and are reported regardless of the outcome of the study or the country in which the 
study was conducted. 
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9 
ETHICS 
9.1 
Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) before human 
subjects participate in research studies. Before study onset, the protocol, informed consent, 
advertisements to be used for the recruitment of study participants, and any other written 
information regarding this study to be provided to the participant or the participant’s legal 
guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of 
the IRB/IEC compliance with ICH harmonised tripartite guideline E6(R2): Good Clinical 
Practice (GCP) will be maintained by the site and will be available for review by the Sponsor 
or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The Investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
Investigator must promptly supply the Sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to participants. 
9.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
9.3 
Participant Information and Consent 
A written informed consent in compliance with regulatory authority regulations or US Title 
21 Code of Federal Regulations (CFR) Part 50 shall be obtained from each participant before 
entering the study or performing any unusual or nonroutine procedure that involves risk to 
the participant. An informed consent template may be provided by the Sponsor to 
investigative sites. If any institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent should be reviewed by the Sponsor or its designee 
or both before IRB/IEC submission. Once reviewed, the consent will be submitted by the 
Investigator to his or her IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participants must be reconsented by 
signing the revised form. 
Before recruitment and enrollment, each prospective participant or his or her legal guardian 
will be given a full explanation of the study, be allowed to read the approved ICF, and have 
any questions answered. Once the Investigator is assured that the participant/legal guardian 
understands the implications of participating in the study, the participant/legal guardian will 
be asked to give consent to participate in the study by signing the ICF. The authorized person 
obtaining the informed consent also signs the ICF. 
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The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research (if applicable) and explain/address the exploratory 
research portion of the study. Participant medical records need to state that written informed 
consent was obtained. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the participant or legal guardian. 
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10 
 INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant (or the participant’s legal guardian), except as necessary for 
monitoring and auditing by the Sponsor, its designee, the US Food and Drug Administration 
(FDA), or the IRB/IEC. 
The Investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 
Data Protection 
All personal data collected related to participants, investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in accordance with 
local data protection law, including laws regarding implementation of technical measures to 
ensure protection of participant data. 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for 
which they are collected. Each category of data must be properly justified and in line with the 
study objective. 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law. 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code (participant 
code). Any participant records or data sets that are transferred to the Sponsor will contain the 
participant code; participant names must not be transferred. All other identifiable data 
transferred to the Sponsor will be identified by this participant code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant code to his or her actual identity and medical record identification. In case of data 
transfer, the Sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws. 
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10.3 
Data Sharing 
The Sponsor will provide investigators secure access to participant-level data or full CSRs 
where required for the purposes of local reporting obligations. Participant-level data will be 
anonymized in accordance with applicable privacy laws and regulations. CSRs will have 
personally identifiable information redacted. 
10.4 
Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the Investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor the CRO is financially responsible for further testing or treatment of 
any medical condition that may be detected during the Screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor the CRO is financially responsible 
for further treatment of the participant’s disease. 
10.5 
Investigator Documentation 
Prior to beginning the study, the Investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and Title 21 of the CFR by providing all essential documents. 
10.6 
Study Conduct 
The Investigator agrees that the study will be conducted according to the principles of 
ICH E6(R2). The Investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of participants begins. 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
10.7 
Adverse Events and Study Report Requirements 
The Investigator agrees to submit reports of SAEs to the sponsor and/or IRB/IEC according 
to the timeline and method outlined in the protocol. In addition, the Investigator agrees to 
submit annual reports to the study site IRB/IEC as appropriate. 
10.8 
Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform the 
institution; the Investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
10.9 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
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discontinuation of clinical development of the Study Vaccine. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. No records 
may be transferred to another location or party without written notification to the sponsor. 
10.10 Publications and Results Disclosures 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the Sponsor and cannot be published without prior authorization 
from the Sponsor, but data and publication thereof will not be unduly withheld. 
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11 
STUDY MANAGEMENT 
The study administrative structure will include an SRC, an independent DSMB, CRO, third 
party vendors, and laboratories. 
11.1 
Monitoring 
11.1.1 
Monitoring of the Study 
This study will be monitored according to an approved monitoring plan based on the 
objectives, purpose, design, and complexity of the study. The Investigator will allocate 
adequate time for all monitoring visits and between visits to facilitate the requirements of the 
study and study timelines. The Investigator will also ensure that the monitor or other 
compliance or quality assurance reviewer is given direct access to all study-related 
documents and study-related facilities (eg, pharmacy, diagnostic laboratory), phone, fax, and 
internet and has adequate space to conduct the monitoring visit (if the monitoring visit is 
conducted in person). In the event that the COVID-19 outbreak does not allow direct access 
to the site by the monitor, the Investigator will make every effort to provide access to source 
documents in a remote fashion. This includes anticipation of medical release forms to be 
signed by the participant at the time of study enrollment. Site monitoring is conducted to 
ensure that the rights of human subjects are protected, that the study is implemented in 
accordance with the protocol and/or other operating procedures, and that the study uses high 
quality data collection processes. The monitor will evaluate study processes based on ICH E6 
and all applicable, regulatory guidelines. 
11.1.2 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the Investigator agrees to allow the Sponsor, representatives 
of the Sponsor, or a regulatory agency access to all study records. 
The Investigator should promptly notify the Sponsor and the CRO of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 
11.2 
Management of Protocol Amendments and Deviations 
11.2.1 
Modification of the Protocol 
Any changes in the required procedures defined in this protocol, except those necessary to 
remove an apparent, immediate hazard to the participant, must be reviewed and approved by 
the Sponsor or designee. Amendments to the protocol (including emergency changes) must 
be submitted in writing to the Investigator’s IRB/IEC, along with any applicable changes to 
the ICF, for approval before participants can be enrolled into an amended protocol. 
11.2.2 
Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the Sponsor and the IRB/IEC and agreed to by the 
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Investigator. A significant deviation occurs when there is nonadherence to the protocol or to 
local regulations or ICH GCP guidelines that may or may not result in a significant, 
additional risk to the participant or impacts the integrity of study data. 
The Investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The Investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard/safety risk to 
study participants without prior IRB/IEC approval. As soon as possible after such an 
occurrence, the implemented deviation or change, the reasons for it, and any proposed 
protocol amendments should be submitted to the IRB/IEC for review and approval, to the 
Sponsor for agreement, and to the regulatory authorities, where required. 
In order to keep deviations from the protocol to a minimum, the Investigator and relevant site 
personnel will be trained in all aspects of study conduct by the Sponsor/Sponsor 
representative. This training will occur either as part of the Investigator meeting or site 
initiation. Ongoing training may also be performed throughout the study during routine site 
monitoring activities. 
As this Phase 2 study is planned for execution during a global health emergency (COVID-19 
pandemic), there may be local restrictions that prevent or modify the performance of certain 
study-related procedures (eg, clinic visits, blood sampling). For protocol deviations attributed 
to COVID-19 interruptions, relevant details leading to the protocol deviation will be captured 
in the source documents and EDC system in accordance with FDA guidance (FDA 2020b). 
11.3 
Study Termination 
Although Arcturus Therapeutics, Inc. has every intention of completing the study, Arcturus 
Therapeutics, Inc. reserves the right to discontinue the study at any time for clinical or 
administrative reasons. 
The end of the study is defined as the date on which the last participant completes the last 
visit (includes Follow-up Visit). 
If the study is prematurely terminated or suspended, the Sponsor or Investigator shall 
promptly inform the investigators, the IRBs/IECs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements. The Investigator shall promptly inform 
the participant and should assure appropriate participant therapy and/or follow-up. 
11.4 
Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
final data are summarized and provided to the regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The Sponsor will also ensure that any CSRs in 
marketing applications (as applicable) meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the CSR. The Investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
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395:1771-8; published online May 13. https://doi.org/10.1016/S0140-6736(20)31103-X. 
VRBPAC 2020 
Vaccines and Related Biological Products Advisory Committee Meeting December 10, 2020. 
FDA Briefing Document. Pfizer-BioNTech COVID-19 Vaccine. Accessed February 10, 
2021. https://www.fda.gov/media/144245/download. 
WHO 2020a 
WHO 2020a: World Health Organization (WHO). Clinical management of COVID-19 – 
Interim Guidance. 27 May 2020. https://www.who.int/publications/i/item/clinical-
management-of-covid-19 Accessed 06 November 2020. 
WHO 2021 
WHO 2021: WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/ Accessed 
05 June 2021. 
Williamson 2020 
Williamson E, Walker AJ, Bhaskaran K, et al. OpenSAFELY: factors associated with 
COVID-19-related hospital death in the linked electronic health records of 17 million adult 
NHS patients. medRxiv 2020; published online May 7. DOI: 
https://www.medrxiv.org/content/10.1101/2020.05.06.20092999v1.full.pdf. 
Yang 2020 
Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients 
infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis 2020; 94: 
91–95. DOI: 10.1016/j.ijid.2020.03.017. 
Zaim 2020 
Zaim S, Chongb JH, Sankaranarayanan V, et al. COVID-19 and Multi-Organ Response. Curr 
Probl Cardiol. 2020.45:100618. DOI: 10.1016/j.cpcardiol.2020.100618 [Epub ahead of 
print]. 
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Zhang 2011 
Zhang 2011: Zhang N, Bevan MJ. CD8+ T Cells: Foot Soldiers of the Immune System. 
Immunity 2011;35:161-168. DOI 
https://www.sciencedirect.com/science/article/pii/S1074761311003037. 
Zhang 2015 
Zhang 2015: Zhang L, Wang W, Wang S. Effect of Vaccine Administration Modality on 
Immunogenicity and Efficacy. Expert Rev Vaccines. 2015; 14(11): 1509–1523. 
DOI:10.1586/14760584.2015.1081067. 
Zhang 2020 
Zhang 2020: Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the 
treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of 
clinical immunologists from China. Immunology 2020; 214:108393. Doi: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102614/. 
Zhou 2020 
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients 
with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020. 395:1054-62. 
https://doi.org/10.1016/S0140-6736(20)30566-3. 
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13 
APPENDICES 
 
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13.1 
Appendix 1: Schedule of Events 
Table 13-1 
Schedule of Events: Priming Vaccinations 
Visit Type 
(Study Day) 
Screen
-ing 
Dose 1 
Administrati
on  
Follow
-up 1 
Follow
-up 2 
Stud
y 
Calls 
Dose 2 
Administrati
on  
Follow
-up 3 
Follow
-up 4 
Stud
y 
Calls 
Follow
-up 5 
Stud
y 
Calls 
Un- 
schedule
d Visit 
Early 
Termin
-ation 
 
 
Clinic 
Clinica 
Clinica 
TC 
Clinic 
Clinica 
Clinica 
TC 
Clinica 
TC 
Clinica 
Clinica 
Study Day  
–14 to 
–1 
0 
7 
14 
21 
28 
35 
42 
 49 
56 
 70, 
98m, 
126m, 
156m, 
198  
n/a 
n/a 
Procedure Visit 
Window (in 
days) 
0 
0 
0 
±1 
±2 
±3 
0 
±1 
±2 
±3 
±2 
n/a 
n/a 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusi
on 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationc 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Vital signs, pulse 
oximetry, and 
body 
temperatured 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 

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Table 13-1 
Schedule of Events: Priming Vaccinations 
Visit Type 
(Study Day) 
Screen
-ing 
Dose 1 
Administrati
on  
Follow
-up 1 
Follow
-up 2 
Stud
y 
Calls 
Dose 2 
Administrati
on  
Follow
-up 3 
Follow
-up 4 
Stud
y 
Calls 
Follow
-up 5 
Stud
y 
Calls 
Un- 
schedule
d Visit 
Early 
Termin
-ation 
 
 
Clinic 
Clinica 
Clinica 
TC 
Clinic 
Clinica 
Clinica 
TC 
Clinica 
TC 
Clinica 
Clinica 
Urine sampling 
for drugs/ 
alcohol 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling 
for eligibilityf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling 
for SARS-CoV-2 
antibodiesg 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood sampling 
for safetyf 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
Blood sampling 
for CMI (CMI 
subset only) h 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Saliva sample for 
SARS-CoV-2 i  
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Study vaccine 
administration j 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Post vaccination 
observation k 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Adverse Events l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
meds collection  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Table 13-1 
Schedule of Events: Priming Vaccinations 
Visit Type 
(Study Day) 
Screen
-ing 
Dose 1 
Administrati
on  
Follow
-up 1 
Follow
-up 2 
Stud
y 
Calls 
Dose 2 
Administrati
on  
Follow
-up 3 
Follow
-up 4 
Stud
y 
Calls 
Follow
-up 5 
Stud
y 
Calls 
Un- 
schedule
d Visit 
Early 
Termin
-ation 
 
 
Clinic 
Clinica 
Clinica 
TC 
Clinic 
Clinica 
Clinica 
TC 
Clinica 
TC 
Clinica 
Clinica 
Recording of 
symptoms of 
COVID 19, and 
exposure to 
COVID 19 cases 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Visits will be performed in person unless the participant is otherwise directed to remain at home or be seen at a hospital. Follow-up visits and 
unscheduled visits may be performed by telemedicine visits or in a hospital setting if warranted by clinical circumstances (eg COVID-19 
lockdown in the vicinity) and permitted by local regulation. The target dates for the Day 7 - Day 28 visits are based on the actual date of the 
Day 0 visit. The target dates for the Day 35- Day 208 visits are based on the actual date of the Day 28 visit. The target dates for visits after 
Day 208 are based on the actual Day 208 visit. 
b 
 On Day 0, participants will be randomly assigned to one of four Study Groups (3 ARCT‑021:1 placebo), where they will receive 2 doses of 
study vaccine on Day 0 and Day 28 and also for participants in Study Groups 1, 2, and 3 further randomly assigned to receive a single booster 
dose of study vaccine (1 ARCT-021:1 placebo) on Day 208. Study Group 4 will not be randomized to receive booster but will receive 1 dose of 
placebo at Day 208 
c 
Complete physical examination will be performed at Screening and Early Termination Visit; symptom-directed examination (if any symptoms) 
will be performed at other time points as indicated to assess changes from Screening. 
d 
Blood pressure, heart rate, respiratory rate, body temperature, and pulse oximetry will be measured. On days of study vaccine administration, 
these will be measured before and after vaccine administration. 
e 
Pregnancy testing will be performed on women who are not surgically sterile or postmenopausal. Pregnancy testing by urine dipstick is 
acceptable. Pregnancy testing will be performed and evaluated prior to study vaccine administration. 
f 
Analytes for eligibility and safety assessments are listed in Appendix 2: Clinical Laboratory Tests. Repeat safety laboratory testing at Screening 
will not be permitted, unless the result is uninterpretable, or Screening assessments are repeated due to lapse of the 14-day screening visit 
window. On days when study vaccines are administered, blood must be drawn prior to vaccine administration. Throughout the study, additional 
laboratory analyses may be performed for enrolled participants if relevant to understanding participant safety. The decision to conduct these 
analyses will be based on discussion between the Medical Monitor and the Investigator and subject to Medical Monitor approval. 
g 
Immunogenicity samples will include anti-SARS-CoV-2 neutralizing and binding antibodies. On days when study vaccines are administered, 
blood must be drawn prior to vaccine administration. See Section 6.3 for further detail. On unscheduled visits that are performed for assessment 
of non-COVID-19-related AEs, a blood sample for immunogenicity is not required. 

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Table 13-1 
Schedule of Events: Priming Vaccinations 
Visit Type 
(Study Day) 
Screen
-ing 
Dose 1 
Administrati
on  
Follow
-up 1 
Follow
-up 2 
Stud
y 
Calls 
Dose 2 
Administrati
on  
Follow
-up 3 
Follow
-up 4 
Stud
y 
Calls 
Follow
-up 5 
Stud
y 
Calls 
Un- 
schedule
d Visit 
Early 
Termin
-ation 
 
 
Clinic 
Clinica 
Clinica 
TC 
Clinic 
Clinica 
Clinica 
TC 
Clinica 
TC 
Clinica 
Clinica 
h 
At each time point blood will be drawn in the participants assigned to the CMI subset. On days when study vaccines are administered, blood 
must be drawn prior to vaccine administration. Participants assigned to the CMI subset and who re-enroll into the study will not undergo blood 
sampling for CMI after re-enrollment. The CMI assays are described in Section 7.6.5. 
i 
 Nasal swabs and nasal turbinate swabs may replace saliva testing with alternate means of confirmatory testing of SARS-CoV-2. Participants 
will receive Home Test Kits if the participant reports possible COVID-19 symptoms or risk of exposure to SARS-CoV-2. 
j 
Study vaccine will be administered by intramuscular injection into the deltoid muscle of the non-dominant arm. Study vaccine administration 
will not be performed at these visits if the participant has not met reasons for study vaccine withdrawal. See Section 4.2.2 for further detail. 
k 
Vaccinated participants will be observed at the site for at least 30 minutes following vaccine administration or until clinically stable. 
l 
Review of AEs will include surveillance for solicited and unsolicited AEs, SAEs, MAAEs, NOCDs, AEs leading to 
discontinuation/withdrawal; data will be gathered by Diary and telephone contacts. See Section 6.4 for further detail. 
m 
At telephone contacts performed from Day 98 through Day 198, participants will be asked if they are interested in re-enrolling into the study to 
receive ARCT-021 vaccine. Participants eligible to re-enroll to receive ARCT-021 vaccine (placebo group only), will complete the Early 
Termination visit. See Section 5.1 for further detail. 
 
 
 

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Table 13-2 
Schedule of Events: Booster Vaccination 
Visit Type (Study Day) 
Booster 
Administration  
Booster 
Follow-up 1 
Study 
Calls 
Booster 
Follow-up 2 
Study 
Calls 
Booster 
Follow-up 3l 
Unscheduled 
Visit 
Early 
Termination 
 
Clinic 
Clinica 
TC 
Clinica 
TCb 
Clinica, b 
Clinica 
Clinica, b 
Study Day  
208 
215 
222, 
229  
236 
264, 292, 
320, 348, 
376 
388 
n/a 
n/a 
Procedure/Visit Window (in 
days) 
+60 
0 
±3 
±3 
±3 
±3 
n/a 
+14 
Physical examinationc 
X 
X 
 
X 
 
X 
X 
X 
Vital signs, pulse oximetry, and 
body temperatured 
X 
X 
 
X 
 
X 
X 
X 
Pregnancy teste 
X 
 
 
 
 
 
 
 
Blood sampling for safetyf 
X 
X 
 
 
 
 
 
 
Blood sampling for 
SARS-CoV-2 antibodiesg 
X 
 
 
X 
 
X 
X 
X 
Blood sampling for CMI (CMI 
subset only)h 
X 
X 
 
X 
 
X 
 
X 
Saliva sample for 
SARS-CoV-2i  
X 
X 
 
X 
 
X 
X 
X 
Study vaccine administrationj 
X 
 
 
 
 
 
 
 
Post vaccination observation k 
X 
 
 
 
 
 
 
 
Adverse Events l 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds collection  
X 
X 
X 
X 
X 
X 
X 
X 

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Table 13-2 
Schedule of Events: Booster Vaccination 
Visit Type (Study Day) 
Booster 
Administration  
Booster 
Follow-up 1 
Study 
Calls 
Booster 
Follow-up 2 
Study 
Calls 
Booster 
Follow-up 3l 
Unscheduled 
Visit 
Early 
Termination 
 
Clinic 
Clinica 
TC 
Clinica 
TCb 
Clinica, b 
Clinica 
Clinica, b 
Recording of symptoms of 
COVID-19, and exposure to 
COVID-19 cases 
X 
X 
X 
X 
X 
X 
X 
X 
 

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13.2 
Appendix 2: Clinical Laboratory Tests 
Table 13-3 
Schedule of Clinical Laboratory Tests 
Safety Laboratory Assessments 
Screening Tests for 
Eligibilitya 
Immunogenicity 
Assessments 
Clinical Chemistry 
Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose (random) 
• 
BUN 
• 
Creatinine 
• 
Cholesterol 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect 
(unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline 
phosphatase 
• 
Creatinine kinase 
• 
GGT 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH 
• 
MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C 
antibody 
• 
HIV antibody 
• 
FSH (women only, 
as clinically 
warranted) 
• 
Serum/urine βhCG 
• 
Urine drug/ alcohol 
screen 
• 
HbA1c (if 
warranted for 
individuals with 
diabetes mellitus 
Type 2) 
• 
SARS-CoV-2 
neutralizing antibody 
titer by pseudoviral 
microneutralization 
assay [all 
participants] and 
optional PRNT assay 
[all/some 
participants] 
• 
[All participants] 
Anti-S, N-, and RBD 
protein IgG by MSD 
multiplex assay 
• 
[CMI subset only] 
Cytokine-producing 
SARS-CoV-2 spike 
protein-specific T-
cells as measured by 
flow cytometry 
• 
[CMI subset only] 
ICS assay (Tumor 
necrosis factor 
(TNF) α, Interleukin-
2 (IL-2), Interferon- 
γ (IFN- γ), IL-4, and 
IL-13) 
• 
Additional 
exploratory 
immunogenicity tests 
will be specified in 
the SAP, if 
performed. 
Virology 
• 
SARS-CoV-2 
detection by RT-
PCR 
a 
Can be performed at a local laboratory if the tests are available. Repeat safety laboratory testing (except 
toxicity screen and pregnancy test) at Screening will not be permitted unless the result is uninterpretable, or 
Screening assessments are repeated due to lapse of the 14-day screening visit window 
 
 
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13.3 
Appendix 3: Contraceptive Guidance 
Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 60 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
• Refrain from donating sperm. 
PLUS, either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR 
• Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in women of childbearing potential (WOCBP) partners of male 
participants (refer to the list of highly effective methods below). 
Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
• Is not a WOCBP (see definitions below). 
OR 
• Is a WOCBP and using an acceptable contraceptive method as described below 
during the intervention period (for a minimum of 60 days after the last dose of study 
intervention). The Investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention. 
The Investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered, including follicle-stimulating hormone (FSH) test. 
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Women in the following categories are not considered WOCBP: 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy. 
o Documented bilateral salpingectomy. 
o Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
• Postmenopausal defined as follows: 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
o A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or hormone replacement therapy (HRT). 
o A female participant on HRT and whose menopausal status is in doubt will be 
required to use one of the nonestrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
Contraception Methods Inclusion Criteria 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
Acceptable and highly effective contraception methods include the following: 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Vasectomized partner: 
o Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential 
and the absence of sperm has been confirmed. If not, an additional highly 
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effective method of contraception should be used. The spermatogenesis cycle 
is approximately 90 days. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
o Injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
• Double barrier methods: a combination of male condom with either cervical cap, 
diaphragm, or sponge with spermicide. 
• Sexual abstinence: 
o Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred 
and usual lifestyle of the participant. 
The following methods of birth control are not regarded as highly reliable methods and are 
therefore discouraged as a single method only for contraception: 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action. 
• Male or female condom with or without spermicide. 
• Cervical cap, diaphragm, or sponge with spermicide. 
 
 
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13.4 
Appendix 4: FDA Toxicity Grading Scales 
Table 13-4 
Toxicity Grading for Solicited Adverse Events 
Solicited Local AEs 
Grade 1 (Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially 
Life 
Threatening) 
Injection Site Erythema *  
2.5 – 5 cm  
5.1 – 10 cm  
>10 cm  
Necrosis or 
exfoliative 
dermatitis  
Injection Site Induration/Swelling 
** 
2.5 – 5 cm and 
does not interfere 
with activity  
5.1 – 10 cm or 
interferes with 
activity  
>10 cm or prevents 
daily activity  
Necrosis  
Injection Site Pain 
Does not interfere 
with activity  
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity  
Any use of 
narcotic pain 
reliever or prevents 
daily activity  
Emergency room 
(ER) visit or 
hospitalization  
Injection Site Tenderness 
Mild discomfort 
to touch  
Discomfort with 
movement  
Significant 
discomfort at rest  
ER visit or 
hospitalization  
Solicited Systemic AEs 
 
 
 
 
Fever (°C) *** 
(°F) ***  
38.0 – 38.4 
100.4 – 101.1  
38.5 – 38.9 
101.2 – 102.0  
39.0 – 40 
102.1 – 104  
>40 
>104  
Nausea/vomiting 
No interference 
with activity or 1 
– 2episodes/24 
hours  
Some interference 
with activity or 
>2 episodes/24hou
rs  
Prevents daily 
activity, requires 
outpatient IV 
hydration  
ER visit or 
hospitalization 
for hypotensive 
shock  
Diarrhoea 
2 – 3 loose stools 
or 
<400 g/24 hours 
4 – 5 stools or 
400 – 800 g/ 
24 hours  
6 or more watery 
stools or 
>800g/24 hours or 
requires outpatient 
IV hydration  
ER visit or 
hospitalization  
Headache 
No interference 
with activity  
Repeated use of 
non- narcotic pain 
reliever >24 hours 
or some 
interference with 
activity  
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity  
ER visit or 
hospitalization  
Fatigue  
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
ER visit or 
hospitalization  
Myalgia  
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
ER visit or 
hospitalization  
Arthralgia, chills, dizziness 
No interference 
with activity  
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization  
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable. 
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Table 13-4 
Toxicity Grading for Solicited Adverse Events 
Solicited Local AEs 
Grade 1 (Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially 
Life 
Threatening) 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
** If oral temperature is taken, take without recent hot or cold beverages or smoking. 
Source: DHHS 2007. 
 
Table 13-5 
Toxicity Grading for Vital Signs 
Vital Signs* 
Grade 1 (Mild) 
Grade 2 
(Moderate) 
Grade 3 (Severe) 
Grade 4 
(Potentially Life 
Threatening) 
Tachycardia - beats per 
minute  
101 – 115  
116 – 130  
>130  
ER visit or 
hospitalization 
for arrhythmia  
Bradycardia - beats per 
minute*** 
50 – 54  
45 – 49  
<45  
ER visit or 
hospitalization 
for arrhythmia  
Hypertension (systolic) – 
mm Hg  
141 – 150  
151 – 155  
>155  
ER visit or 
hospitalization 
for 
malignant 
hypertension  
Hypertension (diastolic) –  
mm Hg  
91 – 95  
96 – 100  
>100  
ER visit or 
hospitalization 
for 
malignant 
hypertension  
Hypotension (systolic) –  
mm Hg  
85 – 89  
80 – 84  
<80  
ER visit or 
hospitalization 
for hypotensive 
shock  
Respiratory Rate – breaths per 
minute  
17 – 20  
21 – 25  
>25  
Intubation  
* Subject should be at rest for all vital sign measurements. 
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when 
characterizing bradycardia among some healthy subject populations, for example, conditioned athletes 
When summary data are prepared for the analysis of vital signs, the toxicity grading scale will be applied and 
is irrespective of investigator assessment of clinical significance. For vital signs that are clinically 
significantly abnormal in the judgment of the investigator, these are reported as unsolicited adverse 
events and the severity scale used for evaluating unsolicited AEs is applied. (Section 6.4.1.2.1) 
 
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Table 13-6 
Toxicity Grading for Safety Laboratory Assessments 
Laboratory Parameter* 
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Potentially Life 
Threatening 
(Grade 4)**  
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
<125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
>150  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
>5.6  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
<3.1  
Glucose – Hypoglycemia 
mg/dL  
65 – 69  
55 – 64  
45 – 54  
<45  
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL  
100 – 110 
110 – 125  
111 – 125 
126 – 200  
>125 
>200  
Insulin 
requirements or 
hyperosmolar 
coma  
Blood Urea Nitrogen 
BUN mg/dL  
23 – 26  
27 – 31  
>31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
>2.5 or requires 
dialysis  
Calcium – hypocalcemia 
mg/dL  
8.0 – 8.4  
7.5 – 7.9  
7.0 – 7.4  
<7.0  
Calcium – hypercalcemia 
mg/dL  
10.5 – 11.0  
11.1 – 11.5  
11.6 – 12.0  
>12.0  
Magnesium – 
hypomagnesemia mg/dL  
1.3 – 1.5  
1.1 – 1.2  
0.9 – 1.0  
<0.9  
Phosphorous – 
hypophosphatemia mg/dL  
2.3 – 2.5  
2.0 – 2.2  
1.6 – 1.9  
<1.6  
Creatinine kinase– mg/dL  
1.25 – 1.5 × 
ULN***  
1.6 – 3.0 × ULN  
3.1 –10 × ULN  
>10 × ULN  
Albumin – 
Hypoalbuminemia g/dL  
2.8 – 3.1  
2.5 – 2.7  
<2.5  
--  
Total Protein – 
Hypoproteinemia g/dL  
5.5 – 6.0  
5.0 – 5.4  
<5.0  
--  
Liver Function Tests –
ALT, AST 
increase by factor  
1.1 – 2.5 × ULN  
2.6 – 5.0 × ULN  
5.1 – 10 × ULN  
>10 × ULN  
Bilirubin – when 
accompanied 
by any increase in Liver 
Function Test  
1.1 – 1.25 × ULN  
1.26 – 1.5 × 
ULN  
1.51 – 1.75 × 
ULN  
>1.75 × ULN  
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Table 13-6 
Toxicity Grading for Safety Laboratory Assessments 
Laboratory Parameter* 
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Potentially Life 
Threatening 
(Grade 4)**  
increase by factor  
Bilirubin – when Liver 
Function Test is normal; 
increase by factor  
1.1 – 1.5 × ULN  
1.6 – 2.0 × ULN  
2.0 – 3.0 × ULN  >3.0 × ULN  
Hemoglobin (Female) - 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
<8.0  
Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 
1.5  
1.6 – 2.0  
2.1 – 5.0  
>5.0  
Hemoglobin (Male) - 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
<8.5  
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 
1.5  
1.6 – 2.0  
2.1 – 5.0  
>5.0  
WBC Increase - cell/mm
3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  >25,000  
WBC Decrease - cell/mm
3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
<1,000  
Lymphocytes Decrease - 
cell/mm
3 
750 – 1,000  
500 – 749  
250 – 499  
<250  
Neutrophils Decrease - 
cell/mm
3 
1,500 – 2,000  
1,000 – 1,499  
500 – 999  
<500  
Eosinophils - cell/mm
3 
650 – 1500  
1501 - 5000  
>5000  
Hypereosinophilic  
Platelets Decreased - 
cell/mm
3 
125,000 – 
140,000  
100,000 – 
124,000  
25,000 – 99,000  
<25,000  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization 
of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium 
value that falls within a grade 3 parameter (125-129 mEq/L) should be recorded as a grade 4 
hyponatremia event if the subject had a new seizure associated with the low sodium value. 
***ULN” is the upper limit of the normal range. 
When summary data are prepared for the analysis of safety laboratory assessments, the toxicity grading scale 
will be applied and is irrespective of investigator assessment of clinical significance. For safety 
laboratory assessments that are clinically significantly abnormal in the judgment of the investigator, 
these are reported as unsolicited adverse events and the severity scale used for evaluating unsolicited 
AEs is applied. (Section Assessment of Severity) 
Source: DHHS 2007. 
 
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13.5 
Appendix 5: Protocol Amendments 
13.5.1 
Protocol Amendment 1 (Version 2.0, 17 January 2021): Summary of Major 
Changes 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Title Page, Protocol 
Approval – Sponsor 
Signatory, Protocol 
Approval – Lead 
Statistician  
Declaration of Investigator 
Page Header 
Revised version and date of 
the protocol from 
19 November 2020, 
Version 1.0 to 
17 January 2021, Protocol 
Amendment 1, Version 2.0 
Updated version and date of the protocol. 
Synopsis – Exploratory 
Objectives 
Antibody response changed 
to immune response. 
Clarified description to state 
that further immunogenicity 
assays and endpoints will be 
defined in the statistical 
analysis plan. 
Objective and endpoint wording updated to 
allow for exploratory immunogenicity testing 
to include broader testing than neutralizing 
antibody responses. 
Synopsis – study design, 
duration of treatment, 
visits, study calls; 
immunogenicity 
assessments 
End-of-study day changed 
from Day 388 to Day 570; 
Changed duration from 
14 months to approximately 
20 months; Booster 
Follow-up 3 (Day 388) 
added, and Final Visit was 
changed from Day 388 to 
Day 570. 
Six months added to study per request by the 
Singapore regulatory agency (HSA Health 
Sciences Authority) for safety assessments. 
Synopsis – study design 
Updated the date of 
randomization for the 
booster dose of study vaccine 
to Day 0 and to occur after 
initial randomization to 
treatment on Day 0 and Day 
28. 
Correction of typographical error 
Synopsis – Table 1 
Primary vaccination day 
changed from Day 1 to 
Day 0 
Corrected error in table. 
Synopsis – Screening 
procedures 
Removed specific method 
(saliva sample or nasal 
turbinate or nasal swab) to 
collect sample for testing of 
SARS-CoV-2 by RT-PCR, 
which is required for testing 
at screening. 
Added text stating a saliva 
sample or nasal turbinate or 
nasal swab can be collected 
Correction of plan to allow flexibility to test 
locally for screening purposes and only if 
clinically warranted. 
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13.5.1 
Protocol Amendment 1 (Version 2.0, 17 January 2021): Summary of Major 
Changes 
Section Number and 
Name 
Description of Change 
Brief Rationale 
at the Investigators 
discretion. 
Synopsis - Visits 
Text related to home health 
nursing visits removed. 
Home health visits are not expected to occur 
based on site feedback on current medical 
practices. 
Synopsis – unscheduled 
visits 
Added text stating that 
additional COVID-19 testing 
could be done as clinically 
warranted for evaluation of 
AEs but with CRO medical 
monitor approval. 
Revisions made to ensure that investigators 
are aware that additional tests may be run in 
order to evaluate participant safety. 
Synopsis – Figure 1-1 
Clarified that testing for 
SARS-CoV-2 could be 
performed at a local 
laboratory. 
Corrections made to figure 
footnotes 
To allow for faster evaluation of SARS-CoV-2 
status for study related decision making 
Synopsis – additional 
procedural specifics, 
immunogenicity 
assessments 
Removed the specific 
antibody assay type (eg, 
changed Nab to “additional 
exploratory antibody” and 
PRNT assay removed). 
Allow antibody assay type to be specified 
when available  
Synopsis – additional 
procedural specifics, 
immunogenicity 
assessments, Section 6.3, 
Section 7.6.5 – Analysis of 
exploratory endpoints 
CMI subset: Added 
exploratory CMI assessments 
may be evaluated, additional 
CMI testing may be 
performed if the assays are 
available. 
Corrected assessment dates 
Allow for additional immunogenicity testing 
Improved accuracy. 
Synopsis—Pausing rules 
Details added and pausing 
rule clarified 
Further specifics added to provide guidance 
for pausing and investigator/regulatory 
notification 
Synopsis – Independent 
DSMB 
Number of planned analyses 
increased from 2 to 3. 
Correction of conflicting statements in the 
protocol relating to the planned number of 
interim analyses. 
Revision of DSMB role in 
dose selection for Phase 3 
Clarified based on DSMB feedback 
Synopsis – statistical 
methods 
Day 388 changed to Day 570 
Six months added to the study. 
Added text about exploratory 
analyses to be described in 
SAP before the analysis. 
As the ongoing characterization of 
SARS-CoV-2 infection and prevention thereof 
occurs, keeping a small reserve of blood for 
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13.5.1 
Protocol Amendment 1 (Version 2.0, 17 January 2021): Summary of Major 
Changes 
Section Number and 
Name 
Description of Change 
Brief Rationale 
additional, sensitive immunogenicity testing 
may inform future development activities. 
Throughout protocol body 
End of study changed from 
Day 388 to Day 570 
Six months added to study 
Section 7, Table 1-1 
Explanation of “huACE-2” 
provided  
Language explaining the mouse model 
provided 
Section 2.3 – Exploratory 
objectives 
Antibody response changed 
to immune response. 
Clarified description to state 
that further immunogenicity 
assays and endpoints will be 
defined in the statistical 
analysis plan. 
Objective and endpoint wording updated to 
allow for exploratory immunogenicity testing 
to include broader testing than neutralizing 
antibody responses. 
Section 3.1 – Study Design 
Clarified that the booster 
vaccine randomization will 
be done on Day 0, and that 
Group 4 will be dosed with 
placebo to maintain the 
blind. 
Booster vaccine must be done on Day 0 for 
logistical reasons. 
Section 4.1.2 – Exclusion 
Criteria 
Clarified that testing for 
SARS-CoV-2 could be 
performed at a local 
laboratory. 
To assess previous exposure to SARS-CoV-2 
if unclear from the interview with the 
participant. 
Added more detail around 
smoking history and that it 
includes vaping, tobacco, 
and marijuana products. 
Additional details to help select appropriate 
participants. 
Further refinement of 
language for exclusion 
relating to cardiovascular 
disease 
Additional details to help select appropriate 
participants. 
Addition of 
approved/emergency use 
SARS-CoV-2 vaccines to list 
of prohibited prior therapies 
or planned therapies  
Excludes use of other vaccines that may 
interfere with study interpretability 
Section 4.2.5—Pausing 
Rules 
Details added and pausing 
rule clarified 
Further specifics added to provide guidance 
for pausing and investigator/regulatory 
notification 
Section 5.1, Table 5-1 
Primary vaccination day 
changed from Day 1 to 
Day 0 
Corrected error in table. 
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13.5.1 
Protocol Amendment 1 (Version 2.0, 17 January 2021): Summary of Major 
Changes 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 5.2 – Treatments 
administered 
Details added 
Further specifics added to provide guidance on 
the evaluation and management of participant 
safety following study vaccination. 
Section 5.3 – Identity of 
study vaccine 
Clarified that sterile water 
for injection and sterile 
saline for reconstitution of 
ARCT-021 will be provided 
to the site by the Sponsor. 
Correction for how these materials would be 
supplied for the study 
Section 5.4 – Preparation 
of study vaccine 
Details added to clarify the 
procedure and added a 
reference to the pharmacy 
manual. 
Improved clarity of instructions for product 
preparation  
Section 5.5.3 – Other 
supplies for participant use 
Clarified that the 
Sponsor/delegate can provide 
electronic devices to 
participants for their diaries. 
To assist in Diary compliance 
Clarified that home test kits 
will be provided if the 
participant reports possible 
COVID-19 symptoms or risk 
of exposure to COVID-19.  
Correction to protocol 
Section 5.8 - Blinding 
Clarified that the Sponsor 
team unblinding will be 
limited to those with direct 
oversite of the study.  
Clarified that the Sponsor team blinding will 
be limited to those with direct oversight of the 
study. Rationale: The Sponsor may have the 
flexibility to review unblinded data if 
warranted for strategic decision making but 
the blinding status of the study team at the 
Sponsor will remain intact. 
The amber sleeve was 
updated to a label to cover 
the syringes. 
Blinding method substitution 
Section 6 – Study 
assessments and 
procedures 
Corrected the definition of 
exposure to COVID-19 
Improved accuracy 
 
Replaced Figure 6-1 with 
updated figure and updated 
footnotes 
Improved accuracy 
Section 6.4.3 – Clinical 
Safety Laboratory 
Assessments 
Clarified that the screening 
laboratory tests will not be 
repeated unless the results 
are uninterpretable or 
Screening assessments are 
repeated due to lapse of the 
Improved accuracy 
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13.5.1 
Protocol Amendment 1 (Version 2.0, 17 January 2021): Summary of Major 
Changes 
Section Number and 
Name 
Description of Change 
Brief Rationale 
14-day screening visit 
window 
Wording clarified 
Improved accuracy 
Section 6.4.5 
Temporal body temperature 
changed to oral body 
temperature. 
Substitution of thermometer provided for body 
temperature measurement 
7.6.5 – Analysis of 
exploratory endpoints 
ITT changed to mITT. 
Improved accuracy 
Table 13-1 
Study days “bimonthly” for 
study calls after Day 56 was 
removed and exact days were 
entered; removed footnote 
“b”. 
Calls are not exactly 2 months apart and this 
could lead to confusion. 
Split blood sampling for 
eligibility and safety into 2 
separate rows 
 
Revised to further specify which of these tests 
is performed at specific visits. 
Row added for urine 
sampling for drugs/alcohol 
Previous version included drugs/alcohol tests 
performed as a blood test but the test run from 
a urine specimen 
Footnote added for CMI 
subset. 
Protocol specified and exploratory CMI tests 
may be performed 
Table 13-2 
Final visit changed to Day 
570 
Six months added to study. 
Booster Follow-up 3 added 
for Day 388 
Six months added to the study. 
Monthly study calls added up 
to Day 556 
Specifies additional calls made based on the 
extension of study duration 
Footnote added for CMI 
subset. 
Protocol specified and exploratory CMI tests 
may be performed 
 
 
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13.5.2 
Protocol Amendment 1.1 (Version 2.1, 19 January 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Title Page, Protocol Approval – 
Sponsor Signatory, Protocol 
Approval – Lead Statistician  
Declaration of Investigator 
Page Header 
Revised version and date of the 
protocol from 17 January 2021, 
Version 2.0 to 19 January 2021, 
Protocol Amendment 1.1, Version 
2.1 
Updated version and date of the 
protocol. 
Section 4.1.2 – Exclusion Criteria 
Correction of number sign in front 
of New York Heart Association 
Congestive Heart Failure grades 
intended for exclusion from ≤ 2 to 
≥ 2 
Correction of typo to ensure 
exclusion of those individuals 
who are at increased risk of severe 
COVID-19 disease 
Table 13-2 
Final visit changed from 388 to 
570. 
Consistency with remaining 
portions of document  
 
13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Title Page 
Previous versions of the protocol 
added. 
Improved tracking of previous 
versions. 
Title Page, Protocol Approval – 
Sponsor Signatory, Protocol 
Approval – Lead Statistician  
Declaration of Investigator 
Page Header 
Revised version and date of the 
protocol from Protocol 
Amendment 1.1, Version 2.1 to 
26 February 2021, Protocol 
Amendment 2, Version 3.0. 
Updated version and date of the 
protocol. 
Title Page, Protocol Approval – 
Sponsor Signatory, Synopsis 
Revised Sponsor zip code 
Improved accuracy. 
Synopsis – Exploratory 
Objectives 
Language added to 
immunogenicity objective to 
reflect that assays evaluating 
immune responses to other 
SARS-CoV-2 variants may be 
performed. 
Cross-reactivity to other 
circulating SARS-CoV-2 strains 
may be relevant to characterizing 
future ARCT-021 responses and 
planning. 
Synopsis—Study Design 
Specific requirement to enroll 
>50% of the older participants in 
the 65 years of age and older age 
group removed. 
Removal of overly stringent 
criterion inhibiting trial 
enrollment. 
Synopsis—Study Design 
Protocol will now offer 
participants randomized to 
placebo a mechanism of being 
vaccinated with ARCT-021 earlier 
in the study after Day 98. Protocol 
also provides guidance for 
Changes made to accommodate 
the interests of participants who 
are seeking access to an active 
vaccine during SARS-CoV-2 
pandemic while participating in 
the trial. Day 98 will allow 
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13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
participants exiting the study to 
seek approved COVID-19 
vaccine. Added Figure 1: Flow for 
Re-enrollment and Day 388 
Withdrawal Options. 
adequate observation of the 
placebo group for primary study 
comparisons of immunogenicity 
and safety. 
Synopsis – Duration of 
Participation 
Section title updated from 
“Duration of Treatment” to reflect 
the information presented in the 
section. 
Improved accuracy. 
Synopsis – Duration of 
Participation 
Participation duration updated 
from 20 months for all 
participants to approximately: 
• 
20 to 24 months for 
participants enrolled in 
Singapore 
• 
14 to 24 months for 
participants enrolled in 
the United States 
Consistency with changes to study 
design. 
Synopsis – Study Assessments 
and Procedures – Visits 
Clarified that participants in Study 
Groups 1, 2, 3 will have up to 
13 scheduled visits. Participants in 
Study Group 4 will have up to 
20 scheduled visits. Clarified that 
participation past Day 388 is 
optional for participants enrolled 
in the US and participation 
through Day 570 is expected for 
participants enrolled in Singapore. 
Consistency with changes to study 
design. 
Synopsis – Study Assessments 
and Procedures – Study Calls 
Clarified that telephone calls will 
be performed again for 
participants enrolled in Study 
Group 4 that re-enroll. 
Clarified that participation past 
Day 388 is optional for 
participants enrolled in the US 
and participation through Day 570 
is expected for participants 
enrolled in Singapore. 
Consistency with changes to study 
design. 
Synopsis – Study Assessments 
and Procedures 
Revised Figure 1-1: Summary of 
Key Study Procedures. 
Improved visualization of revised 
study design. 
Synopsis – Additional procedural 
specifics 
Removed “paper” from verbiage 
regarding diaries. 
Consistency with how diary data 
is actively being captured. 
Revised language regarding the 
end of the reporting period for 
Consistency with changes to study 
design.  
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13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
unsolicited AEs and COVID-19 
exposure to clarify that the Final 
Visit is Day 570, or Day 388 in 
US enrolled participants who 
decline participation past this time 
point. 
Removed “antibody” after 
“receptor binding domain 
(RBD).” 
Improved accuracy. 
Synopsis – Pausing Rules  
Clarified that any anaphylactic 
reaction is a pausing event. 
Clarified that any clinically 
apparent hypersensitivity episode 
that is probably or definitely 
related to study vaccine 
administration, and is at least 
moderate in severity, is not 
confined to the injection site and 
is either immediate in onset or 
delayed and involving more than 
one organ system is a pausing 
event. 
Improved accuracy. 
Clarified that when Pausing Rule 
is confirmed to be met, 
investigators will be notified the 
same day to pause dosing and the 
regulatory authorities will be 
notified within 48 hours of 
determination that a pausing rule 
has been met. 
Improved accuracy of timelines 
and expectations when safety 
events occur. 
Synopsis – Immunogenicity 
Assessments 
Language added to clarify the 
final immunogenicity 
measurement time point. 
Consistency with changes to study 
design. 
Synopsis – Safety Assessments 
Language added from Section 
6.4.5 to clarify the measurement 
of vital signs prior to vaccination  
Improved accuracy 
Synopsis – Study Vaccine, 
Dosage, and Route of 
Administration 
Language added to clarify the 
measurement of vital signs 
following vaccination. 
Improved accuracy. 
Synopsis – Statistical Methods – 
Safety Analyses 
Revised language regarding the 
end of the reporting period for 
unsolicited AEs. 
Consistency with changes to study 
design. 
Definition of seropositivity added. 
Improved accuracy. 
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13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Synopsis – Interim Analyses 
Additional interim analysis added 
for available safety data for all 
participants enrolled as of 05 
February 2021. Day 28 and Day 
56 analyses modified to clarify 
that all participants enrolled as of 
05 February 2021 will be 
included. 
Improved timing of oversight of 
safety and immunogenicity data. 
Section 1.6 – Rationale for Dose 
Regimen Selection 
Language added to clarify the 
DSMB will evaluate the safety of 
each dose schedule. 
Improved accuracy. 
Section 1.7 – Risk: Benefit 
Assessment 
Table 1-1: Risk Minimization 
Measures Included in Clinical 
Trials of ARCT-021- Local and 
Systemic Reactogenicity: 
language added to clarify that 
subsequent doses of study vaccine 
will not be administered to 
participants that experience 
solicited adverse events that are 
confirmed by review by the 
Investigator to be Grade 3 or 
higher. 
Improved accuracy. 
Section 2.3 – Exploratory 
Objectives and Endpoints 
Language added to 
immunogenicity objective to 
reflect that assays evaluating 
immune responses to other 
SARS-CoV-2 variants may be 
performed. 
Cross-reactivity to other 
circulating SARS-CoV-2 strains 
may be relevant to characterizing 
future ARCT-021 responses and 
planning. 
Section 3.1 – Study Design 
Specific requirement to enroll 
>50% of older participants in the 
65 years of age and older age 
group removed 
Figure 3-1: ARCT021-04: Study 
Design updated to remove this 
requirement. 
Removal of overly stringent 
criterion inhibiting trial 
enrollment 
Section 3.1– Rationale for Study 
Design 
Language added to clarify 
rationale for offering participants 
randomized to placebo a 
mechanism of being re-
randomized and subsequently 
vaccinated with ARCT-021 earlier 
in the study after Day 98.  
Changes made to accommodate 
the interests of participants who 
are seeking access to an active 
vaccine during SARS-CoV-2 
pandemic while participating in 
the trial. Day 98 will allow 
adequate observation of the 
placebo group for primary study 
comparisons of immunogenicity 
and safety. 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
139 
Confidential 
13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 4.1.2 – Exclusion Criteria 
– Medical Conditions 
Exclusion Criterion #7: body 
temperature language revised 
from “>100° F (>37.8°C)” to 
“>100.4° F (>38.0°C).” 
Improved accuracy. 
Section 4.1.2 – Exclusion Criteria 
– Medical Conditions 
Exclusion Criterion #19: language 
regarding exclusionary vaccines 
removed from criterion and added 
in separate criterion (Exclusion 
Criterion #22) 
Correction of administrative error 
in which the criteria were 
inadvertently combined. 
Section 4.1.3 – Screen Failure 
Language added to clarify 
procedures to be performed when 
screening visit window lapses. 
Improved accuracy. 
Section 4.2.2 – Discontinuation of 
Study Vaccine (Participant) 
Language added to clarify that 
Grade 3 solicited AEs following 
the administration of study 
vaccine that are confirmed by 
Investigator review are 
contraindications to additional 
administrations of study vaccine. 
Improved accuracy. 
Section 4.2.3 – Withdrawal/ 
Discontinuation from the Study  
Added to the list of reasons: 
“Opportunity to receive an 
approved COVID-19 vaccine.” 
Consistency with changes to study 
design. 
Language added to clarify 
expectations if participants 
terminate the study less than 60 
days after the last study vaccine. 
Consistency with changes to study 
design. 
Language added to clarify 
expectations if participants exit 
the study to received approved 
COVID-19 vaccines. 
Consistency with changes to study 
design. 
Section 4.2.5 – Pausing Rules 
Clarified that any anaphylactic 
reaction is a pausing event. 
Clarified that any clinically 
apparent hypersensitivity episode 
that is probably or definitely 
related to study vaccine 
administration, and is at least 
moderate in severity, is not 
confined to the injection site and 
is either immediate in onset or 
delayed and involving more than 
one organ system is a pausing 
event. 
Improved accuracy. 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
140 
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13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Clarified that when Pausing Rule 
is confirmed to be met, 
investigators will be notified the 
same day to pause dosing and the 
regulatory authorities will be 
notified within 48 hours of 
determination that a pausing rule 
has been met. 
Improved accuracy of timelines 
and expectations when Pausing 
Criteria occur. 
Section 5.1– Method of Assigning 
Participants to Study Groups 
Protocol will now offer 
participants randomized to 
placebo a mechanism of being 
vaccinated with ARCT-021 earlier 
in the study after Day 98. Protocol 
also provides guidance for 
participants exiting the study to 
seek approved COVID-19 
vaccine. Added Figure 5-1: Flow 
for Re-Enrollment and Day 388 
Withdrawal Options 
Changes made to accommodate 
the interests of participants who 
are seeking access to an active 
vaccine during SARS-CoV-2 
pandemic while participating in 
the trial. Day 98 will allow 
adequate observation of the 
placebo group for primary study 
comparisons of immunogenicity 
and safety. 
Section 5.8 – Blinding 
Language updated to clarify that 
the Sponsor team providing direct 
oversight of the study will become 
unblinded at the time of the first 
interim analysis 
Consistency with changes to 
interim analysis strategy. 
Section 5.8.1 – Breaking the Blind 
Language added to clarify the 
protocol will now offer 
participants randomized to 
placebo a mechanism of being 
vaccinated with ARCT-021 earlier 
in the study after Day 98.  
Consistency with changes to study 
design. 
Section 5.11 – Dose Modification 
Language added to clarify the 
protocol will now offer 
participants randomized to 
placebo a mechanism of being 
vaccinated with ARCT-021 earlier 
in the study after Day 98.  
Consistency with changes to study 
design. 
Section 6 – Study Assessments 
and Procedures – Visits 
Clarified that participants in Study 
Groups 1, 2, 3 will have up to 
13 scheduled visits. Participants in 
Study Group 4 will have up to 
20 scheduled visits. Clarified that 
participation past Day 388 is 
optional for participants enrolled 
in the US and participation 
through Day 570 is expected for 
participants enrolled in Singapore. 
Consistency with changes to study 
design. 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
141 
Confidential 
13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 6 – Study Assessments 
and Procedures – Study Calls 
Clarified that telephone calls will 
be performed again for 
participants enrolled in Study 
Group 4 that re-enroll. 
Clarified that participation past 
Day 388 is optional for 
participants enrolled in the US 
and participation through Day 570 
is expected for participants 
enrolled in Singapore. 
Consistency with changes to study 
design. 
Section 6 – Study Assessments 
and Procedures 
Revised Figure 6-1: Summary of 
Key Study Procedures 
Improved visualization of revised 
study design 
Section 6 – Additional procedural 
specifics 
Removed “paper” from verbiage 
regarding diaries 
Consistency with how diary data 
is actively being captured. 
Revised language regarding the 
end of the reporting period for 
unsolicited AEs and COVID-19 
exposure to clarify that the Final 
Visit is Day 570, or Day 388 in 
US enrolled participants who 
decline participation past this time 
point. 
Consistency with changes to study 
design. 
Removed “antibody” after 
“receptor binding domain 
(RBD).” 
Improved accuracy. 
Section 6.1 – Evaluation of 
Participants with Suspected 
COVID-19 
Language added to clarify 
management of participants with 
COVID-19 diagnosis prior to 
7 days after first study 
vaccination. 
Improved accuracy. 
Language added to clarify that 
blood and saliva samples sent to 
the central laboratory are not 
diagnostic tests. 
Improved accuracy. 
Section 6.4.1.1.7 - Clinical Events 
of Special Interest 
Language added to clarify that 
CESI’s that demonstrate untoward 
signs or symptoms that are more 
likely related to the study vaccine 
than SARS-CoV-2, the events will 
be reported as AEs. 
Response to regulatory authority 
(FDA) comment. 
Section 6.4.1.3 – Reporting 
Adverse Events 
Language added to clarify AE 
reporting requirements. 
Consistency with changes to study 
design. 
Section 6.4.1.3.1 - Reporting 
Serious Adverse Events 
Language added to clarify 
mechanism for reporting. 
Improved accuracy. 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
142 
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13.5.3 
Protocol Amendment 2 (Version 3.0, 26 February 2021): Summary of 
Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 6.4.1.4 – Follow-up of 
Participants Reporting Adverse 
Events 
Language added to clarify 
requirements for managing 
Adverse Events for participants 
that terminate from the study. 
Improved accuracy. 
Section 6.4.5 – Vital Signs, Body 
Temperature, Pulse Oximetry 
Language added to clarify 
expectations for vital sign 
evaluation following study 
vaccine administration. 
Improved accuracy. 
Section 7 – Statistical 
Considerations 
Language added to clarify how 
data will be analyzed for 
participants that re-enroll. 
Consistency with changes to study 
design. 
Section 7.6.1 – Data Analyses for 
Re-Enrolled Participants 
Section added; Language added to 
clarify how data will be analyzed 
for participants that re-enroll. 
Consistency with changes to study 
design. 
Section 7.8 – Interim Analyses 
Section title updated from 
“Interim Analysis.”  
Improved accuracy. 
Additional interim analysis added 
for available safety data for all 
participants enrolled as of 
05 February 2021. Day 28 and 
Day 56 analyses modified to 
clarify that all participants 
enrolled as of 05 February 2021 
will be included. 
 
Section 8.1 – Data Management  
Removed reference to paper 
participant diary cards. 
Consistency with how diary data 
is actively being captured. 
Table 13-1 – Schedule of Events 
Priming Vaccinations 
Blood sampling for safety added. 
Correction of administrative error 
in which this was inadvertently 
removed. 
Table 13-1– Schedule of Events 
Priming Vaccinations 
Footnote m added to clarify 
timepoints in which participants 
may re-enroll in the study to 
receive ARCT-021. 
Consistency with changes to study 
design. 
Table 13-2 Schedule of Events 
Booster Vaccination 
Day 208 – Visit Window 
modified from “± 7” to “±3” days. 
Correction to avoid overlap with 
Day 215. 
Table 13-2 Schedule of Events 
Booster Vaccination 
Footnote added to clarify 
voluntary discontinuation at 
Day 388 for US participants. 
Consistency with changes to study 
design. 
Table 13-4 Toxicity Grading for 
Vital Signs 
Table added. 
Consistency with FDA toxicity 
tables. 
Table 13-5 Toxicity Grading for 
Safety Laboratory Assessments 
Table number updated from 13-4 
to 13-5. 
Administrative update. 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
143 
Confidential 
13.5.4 
Protocol Amendment 2.1 (Version 3.1, 29 July 2021, Singapore only): 
Summary of Major Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Signature Page 
Removal of signature page of 
biostatistician 
Alignment in practices for 
obtaining signature across 
Arcturus protocols 
Table 13-2 
Visit window for Day 208 visit 
changed from 3 days to +60 days 
This window allows greater 
flexibility for scheduling the 
booster dose visit which is 
intended to increase visit 
compliance.  
 
13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Title Page, Protocol Approval – 
Sponsor Signatory, Protocol 
Approval – Lead Statistician  
Declaration of Investigator 
Page Header 
Revised version and date of the 
protocol  
Administrative update 
Synopsis – Rationale 
Rationale for addition of more 
booster vaccine options 
(ARCT-054 and ARCT-165) 
provided 
Study will now evaluate 3 
lyophilized booster vaccines 
(ARCT-021, ARCT-154, 
ARCT-165). ARCT-154 and 
ARCT-165 are intended to 
vaccine (protect) against different 
variants of SARS-CoV-2 
Synopsis- Objectives 
Wording updated to specify 
analyses relating to priming and 
booster vaccine administrations 
Clarification of handling of 
priming and boosting vaccine data 
Synopsis—Study Design 
New study group assignments 
added for booster dose 
administration. At Day 208, 
participants will be randomized to 
ARCT-021, ARCT-154, 
ARCT-165 or placebo (1:1:1:1) 
Study group assignments 
reconfigured to allow the 
evaluation of multiple booster 
vaccine candidates 
 
Off-study COVID-19 vaccine 
allowed in some instances 
Although it is preferred 
participants do not receive off-
study COVID-19 vaccine, the 
continued evaluation of 
participants is of scientific value. 
Synopsis – Tables and Figures 
Table 1-1 and Figure 1-1 updated 
to include new booster vaccine 
groups  
Reflects updates to the study 
design. Table 1-1 and Figure 1-2 
were redesigned to clarify study 
group assignments and participant 
flow through priming 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
144 
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13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
vaccinations, potential re-
enrollment of eligible subjects, 
and booster vaccinations. 
Synopsis- Rationale for Dose 
Selection 
Booster dose of 5 µg 
LUNAR-COV19 identified 
Relevant to informing the dose for 
booster administration 
Synopsis – Study Assessments 
and Procedures – Visit Procedures 
Blood sampling will be performed 
prior to vaccination on 
vaccination visits.  
Improved study interpretability. 
Clarification to site staff that 
blood samples for 
immunogenicity should be 
obtained before vaccination.  
Synopsis – Study Assessments 
and Procedures – Unscheduled 
Visits 
Blood sampling for 
immunogenicity will only be 
performed under specific 
circumstances at unscheduled visit 
Blood sampling for antibody 
response will only be obtained for 
participants being evaluated for 
COVID-19 disease. Antibody 
responses during evaluation of 
non-COVID-19-related AE 
assessment not expected to 
generate additional scientific 
value. 
Synopsis – Additional procedural 
specifics 
Blood sampling for CMI will not 
be performed in re-enrolled 
participants 
Will not increase value of the 
existing CMI subset analysis. 
Synopsis – Pausing Rules 
Any death due to SARS-CoV-2 
infection or cases of severe 
SARS-CoV-2 infection will be 
confirmed by the DSMB as 
meeting pausing rules  
To reduce unnecessary pausing of 
the study for AEs that do not meet 
pausing rules 
 
The SRC will be blinded to 
individual participant vaccine 
assignments when reviewing AEs 
for consideration as pausing rules 
Intended to avoid bias in the 
interpretation of study safety data. 
Synopsis – Immunogenicity 
Assessments 
Blood sample added at Day 236 
Correction  
 
Blood sampling for CMI will not 
be performed in re-enrolled 
participants 
Will not increase value of the 
existing CMI subset analysis. 
Synopsis – Study Vaccine, 
Dosage, and Route of 
Administration 
Three different lyophilized 
LUNAR-COV19 study vaccines 
will be offered as booster doses at 
Day 208 
Provides a description of the latest 
LUNAR-COV19 vaccines 
entering the clinic. 
Synopsis—Analysis Set 
Analyses relating to priming 
(ARCT-021) and booster vaccines 
(ARCT-021, ARCT-154, 
ARCT-1650 are clarified 
Improved protocol comprehension 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
145 
Confidential 
13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
 
Reactogenicity set added to 
analysis sets 
Improved precision in the analysis 
of solicited AEs. Reactogenicity 
analysis set will include only 
subjects with data entered into 
daily diary to provide a more 
accurate denominator and 
percentage of participants with 
solicited symptoms. 
Synopsis – Interim Analyses 
Interim Analysis 3 will include all 
enrolled participants and the 
database will be locked for this 
analysis. 
Based on logistics of data 
availability through Day 56 and 
the intent to use Interim Analysis 
3 in an interim clinical study 
report. 
Section 1.1 Background 
COVID-19 statistics updated 
COVID-19 impact has expanded 
and remains severe. Added for 
improved understanding. 
Section 1.2 Current Therapies for 
COVID-19 
Available therapies for the 
prevention or treatment of 
COVID-19 added 
New authorized therapies and 
vaccines for COVID-19 are 
available for clinical use. Added 
for improved understanding. 
Section 1.3 Therapeutic Rationale 
for LUNAR-COV19 Vaccines in 
Prevention of COVID-19 
Update of current understanding 
of COVID-19 mRNA vaccines 
added 
Other COVID-19 mRNA vaccines 
have shown promising early 
vaccine efficacy and real-world 
effectiveness. Added for improved 
understanding. 
Section 1.4 Mechanism of Action 
Features of additional 
LUNAR-COV19 vaccines 
provided 
Each new LUNAR COVID-19 
vaccine has a unique 
SARS-CoV-2 target for variant 
strains. Provided for added 
comprehension. 
Section 1.5: Clinical Trial 
Experience with ARCT-021 
Section updated to include latest 
clinical trial information from 
study of ARCT-021 vaccine 
New data are available that inform 
the ongoing understanding of 
ARCT-021 safety and 
immunogenicity. Provided for 
added comprehension. 
Section 1.6 – Rationale for Dose 
Regimen Selection 
Dose choice for new 
LUNAR-COV19 vaccines 
provided 
Latest ARCT-021 clinical data 
support selection of the 5-µg dose 
of ARCT-021 for further 
evaluation in clinical trials. 
Section 1.7 – Risk: Benefit 
Assessment 
More details added relating to 
vaccine ingredients and risk 
mitigation for neutropenia 
described 
Improved precision in risk 
mitigation 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
146 
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13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 2.1- Primary Objectives 
and Endpoints 
Wording updated to specify 
analyses relating to priming and 
booster vaccine administrations 
Improved precision in study 
analysis 
Section 2.2—Secondary 
Objectives and Endpoints 
Wording updated to specify 
analyses relating to priming and 
booster vaccine administrations 
Improved precision in study 
analysis 
Section 2.3 – Exploratory 
Objectives and Endpoints 
Wording updated to specify 
analyses relating to priming 
(ARCT-021) and booster vaccine 
(ARCT-021, ARCT-154 and 
ARCT-165) administrations 
Improved precision in study 
analysis 
Section 3.1 – Study Design 
New study group assignments 
added for booster dose 
administration 
Additional description of the 
newly added LUNAR-COV19 
vaccines used as booster vaccines 
on Day 208 in the study 
Section 3.1– Study Design 
Figure 3-1 updated to include new 
study group assignments 
As above. Provides clarification 
for the dosing groups. 
Section 3.1.1—Rationale for 
Study Design 
Booster dose of 5 µg for 
3 different LUNAR-COV19 
vaccines identified 
The available data from 
ARCT-021 suggest that single 
dose administration of 
LUNAR-COV19 vaccines is 
expected to be similar across each 
active study vaccine and this dose 
has been well tolerated in and 
immunogenic when given with 
ARCT-021 vaccine  
Section 4.2.2 – Discontinuation of 
Study Vaccine (Participant) 
Off-study COVID-19 vaccine will 
be allowed 
The study will now continue to 
follow participants who have 
received off-study vaccine. 
Informative immunogenicity and 
safety data will be obtained from 
this subgroup. 
Section 4.2.3 – Withdrawal/ 
Discontinuation from the Study 
Off-study COVID-19 vaccine will 
be allowed 
As above 
 
Language added to address 
management of participants who 
decline receipt of study booster 
but who intend to remain on 
study. 
The study will continue to follow 
participants who decline booster 
vaccine receipt. There is scientific 
value in understanding the 
ongoing safety and 
immunogenicity data in 
participants who received no 
booster. 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
147 
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13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 4.2.5 – Pausing Rules 
Any death due to SARS-CoV-2 
infection or cases of severe 
SARS-CoV-2 infection will be 
confirmed by the DSMB as 
meeting pausing rules  
To reduce unnecessary pausing of 
the study for AEs that do not meet 
pausing rules 
 
The SRC will be blinded to 
individual participant vaccine 
assignments when reviewing AEs 
for consideration as pausing rules 
Intended to avoid bias in the 
interpretation of study safety data. 
Section 5.1– Method of Assigning 
Participants to Study Groups 
Language added to address new 
study vaccine assignments and 
allowance of off-study COVID-19 
vaccine 
Updated to align with new study 
design features described 
throughout the rest of the 
document. 
Section 5.2—Treatment 
Administration 
Observer blind procedures 
described in greater detail 
Emphasizes the importance of 
protecting the study blind around 
the time of vaccine preparation 
and administration 
Section 5.3—Identity of Study 
Vaccine 
The key features of each of the 
booster LUNAR-COV19 vaccines 
added 
Provides a description of the latest 
LUNAR-COV19 vaccines 
entering the clinic. 
 
The different presentations of the 
priming ARCT-021 vaccine 
(frozen liquid) and the boosting 
LUNAR-COV19 vaccines 
(lyophilized) are highlighted 
There are important differences to 
highlight to reduce the risk of 
confusion between the study 
vaccines. 
Section 5.4—Preparation of Study 
Vaccine 
The differences between the 
LUNAR-COV19 vaccines are 
specified. 
As above. 
Section 5.5.1—Study Vaccine 
Packaging and Storage 
Each of the sets of vials of 
LUNAR-COV19 vaccine should 
be stored separately from each 
other in the freezer. 
As above. 
Section 5.8 – Blinding 
Clarifies the specific windows 
wherein the full observer blind 
design is in effect and when there 
is a partial blind in effect. 
Improved protocol comprehension  
Section 5.10.1—Concomitant 
Therapy 
Receipt of any off-study vaccine 
will be tracked as a concomitant 
therapy during this study. 
Improved oversight of safety. 
Ensures accurate tracking of 
participants who have received 
off-study vaccination and proper 
analysis of relevant subgroups. 
Section 5.10.2—Prohibited 
Concomitant Therapy 
Off-study COVID-19 vaccine will 
be allowed 
Further clarification of 
considerations relating to off-
study COVID-19 vaccine receipt. 
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Arcturus Therapeutics, Inc. 
ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
148 
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13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 6 – Study Assessments 
and Procedures – Visits 
Blood sampling will be performed 
prior to vaccination on 
vaccination visits.  
Improved study interpretability  
 
Blood sampling for 
immunogenicity will only be 
performed under specific 
circumstances at unscheduled visit 
Blood sampling for antibody 
response will only be obtained for 
participants being evaluated for 
COVID-19 disease. Antibody 
responses during evaluation of 
non-COVID-19-related AE 
assessment not expected to 
generate additional scientific 
value. 
Section 6 – Study Assessments 
and Procedures – Figure 6-1 
Text in footnote describing a sub-
study is deleted. 
Correction 
Section 6.3—Immunogenicity 
Assessments 
Blood sample added at Day 236 
Correction 
 
Blood sampling for CMI will not 
be performed in re-enrolled 
participants 
Will not increase value of the 
existing CMI subset analysis. 
 
Additional assays to evaluate 
immune responses to 
SARS-CoV-2 variants are 
mentioned 
The study intends to better 
characterize vaccines and immune 
responses to vaccines relevant to 
emerging SARS-CoV-2 variants 
Section 6.4.1.1.1—Adverse 
Events 
Text added to specify that 
clinically significant abnormal 
safety laboratory assessments 
should be captured as unsolicited 
AEs. 
Clarification of existing process 
 
Text added to further specify 
conditions under which a solicited 
AE would also be captured as an 
unsolicited AE 
Clarification of existing process 
Section 6.4.3—Clinical Safety 
Laboratory Assessments 
Text added to specify that 
clinically significant abnormal 
safety laboratory assessments 
should be captured as unsolicited 
AEs. 
As above 
Section 7 – Statistical 
Considerations 
Sensitivity analyses may be 
conducted. 
To address issues such as 
administration of off-study 
COVID-19 vaccine. 
Table 7-2 
Updated to specify priming and 
booster vaccine-related 
approaches 
Improved accuracy 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
149 
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13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 7.3—Sample Size 
Determination 
Text added to describe smaller 
sample size considerations for 
vaccine subgroups after booster 
vaccination. 
Characterizes the accuracy of the 
planned analysis with different 
sample sizes that may occur 
following priming and booster 
vaccine doses. Specifically 
provides probability of detecting 
events in a subgroup with as few 
as 25 subjects. 
Section 7.4—Analysis Sets 
Reactogenicity set added 
Improved precision in reporting of 
solicited AEs. Reactogenicity 
analysis set will include only 
subjects with data entered into 
daily diary to provide a more 
accurate denominator and 
percentage of participants with 
solicited symptoms. 
Table 7-4 
Sensitivity analyses may be 
conducted 
Improves study interpretability 
 
Reactogenicity set mentioned 
Improved precision in reporting of 
solicited AEs 
 
Analysis of booster 
LUNAR-COV19 vaccines 
described 
Reflects design updates 
Section 7.8—Interim Analysis 
Interim Analysis 3 will include all 
enrolled participants and the 
database will be locked for the 
interim analysis. 
Based on logistics of data 
availability through Day 56. 
Provides a more accurate 
description of data to be included 
in Interim Analysis 3 and the 
intent to use Interim Analysis 3 in 
an interim clinical study report. 
 
Dose selection (booster, Phase 3) 
based on data from previous 
interim analyses identified. 
Latest ARCT-021 clinical data 
support selection of the 5-µg dose 
of ARCT-021 for further 
evaluation in clinical trials. 
Section 10.3—Data Sharing 
Specified timeframe for data 
sharing removed. Logistics of 
sharing data with investigators 
modified 
Updated for accuracy  
Table 13-1 – Schedule of Events 
Priming Vaccinations 
Updated for alignment with 
protocol text 
Changes from the body of the 
protocol have been summarized in 
this table and footnotes. 
Table 13-2 Schedule of Events 
Booster Vaccination 
Updated for alignment with 
protocol text 
As above 
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ARCT-021 
Protocol ARCT-021-04, Version 6.0 
09 March 2022 
 
150 
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13.5.5 
Protocol Amendment 3 (Version 4.0, 17 June 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Table 13-4 Toxicity Grading for 
Vital Signs 
Footnote added to clarify that 
toxicity grading will be used when 
all vital sign values are analyzed, 
and AE severity grading scales 
will be used when vital signs are 
reported as AEs. 
Improved protocol comprehension 
Table 13-5 Toxicity Grading for 
Safety Laboratory Assessments 
Footnote added to clarify that 
toxicity grading will be used when 
all safety laboratory assessments 
are analyzed, and AE severity 
grading scales will be used when 
abnormal safety laboratory 
assessments are reported as AEs. 
As above 
13.5.6 
Protocol Amendment 4 (Version 5.0, 16 July 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Synopsis – Interim Analyses; 
Section 7.8 - Interim Analysis 
Interim Analysis 3 will include all 
enrolled participants, Interim 
Analysis 4 and newly added 
Interim Analysis 5 will include a 
subset of participants, and the 
database will be locked prior to 
interim analyses 3 and 4. 
Changes made to allow for a 
larger dataset for Interim Analysis 
3 and also to perform Interim 
Analyses 4 and 5 with a subset of 
participants to inform interim 
reporting of study results and 
future clinical development 
planning. 
Table 13-2 Schedule of Events 
Booster Vaccination 
Updated visit window for booster 
dose expanded 
The booster dose visit window has 
been expanded to increase 
protocol compliance.  
13.5.7 
Protocol Amendment 4.1 (Version 5.1, 02 August 2021): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Signature Page 
Removal of signature page of 
biostatistician 
Alignment in practices for 
obtaining signature across 
Arcturus protocols 
Synopsis – Interim Analyses; 
Section 7.8 - Interim Analysis 
Interim Analysis 4 and 5 data lock 
points delayed by 1 month. 
Changes made to allow for a 
larger dataset for Interim Analyses 
4 and 5. 
Section 5.10.2 
Changed concomitant medication 
collection period to 28 days after 
each dose of study vaccine 
Alignment with language in 
Section 5.10.1 and current data 
collection practices 
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Section 6.1 
Figure 4 added and text clarified 
Changes made to improve 
protocol comprehension relating 
to evaluation of participants with 
suspected 
COVID-19/SARS-CoV-2 
exposure. 
Table 13-2 
Visit window for Day 208 visit 
changed from 3 days to +60 days 
This window allows greater 
flexibility for scheduling the 
booster dose visit which is 
intended to increase visit 
compliance.  
 
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13.5.8 
Protocol Amendment 5.0 (Version 6.0, 09 March 2022): Summary of Major 
Changes 
Section Number and Name 
Description of Change 
Brief Rationale 
Global 
The protocol has been updated to 
reflect early termination of the 
study (last study visit targeted for 
16 February 2022). 
The Sponsor (Arcturus) has 
notified the health authorities of 
its intent to discontinue further 
Arcturus-sponsored studies of 
ARCT-021. The milestone of 
16 February allows for at least 
56 days of safety observation to 
occur for participants who have 
received booster vaccine doses. 
The study is being discontinued 
for strategic reasons and there are 
no safety concerns relating to the 
administration of any of the 
Arcturus LUNAR-COV19 
vaccines. 
Global 
New Figure 1 added to synopsis 
and subsequent figures 
renumbered 
New flow chart added to improve 
protocol comprehension. 
Global 
Number of visits reduced, specific 
visits or study calls will no longer 
be performed based on early 
termination 
The changes reconcile study 
specific procedures based on early 
termination. 
Synopsis 
Section 3 
Endpoints updated to reflect study 
Early Termination status  
Changes made to reflect changing 
of endpoint timing based on Early 
Termination prior to Day 570 
Synopsis 
Section 6.3 
Evaluation of cell mediated 
immune responses at Day 215 
confirmed throughout the 
document for participants in the 
CMI subset who do not re-enroll 
Changes made for consistency 
throughout the document 
Synopsis 
Section 7.8 
Interim analysis 4 and 5 removed 
These interim analyses will no 
longer be performed.  
Section 6.4.2 
Removed requirement for 
COVID-19 case reporting for 
12 months after last vaccination. 
This reporting will no longer be 
performed after a participant 
completes study termination. 
Section 7.1 Estimands and 
Intercurrent Events 
Section 7.6 Statistical Analysis 
Methodology 
Clarified time periods for MAAE, 
NOCD, SAE and AEs leading to 
discontinuation reporting 
 
Changes made to improve 
protocol comprehension regarding 
AE reporting time periods 
 
 
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Section Number and Name 
Description of Change 
Brief Rationale 
Synopsis 
Section 7.4 Analysis Sets 
Revised to have separate analysis 
sets for Priming Vaccination 
Period and Booster Vaccination 
Period 
Changes made to support that 
these two periods are summarized 
separately  
Section 7.5 Description of 
Subgroups to be Analyzed 
Removed on study infection 
subgroup. 
On study infections are treated as 
intercurrent events instead of 
subgroups. 
Section 7.6 Statistical Analysis 
Methodology 
Removed sensitivity analyses 
Due to the study terminating 
early, decision was made to focus 
on the primary and supportive 
analyses only. 
Section 7.6 Statistical Analysis 
Methodology 
Added age group to the 
ANCOVA model 
Age group is a stratification factor 
for this study. 
Section 7.6 Statistical Analysis 
Methodology 
Revised to clarify intent to only 
list immunogenicity data for re-
enrolled subjects at this time. 
Change made due to decision to 
not summarize this data for the 
CSR. 
Section 7.8 Interim Analyses 
Removal of Interim Analysis 4 
and Interim Analysis 5 
Changes made due to study 
terminating early 
 
 
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