A Phase 2a, Open Label Extension Study to Assess the Safety and Long-Term Immunogenicity of ARCT-021
Phase: PHASE2
Conditions: SARS-CoV-2
Sponsor: Arcturus Therapeutics, Inc.

A Phase 2a, Open Label Extension Study to Assess the Safety and Long-Term 
Immunogenicity of ARCT-021 
Investigational Product 
ARCT-021 
Protocol Number 
ARCT-021-02 
Version Number 
Version 2.0 
Version Date 
13 January 2021 
Amendment 
1 
Short Title 
A Phase 2a, Open Label Extension Study to Assess the 
Safety and Long-Term Immunogenicity of ARCT-021 
Phase of Development 
2a 
Sponsor 
Arcturus Therapeutics, Inc. 
10628 Science Center Dr #250, 
San Diego,  
CA 92122 
Confidentiality Statement 
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. 
NCT #: NCT04728347

ARCT-021 
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STUDY CONTACTS 
Key Sponsor and CRO contacts for the Study can be found in the Investigator Site File provided 
to site 
 

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ARCTURUS SIGNATURE PAGE 
 
 
Title 
A Phase 2a, Open Label Extension Study to Assess the Safety and Long-
Term Immunogenicity of ARCT-021 
Protocol Number 
ARCT-021-02 
Version Number 
Version 2.0 
Version Date 
13 January 2021 
Amendment 
1 
 
The design of this study as outlined by this protocol has been reviewed and approved by: 
 
 
 
 
Date  
 
 

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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
I hereby acknowledge that I have read the protocol, appendices, and accessory materials related 
to Study ARCT-021-02,” Version 2.0, dated 13 January 2021, and agree to the following: 
• To conduct this study as described by the protocol and any accessory documents 
• To protect the rights, safety, and welfare of the subjects under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all investigational products provided by the Sponsor and maintain records of 
the disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical 
Practices as outlined by ICH E6 and subsequent amendments 
• To obtain approval for the protocol and all written materials provided to subjects prior to 
initiating the study at my site 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all subjects enrolled at my study site prior to initiating any 
study-specific procedures or administering investigational products to those subjects 
• To maintain records of each subject’s participation and all data required by the protocol 
• To ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of Arcturus Therapeutics, Inc.  
 
Physician responsible for all trial-site medical decisions 
Name 
Title 
Institution Address 
 
Phone: 
 
 
Principal Investigator 
Name 
Title 
Institution Address 
Phone: 
Signature 
Date 
 
[DD Month YYYY] 

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TABLE OF CONTENTS 
 
Page 
STUDY CONTACTS .................................................................................................................... 2 
ARCTURUS SIGNATURE PAGE ............................................................................................... 3 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ................................................................. 4 
PROTOCOL SYNOPSIS............................................................................................................. 10 
STUDY DESIGN AND TREATMENT SCHEMA FOR SUBJECTS NOT RECEIVING 
ARCT-021........................................................................................................................ 21 
STUDY DESIGN AND TREATMENT SCHEMA FOR  SUBJECTS RECEIVING A 
SINGLE INJECTION OF ARCT-021 ............................................................................. 22 
STUDY GLOSSARY .................................................................................................................. 23 
1 
OBJECTIVES AND ENDPOINTS ................................................................................. 28 
1.1 
Objectives ..................................................................................................................... 28 
1.1.1 
Primary Objective ...................................................................................................... 28 
1.1.2 
Secondary Objective .................................................................................................. 28 
1.1.3 
Exploratory Objective ................................................................................................ 28 
1.2 
Study Endpoints ............................................................................................................ 28 
1.2.1 
Primary Endpoint(s) ................................................................................................... 28 
1.2.2 
Secondary Endpoints ................................................................................................. 28 
1.2.3 
Exploratory Endpoint ................................................................................................. 28 
2 
BACKGROUND AND RATIONALE ............................................................................ 28 
2.1 
Overview of Disease ..................................................................................................... 28 
2.2 
Therapeutic Rationale ................................................................................................... 29 
2.3 
Rationale for Dose, Regimen and Route of Administration ......................................... 29 
2.4 
Rationale for Study Duration ........................................................................................ 30 
2.5 
Investigational Drug Product ARCT-021 ..................................................................... 30 
2.5.1 
Mechanism of Action ................................................................................................. 30 
2.5.2 
Chemistry ................................................................................................................... 31 
2.5.2.1 
Drug Substance mRNA-2002 ................................................................................. 31 
2.5.2.2 
Drug Product ARCT-021 ........................................................................................ 32 
2.5.3 
Preclinical Experience ............................................................................................... 33 
2.5.4 
Clinical Experience .................................................................................................... 35 
2.6 
Risk:Benefit Assessment .............................................................................................. 35 

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2.6.1 
Potential Risks ........................................................................................................... 35 
2.6.2 
Potential Benefits ....................................................................................................... 38 
2.7 
Ethical Considerations .................................................................................................. 38 
3 
EXPERIMENTAL PLAN ............................................................................................... 38 
3.1 
Compliance ................................................................................................................... 38 
3.2 
Study Design ................................................................................................................. 38 
3.3 
Measures to Minimize/Avoid Bias ............................................................................... 39 
3.4 
Quality Control and Quality Assurance ........................................................................ 39 
3.5 
Number of Study Centers.............................................................................................. 39 
3.6 
Number of Subjects....................................................................................................... 39 
3.7 
Overall Study Duration and Follow-up......................................................................... 39 
3.8 
Study Visit Schedule ..................................................................................................... 39 
3.8.1 
Screening.................................................................................................................... 40 
3.8.2 
Study Drug Administration ........................................................................................ 40 
3.8.3 
Post Treatment ........................................................................................................... 40 
3.9 
End-of-Study ................................................................................................................. 40 
3.10 
Study Stopping Criteria................................................................................................. 41 
4 
SUBJECT ENROLLMENT............................................................................................. 41 
4.1 
Informed Consent.......................................................................................................... 41 
5 
SUBJECT ELIGIBILITY ................................................................................................ 41 
5.1 
Inclusion Criteria .......................................................................................................... 41 
5.2 
Exclusion Criteria ......................................................................................................... 42 
6 
STUDY PROCEDURES ................................................................................................. 44 
6.1 
Study Schedule.............................................................................................................. 44 
6.2 
Study Assessments ........................................................................................................ 44 
6.2.1 
Adverse Event Assessments ...................................................................................... 44 
6.2.2 
Blood Pressure Recording.......................................................................................... 45 
6.2.3 
Immunogenicity Assessments .................................................................................... 46 
6.2.4 
Surveillance for SARS-CoV-2 Infection ................................................................... 46 
6.3 
Restriction on the Lifestyle of Subjects ........................................................................ 47 
6.3.1 
Contraception Requirements ...................................................................................... 47 
7 
STUDY DRUG ................................................................................................................ 48 

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7.1 
Study Drug Description ................................................................................................ 48 
7.2 
Packaging and Labeling ................................................................................................ 48 
7.3 
Study Drug Accountability ........................................................................................... 48 
8 
TREATMENT OF SUBJECTS ....................................................................................... 48 
8.1 
Treatment Precautions .................................................................................................. 48 
8.2 
Study Drug Preparation................................................................................................. 48 
8.3 
Study Drug Administration ........................................................................................... 49 
8.4 
Other Protocol-Required Treatment Procedures ........................................................... 49 
8.5 
Safety Monitoring Rules ............................................................................................... 49 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests.................................................. 50 
8.5.2 
Safety Monitoring Rules for Local and Systemic Reactogenic Events ..................... 50 
8.6 
Treatment Stopping Rules for Individual Subjects ....................................................... 50 
8.7 
Adjustment of Dose and/or Treatment Schedule .......................................................... 50 
8.7.1 
Delay in Vaccination.................................................................................................. 51 
8.8 
Withdrawal of Subjects from the Study Procedures ..................................................... 51 
8.9 
Concomitant Therapy and Procedures .......................................................................... 52 
8.9.1 
Concomitant Therapy................................................................................................. 52 
8.9.2 
Concomitant Procedures ............................................................................................ 53 
8.10 
Treatment Compliance .................................................................................................. 53 
9 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING........................... 53 
9.1 
Sponsor Review of Safety Information......................................................................... 53 
9.2 
Regulatory Requirements.............................................................................................. 53 
9.3 
Definitions..................................................................................................................... 53 
9.3.1 
Adverse Event ............................................................................................................ 53 
9.3.2 
Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction ........... 54 
9.3.3 
Serious Adverse Event (SAE) .................................................................................... 54 
9.3.4 
Medically Attended Adverse Event (MAAE) and New Onset of Chronic Disease 
(NOCD)...................................................................................................................... 55 
9.3.5 
Adverse Event of Special Interest .............................................................................. 55 
9.3.6 
Targeted Medical Event ............................................................................................. 56 
9.3.7 
Clinical Events of Special Interest ............................................................................. 56 
9.4 
Monitoring and Recording Adverse Events .................................................................. 56 
9.4.1 
Serious Adverse Events ............................................................................................. 57 

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9.4.2 
Medically Attended Adverse Events ......................................................................... 57 
9.4.3 
Non-Serious Adverse Events ..................................................................................... 58 
9.4.4 
Evaluation of Adverse Events (Serious and Non-Serious) ........................................ 58 
9.4.4.1 
Relationship to the Study Drug ............................................................................... 58 
9.4.4.2 
Severity ................................................................................................................... 59 
9.4.4.3 
Action Taken with Study Drug ............................................................................... 59 
9.4.4.4 
Treatment Given for Adverse Event ....................................................................... 59 
9.4.4.5 
Outcome of the Adverse Event ............................................................................... 60 
9.4.4.6 
Follow-up of Adverse Events ................................................................................. 60 
9.5 
Procedures for Handling Special Situations ................................................................. 60 
9.5.1 
Abnormalities of Laboratory Tests ............................................................................ 60 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............... 61 
9.5.3 
Dosing Errors ............................................................................................................. 61 
9.5.4 
Contraception and Pregnancy .................................................................................... 62 
9.5.5 
Cases of PCR-confirmed COVID-19 or PCR/Serologically Confirmed SARS-CoV-2 
Infection Without COVID-19 .................................................................................... 62 
10 
STATISTICAL CONSIDERATIONS............................................................................. 63 
10.1 
Sample Size Considerations .......................................................................................... 64 
10.2 
Populations .................................................................................................................... 64 
10.3 
Definition of Baseline ................................................................................................... 65 
10.4 
Interim Analysis ............................................................................................................ 65 
10.5 
Planned Methods of Analysis ....................................................................................... 66 
10.5.1 
General Approach ...................................................................................................... 66 
10.5.2 
Demographic and Baseline Characteristics ............................................................... 66 
10.5.3 
Safety Analysis .......................................................................................................... 66 
10.5.4 
Immunogenicity Analyses ......................................................................................... 67 
10.5.5 
Clinical Events of Special Interest Analyses ............................................................. 68 
10.5.6 
Missing Data Handling .............................................................................................. 68 
11 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................................................. 68 
11.1 
Informed Consent.......................................................................................................... 68 
11.2 
Ethical Conduct of the Study ........................................................................................ 68 
11.3 
Independent Ethics Committee/Institutional Review Board ......................................... 68 
11.4 
Subject Confidentiality ................................................................................................. 69 

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12 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................... 69 
12.1 
Protocol Amendments ................................................................................................... 69 
12.2 
Study Termination ........................................................................................................ 69 
12.3 
Study Documentation and Storage................................................................................ 70 
12.4 
Study Monitoring .......................................................................................................... 70 
12.5 
Site Audit ...................................................................................................................... 71 
12.6 
Language ....................................................................................................................... 71 
12.7 
Compensation for Injury ............................................................................................... 71 
13 
REFERENCES ................................................................................................................ 72 
14 
APPENDICES ................................................................................................................. 76 
 
LIST OF APPENDICES 
Appendix 1: Schedule of Assessments ..................................................................................... 77 
Appendix 2: List of Laboratory Analytes ................................................................................. 83 
Appendix 3: List of Exclusionary Autoimmune Diseases ........................................................ 85 
Appendix 4: Protocol Amendment Summary of Changes........................................................ 90 
 
LIST OF TABLES 
Page 
 
Table 2: Potential Safety Considerations for Clinical Trial ARCT-021-02 ................................ 35 
Table 3: ARCT-021 Characteristics............................................................................................. 48 
Table 4. Dilution Volumes for Preparation of ARCT-021 .......................................................... 49 
 
LIST OF FIGURES 
Page 
Figure 1. mRNA-2002 Structure.................................................................................................. 32 
Figure 2. Schematic Representation of Drug Product, ARCT-021 ............................................. 33 
 
 
 

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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2a, Open Label Extension Study to Assess the Safety 
and Long-Term Immunogenicity of ARCT-021 
Study Phase 
2a 
Indication 
Prevention of disease caused by SARS-CoV-2 
Primary Objective 
Assess safety and reactogenicity of ARCT-021 
Secondary Objective 
Assessment of long-term neutralising antibody and anti-spike 
protein IgG responses following vaccination with ARCT-021 
Exploratory Objective 
Assessment of cell-mediated immune responses following 
vaccination with ARCT-021 
Study Design 
Open label study enrolling healthy adult subjects that 
participated in Study ARCT-021-01 (the Parent Study). 
Subjects will enter this study approximately 3 months after their 
final study visit in the Parent Study. 
Subjects will be followed up for a period of at least 12 months 
after the last injection of ARCT-021 
Number of Subjects 
If all subjects that were treated in Parent Study consent to enroll 
in this study and meet the eligibility criteria then approximately 
99 subjects, up to a maximum of 166 subjects will be enrolled. 
Study Population 
To be eligible to participate in this study candidates must meet 
the following eligibility criteria within 28 days prior to Study 
Day 1. Subjects who fail screening due to out of range lab 
values may have these labs retested up to two times, subject to 
approval by the Sponsor Medical Monitor (or designee), to 
determine eligibility. 
Inclusion Criteria 
1. Must have given written informed consent (signed and 
dated) and any authorizations required by local law and be 
able to comply with all study requirements 
2. Must have completed Study ARCT-021-01 without early 
termination 
3. Willing and able to comply with all protocol-defined 
procedures and complete all study visits 

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Only for subjects that will receive ARCT-021 in this study: 
4. Are healthy in the opinion of the Investigator 
5 Temperature is less than 99.3 degrees Fahrenheit (37.4 
degrees Celsius) at screening AND at the pre-dose 
evaluation on Day 1 (if temperature is higher than this 
range at Day 1 then please refer to Section 8.7.1) 
6. Willing to refrain from donating blood or plasma from 
signing of the informed consent until 28 days after the last 
dose of ARCT-021. 
7. Willing to refrain from strenuous exercise/activity (for 
example heavy lifting, weight training, intense aerobics 
classes etc.) and alcohol for at least 72 hours prior to study 
visits until 28 days after the last dose of ARCT-021. 
8. Males must be surgically sterile or, if engaged in sexual 
relations with a female of child-bearing potential, the 
subject must be using an acceptable contraceptive method 
(refer to Section 6.3.1) from the time of signing the 
informed consent form until at least 56 days after the last 
dose of Study Drug. 
Male subjects with partners that are pregnant must use 
condoms until at least 56 days after the last dose of Study 
Drug to ensure that the fetus is not exposed to the Study 
Drug. 
Male subjects must refrain from sperm donation from the 
time of signing the informed consent form until at least 56 
days after the last dose of Study Drug. 
Note: Males who are incapable of fathering a child 
(documented bilateral vasectomy with confirmation of 
aspermia or bilateral orchiectomy) will not be required to 
use birth control during the study. 
Females: must be non-pregnant and non-lactating and 
either: 
i. 
surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy); 
ii. post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of 
age or, in females ≤ 55 years, 12 months of 
spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the 
postmenopausal range for the laboratory involved); 

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iii. if engaged in sexual relations and of child-bearing 
potential, agree to use 2 highly effective 
contraceptive methods (refer to Section 6.3.1) from 
the time of signing the informed consent form until 
at least 56 days after the last dose of Study Drug  
For female subjects and female partners of male subjects, 
highly effective female contraception methods comprise 
surgical sterilization (e.g., bilateral tubal occlusion), 
hormonal contraception associated with inhibition of 
ovulation (combined estrogen and progestogen containing, 
or progestogen-only), intrauterine contraception device or 
intrauterine hormone-releasing system (IUS). 
Women of childbearing potential (WOCBP) must refrain 
from egg donation from the time of signing the informed 
consent form until at least 56 days after the last dose of 
Study Drug. 
 
Exclusion Criteria 
1. Significant (as determined by Principal Investigator) 
noncompliance with the study visits or procedures in Study 
ARCT-021-01 
2. Any subject that received placebo in the Parent Study and 
who is not willing to receive ARCT-021 in this study. 
Only for subjects that will receive ARCT-021 in this study: 
3 Receipt of any other SARS CoV-2 or other experimental 
coronavirus vaccine since completion of the Parent Study 
or planned during this study. 
4. Diagnosis of new clinically significant abnormalities in 
medical history or physical examination since enrolment in 
the Parent Study, including but not limited to:  
• Respiratory disease (e.g., chronic obstructive 
pulmonary disease [COPD], asthma) requiring daily 
medications or oxygen currently or any treatment of 
respiratory disease exacerbations (e.g., COPD or 
asthma exacerbation) warranting hospitalization or an 
emergency room visit or supplemental oxygen. 
• Significant cardiovascular disease (e.g., congestive 
heart failure, cardiomyopathy, ischemic heart disease), 
myocarditis or pericarditis. 
• Neurological or neurodevelopmental conditions (e.g., 
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focal neurologic deficits, Guillain-Barré syndrome, 
encephalomyelitis or transverse myelitis). 
• New diagnosis of a significant hematologic 
abnormality (e.g., sickle cell disease, beta thalassemia) 
• New Diagnosis of autoimmune disease as listed by the 
American Autoimmune Related Disease Association 
(Appendix 3) 
• Major surgery 
5. Screening laboratory results as follows, or any other 
clinically significant abnormalities in screening laboratory 
values that would render a subject unsuitable for inclusion 
• ALT, AST, GGT, total bilirubin or alkaline 
phosphatase, > ULN unless approved by Sponsor 
Medical Monitor (or designee). 
• Hb <10 g/dL for females and <12 g/dL for males 
• Platelet count < 100x109/L 
• eGFR < 50 ml/min/1.73m2 calculated by Modification 
to Diet in Renal Disease [MDRD] study equation, 
unless approved by the Sponsor Medical Monitor (or 
designee) 
6. Diabetes that is not, in the opinion of the investigator, 
adequately controlled with diet +/- antidiabetic medication 
7. Use of any prescription or over-the-counter medications 
within 7 days prior to vaccination, unless approved by the 
Sponsor Medical Monitor (or designee). 
8. Received immunoglobulins and/or any blood or blood 
products since completion of the Parent Study. 
9. Has any blood dyscrasias or significant disorder of 
coagulation. 
10. Uncontrolled hypertension (BP > 160/100 mm Hg) 
11. Treatment with another investigational drug, biological 
agent, or device since completion of the Parent Study 
12. Received or plans to receive: 
• A licensed, live vaccine within 4 weeks before or after 
study vaccination, or  
• A licensed, inactivated vaccine within 2 weeks before 
or after study vaccination. 

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13. Has traveled outside of Singapore within 30 days before 
the vaccination or planned travel outside of Singapore 
within 60 days after vaccination. 
14. Have any other conditions, which, in the opinion of the 
Investigator or Sponsor would make the subject unsuitable 
for inclusion, or could interfere with the subject 
participating in or completing the Study 
Treatment Groups 
No separate groups are defined for this study. However, results 
may be analyzed by age group (≤55 years and > 55 years) and 
cumulative dose of ARCT-021 received. Additional sub-group 
evaluations may be defined and will be described in the 
statistical analysis plan. 
Study Drug Dosage and 
Administration 
Subjects who received placebo and subjects who received a 
single injection of ARCT-021 in the Parent Study and are 
seronegative for SARS-CoV-2 neutralising antibodies at 
screening will receive ARCT-021 in this study at a 7.5 µg dose 
level.  
Subjects who received two injections of ARCT-021 in the 
Parent Study will not receive any further injections of ARCT-
021 in this study. 
ARCT-021 will be administered by IM injection into the lateral 
aspect of the deltoid muscle of the non-dominant arm. Subjects 
should remain at the center for at least 30 minutes for 
observation following vaccine administration.  
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. 
Rationale for Dose and 
Schedule Selection 
The dose level of ARCT-021 selected for use in this study (7.5 
µg) is based on the safety, tolerability, immunogenicity and T-
cell response results observed in younger and older adults in 
Study ARCT-021-01. These results suggest single dose 7.5 µg 
ARCT-021 administration has a favorable safety profile, 
binding and neutralising antibody response, and T-cell immune 
response following single dose administration to both younger 
and older adults.   
Adjustment of Dose  
Adjustment of dose is not permitted.  
Study Stopping Criteria 
As this is an extension study to determine long-term safety there 
are no study stopping criteria for the study.  

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Stopping rules for dosing of individual subjects are found in 
Section 8.6 
Study Visit Schedule and 
Procedures 
Detailed Information regarding the study procedures are 
outlined in Section 6 and Appendix 1 and Appendix 2. 
All subjects will have blood samples taken at intervals 
throughout the study for assessment of immunogenicity as 
detailed in Appendix 1. Appendix 2 shows a list of analytes 
required for the study. 
For subjects that received ARCT-021 in the Parent Study, SAE, 
MAAE, CESI and NOCD occurring since completion of the 
Parent Study and the Screening visit for this study will be 
solicited at the Screening visit and recorded in the EDC to 
ensure continuity of safety follow-up from the Parent Study to 
this study. 
The safety of ARCT-021 will be monitored in an ongoing 
fashion during the study by the Sponsor Medical Monitor (or 
designee) and Principal Investigator.  
The duration of participation is designed such that all subjects 
will be followed up until at least 12 months after their last 
injection of ARCT-021, irrespective of whether the last 
injection was in the Parent Study or in this study. In addition to 
the visit schedule described below, subjects may be required to 
attend additional visits for monitoring of adverse events or 
abnormal investigation results.  
Any subject that develops PCR confirmed SARS-CoV-2 
infection may have subsequent study visits performed in 
hospital. 
Subjects should be reminded to contact the site within 24 hours 
if experiencing COVID-19-like symptoms (Section 6.2.4) or if 
exposed to a confirmed COVID-19 case or person with 
confirmed SARS-CoV-2 infection.   
Any subject with exposure to a confirmed COVID-19 case or 
confirmed SARS-CoV-2 infection or that reports symptoms 
suggestive of possible COVID-19 infection should undergo 
testing by PCR preferably within 72 hours to determine if the 
subject may have COVID-19 or SARS-CoV-2 infection 
(Sections 6.2.4 and  9.5.5).  
Subjects will be instructed to contact the study site staff 
immediately if they receive a diagnosis of SARS-CoV-2 
infection or COVID-19. 

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Subjects that terminate from the study before completion will 
be told to inform the Study Site staff immediately if they 
develop symptoms compatible with COVID-19 (Section 6.2.4) 
or a diagnosis of COVID-19 or SARS-CoV-2 infection until 1 
year post last dose of ARCT-021 so that they can be adequately 
followed up. Reporting instructions for cases of PCR-confirmed 
COVID-19 are contained in Section 9.5.5. 
Subjects that are not receiving ARCT-021 in this study 
All participants who received 2 injections of ARCT-021 as part 
of participation in Cohorts E, F, G, and H in Study ARCT-021-
01 and any participant who received 1 injection of ARCT-021  
in Cohorts A, B, C, D1 and D2 in Study ARCT-021-01 AND 
who is seropositive by SARS-CoV-2 PRNT50 neutralising 
antibody test at screening in this study (ARCT-021-02). 
The study comprises an up to a 4-week Screening Period 
followed by a 9-month observation period. The length of each 
subject’s participation is approximately 10 months from 
screening to last study visit.  
After screening subjects will return for outpatient visits on Days 
1, 29, 85, 197 and then 281. The final visit will be on Day 281. 
Subjects that do not receive ARCT-021 in this study will not 
have any further laboratory safety evaluations performed in this 
study and only Serious Adverse Events (SAE) and Medically 
Attended AE (MAAE) will be recorded. Subjects will be 
instructed to contact the study site staff immediately if they 
experience an adverse event that requires them to seek medical 
attention or if they become hospitalised. 
 
Subjects receiving ARCT-021 
All participants who received placebo as part of participation in 
Study ARCT-021-01 and any participant who received 1 
injection of ARCT-021 in Cohorts A, B, C, D1 and D2 in Study 
ARCT-021-01 AND who is seronegative by SARS-CoV-2 
PRNT50 neutralising antibody test at screening in this study 
(ARCT-021-02). 
Blood and urine samples will be collected for safety evaluations 
up to 28 days after the last injection of ARCT-021 (Appendix 
1).  
Local and systemic solicited and unsolicited AEs will be 
recorded daily by the subject in a symptom diary for at least 7 
days post vaccination and up to 14 days post vaccination if any 
events are persisting at 7 days (Section 6.2.1 and Appendix 1). 

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Should a solicited AE persist beyond 14 days post vaccination, 
this will be followed by interview and/or physical examinations 
at follow-up visits until resolution or stabilization.  
Solicited events will be recorded by study site staff in the EDC 
until 7 days after each injection (14 days post vaccination if any 
events are persisting at 7 days).  Unsolicited AEs will be 
recorded until 28 days after the last injection of ARCT-021. 
Thereafter only SAE and MAAE will be recorded. 
Subjects will be instructed to contact the study site staff 
immediately if they experience a grade 3 or above solicited AE 
or an adverse event that requires them to seek medical attention 
or if they become hospitalised.   
Subjects receiving a single injection of ARCT-021 
The study comprises an up to 4-week Screening Period, a 1-day 
Study Drug Administration Period and a 12-month Post 
Treatment observation period. The length of each subject’s 
participation is approximately 13 months from screening to last 
study visit.  
Baseline evaluations will be performed pre-dose on Day 1. 
Study Drug will be administered on Day 1. Subjects will be 
observed for at least 30 minutes after dosing. After this, subjects 
may be discharged if clinically stable. Subjects will return for 
outpatient visits on Days 8, 15, 29, 57, 169, 253 and 365. The 
final visit will be on Day 365. 
 
Primary Endpoint 
The safety and reactogenicity of ARCT-021 will be assessed by 
determining the incidence, severity, and dose-relationship of 
solicited local and systemic adverse events, unsolicited adverse 
events (including serious adverse events (SAEs), a new onset of 
chronic disease (NOCDs), medically attended adverse events 
(MAAEs), changes in vital signs and changes in the laboratory 
parameters by dose.  
Secondary Endpoints 
1. Mean and geometric mean titer (GMT) and the geometric 
mean fold rise (GMFR) in SARS-CoV-2 neutralising 
antibody titer and IgG antibodies against the full-length 
SARS-CoV-2 recombinant spike protein antigen and/or 
spike protein subunits at multiple time points in each cohort. 
2. Proportion of ARCT-021-naïve subjects seroconverting for 
neutralising antibodies and IgG antibodies against the full-
length SARS-CoV-2 recombinant spike protein antigen 

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and/or spike protein subunits will be assessed at multiple 
time points. 
Exploratory Endpoint 
T-cell subclass responses will be assessed at multiple time 
points. 
Statistical Considerations 
Sample Size 
As this is an open label follow-on study, the sample size is 
determined by the number of subjects enrolled in the Parent 
Study who consent to enroll in this study and fulfill the 
eligibility criteria; therefore, formal sample size calculations are 
not applicable. 
Safety and Tolerability 
For subjects who received ARCT-021 in the Parent Study, 
SAE,MAAE, CESI, NOCD occurring since completion of the 
Parent Study and the Screening visit for this study will be 
recorded in the EDC to ensure continuity of safety follow-up 
from the Parent Study to this study. 
Subject incidence rates of all treatment emergent adverse events 
(TEAEs) will be tabulated by MedDRA system organ class, and 
by preferred term. TEAEs will also be summarised by 
relationship to Study Drug, seriousness, and severity. Injection 
site and systemic (fever, fatigue, headache, chills, nausea, 
vomiting, diarrhoea, new or worsened myalgia, and new or 
worsened arthralgia) solicited adverse events will be 
summarised separately and solicited events with onset within 7 
days of injection will be considered related. Tables and/or 
narratives of treatment emergent deaths, serious and significant 
adverse events, including early withdrawals due to adverse 
events, will also be provided. 
Laboratory tests including chemistry panel, complete blood 
count with differential, coagulation panel, etc., will be 
summarised by study visit.  
Vital sign measures will be tabulated. In addition, the number of 
subjects who experience abnormalities in clinical laboratory 
evaluations will be summarised by grade (Section 9.4.4.2). 
The severity of AEs and SAEs will be graded according to the 
Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials, Sept 
2007.  
Any AE not listed in this scale will be graded as follows: 

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• Mild:  The event is easily tolerated by the subject and 
does not affect the subject’s usual daily activities 
• Moderate:  The event causes the subject more 
discomfort and interrupts the subject’s usual daily 
activities 
• Severe:  The event is incapacitating and causes 
considerable interference with the subject’s usual daily 
activities 
Cases of PCR confirmed COVID-19 and PCR-confirmed or 
serologically confirmed asymptomatic SARS-CoV-2 infection 
will be recorded as Clinical Events of Special Interest (CESI). 
These events will not be regarded as adverse events and will be 
analyzed separately from safety data (Sections 9.3.7 and 9.5.5). 
PCR confirmed COVID-19 disease will be graded as follows: 
• Mild:  No requirement for supplemental oxygen to 
maintain oxygen saturation ≥ 93% 
• Moderate:  Oxygen supplementation at a concentration 
of < 50% required to maintain oxygen saturation ≥ 93% 
• Severe:  Oxygen supplementation at a concentration of 
> 50% or any form of mechanical ventilatory support 
required 
Immunogenicity 
Immunogenicity measures include mean titer, GMT and GMFR 
in neutralising antibody titer to SARS CoV-2 spike protein and 
anti-spike protein IgG titer and the proportion of subjects 
seroconverting. Descriptive statistics, by assessment time point, 
will be used to describe these results. Statistical testing, if 
performed, will be prespecified in the final statistical analysis 
plan and will be exploratory in nature. 
SARS-CoV-2 neutralising antibody titer will be tested using a 
clinical isolate of SARS CoV-2 (hCoV-19/Singapore/2/2020) in 
BSL-3 settings on an in vitro plaque reduction neutralisation 
test (PRNT) and/or pseudovirus neutralization test and/or 
surrogate virus neutralization test (sVNT) and/or 
microneutralization test.  Testing using other SARS-CoV-2 
isolates may also be performed. 
Total IgG against the full-length SARS-CoV-2 recombinant 
spike protein and/or spike protein subunits will be assessed 
using an immune-Luminex and/or ELISA assay.  

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Seroconversion will be assessed across a range of dilutions and 
will be defined as an antibody titer above 20 for subjects that 
are seronegative at baseline and as a 4-fold increase in antibody 
titer from baseline for subjects that are seropositive at baseline. 
T-cell subclass responses will be tested by flow cytometry and 
ELISPOT assay using peptide pools from SARS CoV-2 spike 
protein. 
Sponsor 
Arcturus Therapeutics, Inc. 
 

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STUDY DESIGN AND TREATMENT SCHEMA FOR SUBJECTS NOT 
RECEIVING ARCT-021 
 
 
 
END-OF-STUDY 
PROCEDURES 
Early termination or Day 281 
OBSERVATION PERIOD 
Day 1 to Day 281 
EARLY 
TERMINATION 
SCREENING 
28 to 1 days before 
Day 1 

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STUDY DESIGN AND TREATMENT SCHEMA FOR  
SUBJECTS RECEIVING A SINGLE INJECTION OF ARCT-021 
 
END-OF-STUDY 
PROCEDURES 
Early termination or Day 365 
POST-TREATMENT 
EVALUATIONS                     
Days 2 to 365 
STUDY DRUG 
ADMINISTRATION PERIOD 
Day 1 
EARLY 
TERMINATION 
SCREENING 
28 to 1 days before 
Day 1  

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STUDY GLOSSARY 
Abbreviation 
Definition 
3´ 
On the 3-prime end of the nucleotide sequence 
5´ 
On the 5-prime end of the nucleotide sequence 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
aPTT 
Activated partial thromboplastin time 
ARCT-021 
Investigational drug product comprising mRNA-2002 
(coding for SARS-CoV-2 full length spike glycoprotein) 
formulated in the LUNAR® lipid nanoparticle delivery 
system 
ARCT-810 
Investigational drug product comprising mRNA-1801 
(coding for human ornithine transcarbamylase enzyme) 
formulated in the LUNAR® lipid nanoparticle delivery 
system 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
Bb 
Complement factor Bb (activated complement split product) 
βhCG 
Beta-subunit of human chorionic gonadotropin (pregnancy 
test) 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C 
Centigrade 
C3 
Complement factor 3 
C3a 
Complement factor C3a (activated complement split 
product) 
C4 
Complement factor 4 
C4a 
Complement factor C4a (activated complement split 
product) 
C5a 
Complement factor C5a (activated complement split 
product) 
CBC 
Complete blood count 
CESI 
Clinical Event of Special Interest 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 

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COVID-19 
Coronavirus disease 2019, the disease caused by SARS-
CoV-2 virus infection. 
CRF 
Case report form 
CRP 
C-reactive protein 
CS 
Clinically significant 
CV 
Cardiovascular 
dL 
Deciliter 
DNA 
Deoxyribonucleic acid 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
ED50 
50% effective dose 
ELISA 
Enzyme-linked immunosorbent assay 
ESR 
Erythrocyte sedimentation rate 
Enrolled 
A subject will be considered enrolled into the study once 
they have signed the informed consent form and is 
determined to be eligible by the Principal Investigator 
G 
Gram 
GCP 
Good Clinical Practices 
G-CSF 
Granulocyte-colony stimulating factor 
GLP 
Good Laboratory Practices 
HAV 
Hepatitis A virus 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
hERG 
Human Ether-á-go-go-Related-Gene (a cardiac potassium 
channel) 
HIV 
Human immunodeficiency virus 
HPLC 
High performance liquid chromatography 
HR 
Heart rate 
hr, hrs 
Hour(s) 
HSA 
Health Sciences Authority (of Singapore) 
hsCRP 
C-reactive protein measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
ID 
Intradermal 
IEC 
Independent Ethics Committee 

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IFN-γ 
Interferon-gamma 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL-1β 
Interleukin-1 beta 
IL-1RA 
Interleukin-1 receptor antagonist 
IL-6 
Interleukin-6 
IL-8 
Interleukin-8 
IL-10 
Interleukin-10 
IL-12 
Interleukin-12 
IL-12p70 
The bioactive form of interleukin-12 comprising the p35 and 
p40 subunits. 
IM 
Intramuscular 
INR 
International normalized ratio 
IP-10 
Interferon γ-induced protein 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LNP 
Lipid nanoparticle 
LOAEL 
Lowest observed adverse effect level 
LUNAR® 
Arcturus’ proprietary LNP technology 
MAAE 
Medically Attended Adverse Event 
MABEL 
Minimum anticipated biological effect level 
m2 
Square meter 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCP-1 
Monocyte chemoattractant protein-1 
MCV 
Mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities  
Mg 
Milligram 
Min 
Minute 
mL 
Milliliter 
Mm 
Millimeter 

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mRNA 
Messenger ribonucleic acid 
mRNA-2002 
RNA construct encoding the VEEV non-structural proteins, 
and an RNA sequence encoding the SARS-CoV-2 spike 
glycoprotein 
MRT 
Mean residence time 
MRT0-∞ 
Mean residence time extrapolated to infinity 
Msec 
Milliseconds 
MTD 
Maximum tolerated dose 
N, n 
Number 
NCS 
Not clinically significant 
NHP 
Nonhuman primate 
NIH 
National Institutes of Health 
NOAEL 
No observed adverse effect level 
NOCD 
New onset chronic disease 
NSAID 
Non-steroidal anti-inflammatory drug 
OLE 
Open label extension 
On study 
The subject is ‘on study’ from signing of the informed 
consent until their last study visit 
PC 
Personal computer 
PEG2000-DMG 
1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-
2000, a polyethylene glycol-lipid conjugate 
pH 
Measure of the acidity or basicity of a solution 
PK 
Pharmacokinetic(s) 
PLT 
Platelet(s) 
PolyA 
Polyadenylated 3 prime end of mRNA 
pRBC 
Packed red blood cells 
PRNT 
Plaque reduction neutralisation test 
PRNT50 
The titer of serum required to reduce the number of plaques 
by 50% in a PRNT assay 
PT 
Prothrombin time 
QT 
Interval between the beginning of the QRS complex and the 
end of the T-wave on ECG 
Randomized 
In randomized studies a subject is to be randomly assigned 
to a treatment group once they have completed all screening 
procedures and been confirmed as eligible to enter the 
Treatment Period. Once this has occurred the subject is 
considered to be randomized in the trial. 

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RBD 
Receptor binding domain of the SARS-CoV-2 spike 
glycoprotein 
RNA 
Ribonucleic acid 
S glycoprotein 
Spike glycoprotein 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 (the strain 
of coronavirus that COVID-19) 
SC 
Subcutaneous(ly) 
SD 
Standard deviation 
SMQ 
Standardised MedDRA Queries 
STARRTM 
Arcturus’ proprietary ‘Self-Transcribing and Replicating 
mRNA’ replicon technology used in investigational vaccine 
ARCT-021 
Study Day 1 
Defined as the first day Study Drug product is administered 
to the subject 
Study Drug 
ARCT-021 or placebo 
SUSAR 
Suspected unexpected serious adverse reaction 
sVNT 
Surrogate virus neutralization test 
T1/2 
Half-life 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment-emergent adverse event 
Th 
T-helper cell 
TME 
Targeted Medical Event 
TNF-α 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
UPCR 
Urine protein/creatinine ratio 
UTR 
Untranslated region of RNA 
VEEV 
Venezuela equine encephalitis virus 
WBC 
White blood cell 
WHO 
World Health Organization 
WMA 
World Medical Association 
 
 
 

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1 
OBJECTIVES AND ENDPOINTS 
1.1 
Objectives 
1.1.1 
Primary Objective 
To assess the safety and reactogenicity of ARCT-021 
1.1.2 
Secondary Objective 
Assessment of long-term neutralising antibody and anti-spike protein IgG responses following 
vaccination with ARCT-021 
1.1.3 
Exploratory Objective 
Assessment of cell-mediated immune responses following vaccination with ARCT-021 
1.2 
Study Endpoints 
1.2.1 
Primary Endpoint(s) 
The safety and reactogenicity of ARCT-021 will be assessed by determining the incidence, 
severity, and dose-relationship of solicited local  and systemic  adverse events, unsolicited 
adverse events (including serious adverse events (SAEs), new onset of chronic disease (NOCDs), 
medically attended adverse events (MAAEs), changes in vital signs and changes in the 
laboratory parameters by dose. 
1.2.2 
Secondary Endpoints 
1. Mean and geometric mean titer (GMT) and the geometric mean fold rise (GMFR) in SARS-
CoV-2 neutralising antibody titer and IgG antibodies against the full-length SARS-CoV-2 
recombinant spike protein antigen and/or spike protein subunits at multiple time points in 
each cohort. 
2. Proportion of ARCT-021-naïve subjects seroconverting for neutralising antibodies and IgG 
antibodies against the full-length SARS-CoV-2 recombinant spike protein antigen and/or 
spike protein subunits will be assessed at multiple time points. 
1.2.3 
Exploratory Endpoint 
T-cell subclass responses will be assessed at multiple time points.   
2 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
ARCT-021 is a self-replicating RNA vaccine being developed for prevention of Coronavirus 
Disease 2019 (COVID-19), the disease 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 

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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). 
Age, male sex, ethnic minority status and comorbidity, particularly hypertension, cardiovascular 
disease, diabetes and obesity, are risk factors for more severe disease (de Lusignan 2020; 
Williamson 2020; Yang 2020; Li 2020; Zhou 2020; Grasselli 2020), although the relative 
importance of these risk factors varies between reports. 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). 
Several million cases of COVID-19 been confirmed worldwide and hundreds of thousands of 
people have died (ECDC 2020), and the number of cases continues to grow in most countries. To 
date, only a few vaccines with proven clinical efficacy are available, thus there remains a large, 
unmet clinical need to develop a vaccine to prevent the spread of infection.  
2.2 
Therapeutic Rationale 
SARS-CoV-2 is a novel virus belonging to the β-coronavirus genus. Host cell infection is 
mediated by the attachment of the transmembrane spike (S) glycoprotein to the host cell 
angiotensin converting enzyme 2 (ACE-2) receptors and subsequent fusion with host cell 
membranes. The S glycoprotein forms homotrimers protruding from the viral surface (Tortorici 
and Vessler 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) which 
allows SARS-CoV-2 to directly bind to the peptidase domain of the ACE-2 receptor 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.  
2.3 
Rationale for Dose, Regimen and Route of Administration 
The dose level and regimen of ARCT-021 (7.5 µg, single dose) selected for use in this study will 
have been selected based on the safety, tolerability, immunogenicity and T-cell response results 
observed in Study ARCT-021-01.  
Data from the first interim analysis of ARCT-021-01 study indicate that single dose 
administration of 7.5 µg ARCT-021-01 demonstrated:  
• Primarily mild or moderate solicited local and systemic AEs (no severe or life-
threatening solicited AEs) 
• No severe unsolicited AEs with the exception of reversible, asymptomatic grade 3 
lymphopenia 
• Neutralising antibody responses in younger and older participants that were within the 
range of neutralising antibody responses of convalescent COVID-19 patients  
• CD4+ and CD8+ T cell activation in younger and older adults following vaccination 
• CD4+ immune responses reflect a Th1 bias 
• While the data following single dose administration was compared only across dose 
groups for the younger adults, 7.5 µg demonstrated higher neutralisingbinding  antibody 

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titers than lower doses, similar neutralising antibody titers to lower doses, a similar safety 
profile to the 5 ug dose single and yielded a better safety profile than the higher dose 
evaluated (10 µg) 
Based on these interim data, the dose regimen of 7.5 µg appears to demonstrate acceptable safety 
and immunogenicity for continued administration to subjects >55 years and subjects ≤55 years of 
age for this study. 
Vaccines are frequently given via the intramuscular (IM) route (Zuckerman 2000), which results 
in a lower rate of local reactions than intradermal (I.D.) or subcutaneous (S.C) injection (Zhang 
2015). In a Phase 1 study of a virus-like replicon particle (VRP) vaccine for prevention of CMV 
(Bernstein 2010), S.C. and IM administration produced similar neutralising antibody and T-cell 
responses, but local reactions were more frequent with the S.C. route. Other VRP formulated 
replicon vaccines administered via the IM route have also proven to be both well tolerated and 
immunogenic (Crosby 2019; Morse 2010). Lipid nanoparticle (LNP) formulated mRNA 
vaccines administered IM have also proven to be well tolerated and immunogenic (Moderna 
2019, Bahl 2017, Feldman 2019).   
2.4 
Rationale for Study Duration 
A 1-year follow-up period after the last injection of ARCT-021 ensures sufficient period of 
observation after vaccination to characterize the long-term safety and immunogenicity profile of 
ARCT-021. 
2.5 
Investigational Drug Product ARCT-021 
2.5.1 
Mechanism of Action 
ARCT-021 comprises an RNA replicon construct (mRNA-2002) derived from the alphavirus 
Venezuela equine encephalitis virus (VEEV), formulated in a lipid nanoparticle. The replicon 
consists of a replicase gene and an RNA sequence encoding the SARS-CoV-2 spike 
glycoprotein. 
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 structural proteins with RNA coding for a protein antigen of interest (in this case the SARS-
CoV-2 full length spike 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 compliment 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. 
The composition of mRNA-2002 is shown in Figure 1. On entry into the cytoplasm, the replicase 
gene, encoding the four non-structural proteins (nsP1 to nsP4), is translated from the mRNA-2002 

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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 transcribes the complementary RNA strand of the entire mRNA-2002, including the 
SARS-CoV-2 spike glycoprotein RNA and poly A tail.  The remaining polyprotein is processed 
into nsP1, nsP2 and nsP3 and in combination with nsP4, transcribes only 5´-G-methyl capped 
spike glycoprotein mRNA from the 3´-5´ complementary strand of mRNA-2002. The multiple 
copies of spike glycoprotein mRNA transcript are then translated to produce full length spike 
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 mRNA-2002 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 spike glycoprotein and thereby behaving as an 
adjuvant. 
At the injection site, the LNP-formulated RNA is taken up by myocyte and antigen presenting 
cells, the latter 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 develop germinal center (GC) 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). 
2.5.2 
Chemistry 
2.5.2.1 
Drug Substance mRNA-2002 
The drug substance mRNA-2002 is an ~11.86 kilobase RNA that consists of 5’ cap, a replicase 
gene encoding the VEEV non-structural proteins, and an RNA sequence encoding the SARS-
CoV-2 spike glycoprotein. The general structure of mRNA-2002 is illustrated in Figure 1.  

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Figure 1. mRNA-2002 Structure 
The replicase gene encodes for 4 non-structural proteins (nsP1 to nsP4) from the Venezuela equine encephalitis 
virus (VEEV). The replicase is followed by an RNA sequence encoding the SARS-CoV-2 full length spike 
glycoprotein. 
2.5.2.2 
Drug Product ARCT-021 
The composition of the drug product, ARCT-021 is shown in Table 1, and a schematic 
representation is shown in Figure 2. For further information please refer to the Investigator’s 
Brochure. 
 
 
mRNA-2002 
mRNA 
Viral Protein 
Replicase 
 Spike Protein 
Poly A 
il
5-Cap- 
-3´ 
-5´ 
3´- 
 Spike Protein Poly A tail 
-3´ 
5´Cap- 
Stop 
 Spike Protein 
Complementary RNA Strand 
Replicase 
-C 
N- 
Translation 

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Figure 2. Schematic Representation of Drug Product, ARCT-021 
 
2.5.3 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ARCT-021 can be found 
in the Investigator’s Brochure.  A summary is included below. 
Mice were injected IM with 0.2 µg, 2.0 µg or 10.0 µg of ARCT-021 in a fixed injection volume 
of 0.5 ml. Robust anti-spike glycoprotein IgG levels were induced in by ARCT-021 in Balb/c 
mice at all dose levels and continued to increase at 40 to 50 days after vaccination dependent on 
RNA dose . SARS-CoV-2 neutralising antibody titers were assessed at day 30 post-vaccination 
using a plaque reduction neutralisation test (PRNT). 80% of mice vaccinated with 0.2 µg ARCT-
021 had a PRNT50 titer of 20 and above. The geometric mean titer of the 4 animals with titers 
>20 is 57.72 (SD = 2.032). At the same time point, 100% animals vaccinated with 2 µg of 
ARCT-021 developed PRNT50 antibody titers >20, with geometric mean titer of 217.9 (SD = 
1.365). The 10-µg dose of ARCT-021 vaccine produced PRNT50 titers of 320 or greater in 80% 
of animals, which was the upper limit of dilution of this test.  
T-cell responses were evaluated at Day 7 post vaccination in C57BL/6 mice using flow 
cytometry for % CD4+ and % CD8+ T-cells and intracellular staining for IFN-γ and IL-4 for 
Th1/Th2 ratio. Results showed a robust cytotoxic T-cell response and a balanced, Th1 biased T-
Helper cell response. Splenocyte S glycoprotein specific IFN-γ ELISPOT results showed spike 
glycoprotein specific T-cell activation in mice vaccinated with ARCT-021. 
A single dose tissue distribution study was conducted in which mice received a single, unilateral 
IM administration of ARCT-021 doses of 25 µg and 50 µg. Plasma, injection site (rectus femoris 
muscle), lymph nodes (popliteal, inguinal), brain, heart, lung, kidney, spleen, liver, ovaries, and 
testes were collected at various time points up to 29 days post dose to characterize the 
distribution and clearance of the replicon RNA, the 
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mRNA-2002 and 
 was detected in all tissues evaluated, namely plasma, muscle (rectus 
femoris, site of injection), lymph nodes (popliteal and inguinal, liver, kidney, spleen, heart, lung, 
ovaries, and testes.  mRNA-2002 was only detected at very low levels in the brains of female 
mice at 2 hours post dose and 
 was not detected in the brain at any timepoint.  The 
highest concentrations of mRNA-2002 and 
 were observed in the muscle and lymph 
nodes with substantially lower amounts observed in all other tissues.  mRNA-2002 was no 
longer detected in most tissues by Day 31 post dose with the exception of the muscle where it 
was detected at very low concentrations for both dose groups, and the popliteal lymph nodes for 
the 50 µg dose group.  
 was detected at low levels in all tissues (except brain) up to 
Day 31, the last time point evaluated; however, for both the 25 and 50 g doses most of the 
tissues contained <1% of the administered dose by Day 31 post dose, except the muscle and liver 
which had an average of 3% and 4%, respectively. Transient expression of the SARS-CoV-2 S 
glycoprotein was observed in the muscle, lung, and ovaries, but rapidly cleared from all tissues 
by 15 days post dose with the exception of the popliteal and inguinal lymph nodes at the 50 µg 
dose. 
Data from a two dose GLP repeat-dose local tolerability/reactogenicity toxicity study with 
ARCT-021 in rabbits evaluating two injections at doses of 20 g and 40 g indicates that 
repeated administration of ARCT-021 was well tolerated with no test article-related adverse 
effects on mortality, clinical observations, body weight, body temperature, food consumption, 
injection site reactogenicity/tolerability, clinical chemistry, haematology, coagulation, organ 
weight, macroscopic pathology or histopathology. Following the first dose, injection site 
reactions comprising erythema and eschar (very slight to well defined, with one animal moderate 
to severe) and edema (very slight) have been transient and not observed at all injection sites. No 
worsening of injection site reactions was observed with repeat dosing. Dose dependent, transient 
elevations in IL-6, IP-10, and MCP-1 were observed at 6 hours following each dose compared to 
the pre-dose values and returned to baseline within 48 hours post dose. Transient elevation of 
CRP, which peaked at 48 hours and returned to baseline by Day 8 was also observed (NOTE: 
post-dose sampling time points only at 48 hours and Day 8). Histopathology findings at the 
injection site included minimal to mild (rarely moderate) heterophilic and mononuclear 
inflammatory infiltrates in the muscle, myofiber degeneration/necrosis, myofiber regeneration, 
subcutaneous to dermal mixed inflammation and/or fibrosis, and intermittent 
perivascular/vascular mononuclear infiltrates in ≥20 µg dose groups. This was generally similar 
between the 20 µg and 40 µg dose groups of the ARCT-021 dosed animals. Findings tended to 
be more prominent and/or acute in nature (increased myofiber degeneration/necrosis and 
heterophilic inflammation) at the more recent injection sites compared to the more chronic sites, 
where myofiber regeneration was more prevalent. Generally, severity and incidence of 
inflammatory infiltration and myofiber degeneration/necrosis decreased at the recovery 
euthanasia (14-day recovery), demonstrating partial recovery. No findings were considered 
adverse. 
A three dose GLP repeat-dose local tolerability/reactogenicity toxicity study with ARCT-021 in 
rabbits evaluating injections at doses of 20 g and 40 g at 15-day intervals has also been 
conducted. Preliminary audited data shows similar test article-related trends to the 2-dose study 
with respect to in-life observations, clinical pathology, coagulation, CRP and cytokine inductions 
(with the exception of IFN in females which was elevated in the 3-dose study), and effects on 
leukocytes. Following each of the vaccinations, injection site reactions comprising erythema and 

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eschar (very slight) and edema (very slight to slight) were observed only in the 40 g cohorts, 
however, observations were transient, not observed at all injection sites and did not progress with 
repeated administration. On Day 17 and 31, in both sexes at ≥ 20 µg/dose, there were mild 
increases in mean monocyte counts, which had resolved by 7 days post second and third dose. 
These changes were considered test article-related and indicative of an immune/inflammatory 
response in conjunction with increases in fibrinogen, CRP, IL-6, IP‑10, and MCP-1 
concentrations. On Days 8, 22, and/or 36 both sexes at ≥ 20 µg/dose also had minimal to mild 
increases in mean platelet counts, which had also resolved by Days 15, 29, and/or 57, 
respectively. These changes were considered test article-related and were most likely associated 
with the immune/inflammatory response.  
2.5.4 
Clinical Experience 
At the time of the first subjects entering this study, first-in human study ARCT-021-01 will not 
yet have completed. Safety data for the dose and regimen to be administered in this study will 
have been reviewed by the Safety Review Committee for Study ARCT-021-01 and deemed to be 
adequately safe, tolerated and immunogenic for further study. 
2.6 
Risk:Benefit Assessment 
2.6.1 
Potential Risks 
For a full discussion of the potential risks associated with ARCT-021 treatment please refer to 
the Guidance for the Investigator section of the Investigators’ Brochure.  A summary of the 
potential risks of treatment with ARCT-021, together with potential mitigation for these risks is 
shown in Table 2.  Study ARCT-021-02 has been designed with appropriate exclusion criteria, 
guidance for study vaccine discontinuation for individual subjects (Section 8.6), dose escalation 
and safety monitoring rules and ongoing review of safety data in order to minimize potential 
risks to study subjects. Overall, the risk to healthy volunteers is minimal.  
  
Table 2: Potential Safety Considerations for Clinical Trial ARCT-021-02 
Potential Safety 
Consideration 
Basis for Consideration 
Mitigation 
Local and Systemic 
Reactogenicity 
Vaccines are commonly associated 
with local inflammatory reactions 
at the injection site and systemic 
constitutional reactions due to 
immune stimulation.  RNA based 
vaccines have a similar profile to 
other vaccine platforms (Bahl 
2017; Feldman 2019; Crosby 
2019; Morse 2010). Data from the 
GLP two and three dose local 
tolerability/reactogenicity toxicity 
studies with ARCT-021 in rabbits 
indicate that ARCT-021 was 
associated with transient elevation 
of some cytokines and CRP  but 
• 
It is not possible to completely mitigate 
against these reactions for the first 
administration of study vaccine since 
immune stimulation is essential for 
development of reactive immunity to the 
vaccine antigens. However, vaccination 
via the IM route results in a lower rate of 
local reactions than intradermal (I.D.) or 
subcutaneous (S.C) injection (Zhang 
2015). 
• 
Reactions can be treated symptomatically 
with ibuprofen or acetaminophen, as 
indicated. Severe effects can be treated 
with corticosteroids as indicated. 
Resuscitation equipment must be 

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Potential Safety 
Consideration 
Basis for Consideration 
Mitigation 
was well tolerated without any 
adverse effects on clinical 
observations, body weight, body 
temperature, food consumption, 
organ weight, or macroscopic 
pathology or histopathology. All 
local reactions (eschar, erythema, 
and edema) have been transient 
and most mild to moderate, with 
one moderate to severe. There was 
no worsening of local reactions 
with repeated administration. 
There have been no abnormalities 
suggestive of significant systemic 
reactions on gross observations.    
available in the room where Study Drug 
is administered (Section 8.1).  
• 
For solicited adverse events that are grade 
3, anaphylaxis or unexpected systemic 
hypersensitivity reactions, subsequent 
doses of study vaccine will not be 
administered (Section Error! Reference s
ource not found.). 
• 
Local and systemic reactions will be 
proactively elicited in order to 
characterise the profile of ARCT-021 
(Section 8.5.2). 
• 
All dose levels evaluated in this study 
will already have been assessed in the 
Parent Study 
Hepatic Events 
Liver is a target organ for LNPs 
such as those used in ARCT-021 
and elevated transaminases have 
been observed in animal and 
human studies of other LNPs. Data 
from the GLP two and three dose 
local tolerability/reactogenicity 
toxicity studies with ARCT-021 in 
rabbits indicates that repeated 
administration of ARCT-021 was 
well tolerated without any adverse 
effects on hepatic enzymes or 
histopathology.   
• 
AST, ALT, ALP and bilirubin will be 
monitored  up to 28 days after the last 
administration of Study Drug (Appendix 
1). 
• 
Dose pause and stopping rules for hepatic 
enzymes are included in the clinical study 
protocol (Sections 8.5.1 and Error! 
Reference source not found.) 
• 
All dose levels evaluated in this study 
will already have been assessed in the 
Parent Study 
Pro-inflammatory effects 
Cytokine increases and/or 
complement activation have been 
observed with other LNP 
encapsulated drugs. Data from the 
GLP two and three dose local 
tolerability/reactogenicity toxicity 
studies with ARCT-021 in rabbits 
indicates that ARCT-021 was 
associated with transient elevation 
of some cytokines and CRP  but 
was well tolerated without any 
adverse effects on clinical 
observations, body weight, body 
temperature, food consumption, 
organ weight, or macroscopic 
pathology.  All local reactions 
(eschar, erythema, and edema) 
have been transient and most mild 
to moderate, with one moderate to 
severe. There was no worsening of 
local reactions with repeated 
administration. There have been no 
• 
Reactions can be treated symptomatically 
with ibuprofen or acetaminophen, as 
indicated. Severe effects can be treated 
with corticosteroids as indicated. 
Resuscitation equipment must be 
available in the room where Study Drug 
is administered (Section 8.1).  
• 
Local and systemic reactions will be 
proactively elicited in order to 
characterise the profile of ARCT-021 
(Section 8.5.2). 
• 
For solicited adverse events that are grade 
3, anaphylaxis or unexpected systemic 
hypersensitivity reactions, subsequent 
doses of study vaccine will not be 
administered (Section Error! Reference s
ource not found.). 
• 
All dose levels evaluated in this study 
will already have been assessed in the 
Parent Study 

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Potential Safety 
Consideration 
Basis for Consideration 
Mitigation 
abnormalities suggestive of 
significant systemic reactions on 
gross observations. 
Coagulation effects 
Activation of the intrinsic and 
extrinsic coagulation pathways has 
been reported with LNP 
formulated RNA drugs. Data from 
the GLP two and three dose local 
tolerability/reactogenicity toxicity 
studies with ARCT-021 in rabbits 
indicates that repeated 
administration of ARCT-021 was 
well tolerated without any adverse 
effects on coagulation parameters.  
• 
All dose levels evaluated in this study 
will already have been assessed in the 
Parent Study 
Enhancement of 
respiratory disease if 
subsequently infected 
with SARS-CoV-2 
Vaccine- associated enhanced 
respiratory disease has been 
observed following other 
vaccinations (de Alwis 2020; 
Polack 2007).  This is thought to 
be mediated by an abnormal 
Th1/Th2 response that is biased 
towards Th2 (de Alwis 2020; 
Acosta 2016; Polack 2007) and or 
failure to generate a strong 
neutralising antibody response 
(Polack 2007). Since older 
individuals are more at risk of 
severe respiratory symptoms this 
risk may be greater for this age 
group. 
• 
Vaccination of mice with ARCT-021 
produced robust neutralising antibody and 
CD8+ T-cell response and a balanced, 
Th1-biased  Th1/Th2 response across all 
doses (Section 2.5.3) 
• 
Eligibility criteria for the Parent Study 
ARCT-021-01 exclude subjects with 
major comorbidities that increase risk for 
severe COVID-19 (Section 5.2). 
• 
Th1/Th2 responses will have been 
assessed in Study ARCT-021-01 prior to 
vaccination of subjects in this study  
• 
Explanation of the theoretical risks of 
enhanced COVID-19 disease as a 
consequence of ARCT-021 
administration will be included as part of 
informed consent process. (Section 11.1) 
• 
Subjects that enroll in this study will be 
followed for 1-year after their last 
injection of ARCT-021 (Section 3.9) 
• 
For the duration of participation in the 
study and at the time of termination of 
study participation, subjects will be told 
to inform the Investigator if they develop 
symptoms compatible with COVID-19 or 
a diagnosis of SARS-CoV-2 infection or 
COVID-19 so that they can be adequately 
followed up (Section 3.9). 
SRC= Safety Review Committee; Th = T-helper cell;  

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2.6.2 
Potential Benefits 
This is the OLE to the first-in-human study of ARCT-021 so it is not known if there will be any 
direct benefits to subjects participating in the study. If ARCT-021 is effective as a vaccine, then 
subjects may get effective protection against COVID-19. There is an indirect societal benefit of 
gaining medical knowledge to further develop ARCT-021. 
2.7 
Ethical Considerations 
There are no relevant ethical considerations. 
3 
EXPERIMENTAL PLAN 
3.1 
Compliance 
The study will be conducted in compliance with this clinical study protocol, International 
Conference on Harmonization (ICH) Good Clinical Practices (GCP), as outlined by ICH E6(R2) 
and subsequent amendments, as well as the demands of national drug and data protection laws 
and all applicable local and national regulatory requirements. 
3.2 
Study Design 
This is an open label study enrolling healthy adult subjects that participated in Study 
ARCT-021-01 (the Parent Study). Subjects will enter this study approximately 3 months after 
their final study visit in the Parent Study. 
Subjects who received placebo and subjects who received a single injection of ARCT-021 in the 
Parent Study and are seronegative for SARS-CoV-2 PRNT50 neutralising antibodies at 
screening will receive a single injection of ARCT-021 in this study at a 7.5 µg dose level.  
Subjects who received two injections of ARCT-021 in the Parent Study and subjects who 
received a single injection of ARCT-021 but are seropositive for SARS-CoV-2 PRNT50 
neutralising antibodies at screening will not receive any further injections of ARCT-021 in this 
study. 
ARCT-021 will be administered by IM injection into the lateral aspect of the deltoid muscle of 
the non-dominant arm.  
Subjects should remain at the center for at least 30 minutes for observation following vaccine 
administration.  
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. 
If the subject experiences a severe reaction following vaccine administration, the CRO Medical 
Monitor should be contacted as soon as feasible to discuss if additional assessments may be 
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3.3 
Measures to Minimize/Avoid Bias 
Critical study end points will be pre-specified in the Statistical Analysis Plan. As this is an OLE 
to the Parent Study other measures to minimize bias are not relevant. 
3.4 
Quality Control and Quality Assurance 
Quality control (QC) and quality assurance measures include: 
• On-site and remote monitoring of sites by Sponsor (or designee) with 100% source data 
verification to ensure compliance with protocol and accuracy of data 
collection/transcription 
• Remote Sponsor (or designee) review of study protocol compliance and study data with 
issuance of data queries to correct errors as appropriate 
• Audit of study centre as required 
• Retraining of site staff as required 
3.5 
Number of Study Centers 
This study will be conducted at a single center in Singapore.  
3.6 
Number of Subjects 
If all subjects who were treated in Parent Study consent to enroll in this study and meet the 
eligibility criteria then approximately 99 subjects, up to a maximum of 166 subjects will be 
enrolled. 
3.7 
Overall Study Duration and Follow-up 
The duration of participation is designed such that all subjects will be followed up until at least 
12 months after their last injection of ARCT-021, irrespective of whether the last injection was in 
the Parent Study or in this study.  
Subjects who are not receiving ARCT-021 in this study 
The study comprises an up to a 4-week Screening Period followed by a 9-month observation 
period. The length of each subject’s participation is approximately 10 months from screening to 
last study visit.  
Subjects receiving a single injection of ARCT-021 
The study comprises an up to 4-week Screening Period, a 1-day Study Drug Administration 
Period and a 12-month Post Treatment observation period. The length of each subject’s 
participation is approximately 13 months from screening to last study visit. 
3.8 
Study Visit Schedule 
Detailed Information regarding the study is contained in Appendix 1. 
Subjects will be instructed to contact the study site staff immediately if they receive a diagnosis 
of SARS-COV-2 infection or COVID-19 or if they experience an adverse event that requires 
them to seek medical attention or if they become hospitalized. In addition, subjects receiving 
ARCT-021 in this study will be instructed to contact the study site staff immediately if they 
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case or confirmed SARS-CoV-2 infection, or that reports symptoms suggestive of possible 
COVID-19 infection (Section 6.2.4) should undergo testing by PCR to determine if the subject 
may have COVID-19 or SARS-CoV-2 infection. (Sections 6.2.4 and 9.5.5). The Investigator will 
make reasonable efforts to perform a SARS-CoV-2 PCR test preferably within 72 hours to 
confirm diagnosis.   
Any subject that develops PCR confirmed SARS-CoV-2 infection may have subsequent study 
visits performed in hospital. Subjects should be reminded to contact the site within 24 hours if 
experiencing COVID-19-like symptoms (Section 6.2.4) or if exposed to a confirmed COVID-19 
case or person with confirmed SARS-CoV-2 infection.   
In addition to the visit schedule described below, subjects may be required to attend additional 
visits for monitoring of adverse events or abnormal investigation results.  
3.8.1 
Screening 
Informed consent (Section 4.1) and subject eligibility for the study will be determined within 28 
days prior to study Day 1. A screen failure is defined as any individual who participated in the 
ARCT-021-01 study and does not consent to participate in the ARCT-021-02, any individual 
who does not enter screening procedures, any individual who does not meet entry criteria for the 
ARCT-021-02 study or any individual who withdraws consent for participation in the ARCT-
021-02 prior to Day 1 study procedures. 
3.8.2 
Study Drug Administration 
Subjects receiving a single injection of ARCT-021 
ARCT-021 will be administered on Day 1 following Baseline evaluations. Subjects will be 
observed for at least 30 minutes after dosing. After this, subjects may remain at the study center 
or be discharged. 
3.8.3 
Post Treatment 
Subjects who are not receiving ARCT-021 in this study 
Subjects will have visits on Day 1, Day 29, Day 85, Day 197 and Day 281. The Final visit will 
be on Day 281. 
Subjects receiving a single injection of ARCT-021 
Subjects will return for outpatient visits on Days 8, 15, 29, 57, 169, 253 and 365. The final visit 
will be on Day 365. 
3.9 
End-of-Study 
The End-of-Study is last subject, last visit. 
Subjects who terminate from the study before completion will be told to inform the Study Site 
staff if they develop symptoms compatible with COVID-19 (Section 6.2.4) or a diagnosis of 
SARS-CoV-2 infection or COVID-19 until 1 year post last dose of ARCT-021 so that they can 
be adequately followed up. Reporting instructions for cases of PCR-confirmed SARS-CoV-2 
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3.10 
Study Stopping Criteria 
As this is an extension study to determine long-term safety there are no stopping criteria for the 
study.  
Stopping rules for dosing of individual subjects are found in Section 8.6 
4 
SUBJECT ENROLLMENT 
4.1 
Informed Consent 
Before subjects may be enrolled into the study, the Sponsor or designee requires a copy of the 
Study Center’s written independent ethics committee (IEC)/institutional review board (IRB) 
approval of the protocol, informed consent form, and all other subject information and/or 
recruitment material, as applicable. 
Subjects must sign the consent form before any screening tests or study assessments are 
performed.  At the time of consent, the subject will be considered enrolled into the study and will 
be assigned a screening number before any study procedures, including Screening procedures, 
are performed. Once eligibility is confirmed subjects will be assigned a subject number. This 
number will be used to identify the subject throughout the trial and must be used on all study 
documentation related to that subject. Subject identification number must remain constant 
throughout the entire trial. Subjects in this study will keep the same screening number and 
subject number as in the Parent Study.   
5 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 28 days prior to Study Day 1. Subjects who fail screening due to out of range lab values 
may have these labs retested up to two times, subject to approval by the Sponsor Medical 
Monitor (or designee), to determine eligibility. 
5.1 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements 
2. Must have completed Study ARCT-021-01 without early termination 
3. Willing and able to comply with all protocol-defined procedures and complete all study 
visits 
Only for subjects that will receive ARCT-021 in this study: 
4. Are healthy in the opinion of the Investigator 
5 Temperature is less than 99.3 degrees Fahrenheit (37.4 degrees Celsius) at screening AND at 
the pre-dose evaluation on Day 1 (if temperature is higher than this range at Day 1 then 
please refer to Section 8.7.1) 
6. Willing to refrain from donating blood or plasma from signing of the informed consent  until 
28 days after the last dose of ARCT-021. 

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7. Willing to refrain from strenuous exercise/activity (for example heavy lifting, weight 
training, intense aerobics classes etc.) and alcohol for at least 72 hours prior to study visits 
until 28 days after the last dose of ARCT-021. 
8. Males must be surgically sterile or, if engaged in sexual relations with a female of child-
bearing potential, the subject must be using an acceptable contraceptive method (refer to 
Section 6.3.1) from the time of signing the informed consent form until at least 56 days after 
the last dose of Study Drug. 
Male subjects with partners that are pregnant must use condoms until at least 56 days after 
the last dose of Study Drug to ensure that the fetus is not exposed to the Study Drug. 
Male subjects must refrain from sperm donation from the time of signing the informed 
consent form until at least 56 days after the last dose of Study Drug. 
Note: Males who are incapable of fathering a child (documented bilateral vasectomy with 
confirmation of aspermia or bilateral orchiectomy) will not be required to use birth control 
during the study. 
Females: must be non-pregnant and non-lactating and either: 
i. 
surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy); 
ii. post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 
years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea 
without an alternative medical cause and FSH levels in the postmenopausal range for 
the laboratory involved); 
iii. if engaged in sexual relations and of child-bearing potential, agree to use 2 highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of signing the 
informed consent form until at least 56 days after the last dose of Study Drug  
For female subjects and female partners of male subjects, highly effective female 
contraception methods comprise surgical sterilization (e.g., bilateral tubal occlusion), 
hormonal contraception associated with inhibition of ovulation (combined estrogen and 
progestogen containing, or progestogen-only), intrauterine contraception device or 
intrauterine hormone-releasing system (IUS). 
Women of childbearing potential (WOCBP) must refrain from egg donation from the time of 
signing the informed consent form until at least 56 days after the last dose of Study Drug. 
5.2 
Exclusion Criteria 
1. Significant (as determined by Principal Investigator) noncompliance with the study visits or 
procedures in Study ARCT-021-01 
2. Any subject that received placebo in the Parent Study and who is not willing to receive 
ARCT-021 in this study. 
Only for subjects that will receive ARCT-021 in this study: 
3 Receipt of any other SARS CoV-2 or other experimental coronavirus vaccine since 
completion of the Parent Study or planned during this study. 

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4. Diagnosis of new clinically significant abnormalities in medical history or physical 
examination since enrolment in the Parent Study, including but not limited to:  
• Respiratory disease (e.g., chronic obstructive pulmonary disease [COPD], asthma) 
requiring daily medications or oxygen currently or any treatment of respiratory disease 
exacerbations (e.g., COPD or asthma exacerbation) warranting hospitalization or an 
emergency room visit or supplemental oxygen. 
• Significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, 
ischemic heart disease), myocarditis or pericarditis. 
• Neurological or neurodevelopmental conditions (e.g., migraines, epilepsy, stroke, 
seizures, encephalopathy, focal neurologic deficits, Guillain-Barré syndrome, 
encephalomyelitis or transverse myelitis). 
• New diagnosis of a significant hematologic abnormality (e.g., sickle cell disease, beta 
thalassemia) 
• New Diagnosis of autoimmune disease as listed by the American Autoimmune Related 
Disease Association (Appendix 3) 
• Major surgery 
5. Screening laboratory results as follows, or any other clinically significant abnormalities in 
screening laboratory values that would render a subject unsuitable for inclusion 
• ALT, AST, GGT, total bilirubin or alkaline phosphatase, > ULN unless approved by 
Sponsor Medical Monitor (or designee). 
• Hb <10 g/dL for females and <12 g/dL for males 
• Platelet count < 100x109/L 
• eGFR < 50 ml/min/1.73m2 calculated by Modification to Diet in Renal Disease 
[MDRD] study equation, unless approved by the Sponsor Medical Monitor (or 
designee) 
6. Diabetes that is not, in the opinion of the investigator, adequately controlled with diet +/- 
antidiabetic medication 
7. Use of any prescription or over-the-counter medications within 7 days prior to vaccination, 
unless approved by the Sponsor Medical Monitor (or designee). 
8. Received immunoglobulins and/or any blood or blood products since completion of the 
Parent Study. 
9. Has any blood dyscrasias or significant disorder of coagulation. 
10. Uncontrolled hypertension (BP > 160/100 mm Hg) 
11. Treatment with another investigational drug, biological agent, or device since completion of 
the Parent Study 
12. Received or plans to receive: 
• A licensed, live vaccine within 4 weeks before or after study vaccination, or  

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• A licensed, inactivated vaccine within 2 weeks before or after study vaccination. 
13. Has traveled outside of Singapore within 30 days before the vaccination or planned travel 
outside of Singapore within 60 days after vaccination. 
14. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make 
the subject unsuitable for inclusion, or could interfere with the subject participating in or 
completing the Study  
6 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study visits and procedures are outlined in Appendix 1. 
6.2 
Study Assessments  
The safety of ARCT-021 will be monitored in an ongoing fashion during the study by the 
Sponsor Medical Monitor (or designee) and Principal Investigator. 
All subjects will have blood samples taken at intervals throughout the study for assessment of 
immunogenicity as detailed in Appendix 1. Appendix 2 shows a list of analytes required for the 
study. 
Subjects who do not receive ARCT-021 in this study will not have any further laboratory safety 
evaluations performed in this study.  
For subjects receiving ARCT-021 in this study, blood and urine samples will be collected for 
safety evaluations up to 28 days after the last injection of ARCT-021 (Appendix 1). Additionally, 
local and systemic solicited and unsolicited AEs will be recorded daily by the subject in a 
symptom diary as described in Section 6.2.1. 
In both subjects who do not receive ARCT-021 and in subjects who do receive ARCT-021 in this 
study, Serious Adverse Events (SAE), New Onset of Chronic Disease (NOCD), Clinical Events 
of Special Interest (CESI) and Medically Attended AE (MAAE) will be collected for the 
duration of the study. 
Additionally, subjects that receive ARCT-021 in this study will have local and systemic solicited 
AE recorded for 7 days (and up to 14 days if still persisting at 7 days) after injection and non-
serious unsolicited AE recorded for 28 days after injection. 
6.2.1 
Adverse Event Assessments 
See also Section 9.4 and Appendix 1. 
For those subjects who receive a dose of ARCT-021 in this study:  
Local and systemic solicited and unsolicited AEs will be recorded daily by the subject in a 
symptom diary for at least 7 days post injection and up to 14 days post injection if any events are 
persisting at 7 days. Subjects will record their temperature daily in the symptom diary during 
these 7 days. Additionally, any injection site erythema or swelling will be measured in the 
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Unsolicited adverse events will be collected at each study visit from post injection on Day 1 
throughout the participation of the subject in the study; however, after a subject reaches Day 29 
of study participation only the unsolicited AEs defined as MAAEs, SAEs, CESIs, NOCDs will 
be summarized.  Unsolicited adverse events will be determined from reporting of these events in 
the diary card, review of clinical laboratory values, performance of physical exam, and interview 
of the subject.  
The symptom diaries will be reviewed by site staff at the Day 8 (and Day 15 if subject 
completing diary for an additional 7 days) visit for the first injection and at the Day 36 (and Day 
43 if subject completing diary for an additional 7 days) visit for the second injection. Subjects 
will be specifically questioned about injection site and systemic (fever, fatigue, headache, chills, 
nausea, vomiting, diarrhoea, new or worsened myalgia, and new or worsened arthralgia) at these 
visits.  
Should a solicited AE persist beyond 14 days post injection (past Day 15 for the first injection or 
Day 43, if second injection), this will be followed by interview and/or physical examinations at 
follow-up visits until resolution or stabilization.  
Study site staff will enter the temperature and erythema/swelling dimension measurements 
recorded in the symptom diary into the EDC. Subjects grading of reactogenic events, as recorded 
in the symptom diary, will be entered in the EDC without change. Any unsolicited events 
recorded by the subject in the symptom diary will be entered verbatim into the EDC. 
Any recorded temperature ≥38ºCelsius (≥100.4º Fahrenheit) or injection site erythema/swelling 
≥ 25mm in size will be reported as an adverse event and graded according to Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials, Sept 2007.  
Solicited events with onset within 7 days of injection will be considered related. 
Symptom diaries will be collected at the Day 8 or 15 (depending on completion status) visits for 
the first injection and 36 or 43 visits for the second injection and will serve as source documents. 
For those subjects who received ARCT-021 in the Parent Study:  
At Screening, SAEs, NOCDs, CESIs and MAAEs occurring between completion of the Parent 
Study and the Screening visit for this study will be solicited and recorded in the EDC to ensure 
continuity of safety follow-up from the Parent Study to this study. Events that occurred prior to 
dosing in this study will be recorded as medical history. 
For subjects who received ARCT-021 in either the Parent Study or this study: 
SAEs, NOCDs, CESIs, and MAAEs will be collected for all enrolled subjects for the duration of 
the study until the Final Visit (Day 365 or Day 281 if vaccinated or not vaccinated with ARCT-
021 in this study) or Early Termination visit (if applicable).  
6.2.2 
Blood Pressure Recording 
The following procedure should be followed for recording of blood pressure (note if an 
automated BP recording device is used then only the first 3 points need to be observed): 
• Subject should be seated comfortably or semi-recumbent, with back supported, legs 
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• The subject’s arm should be supported at heart level. 
• Cuff bladder should encircle 80 percent or more of the subject’s arm circumference. 
• Neither the subject nor the person taking the measurement should talk during the 
procedure. 
• The cuff should be deflated at 2 to 3 mm per second. 
• The first and last audible sounds should be recorded as systolic and diastolic pressure, 
respectively. Measurements should be given to the nearest 2 mm Hg. 
6.2.3 
Immunogenicity Assessments 
SARS-CoV-2 neutralising antibody titer will be tested using an in vitro plaque reduction 
neutralisation test (PRNT) and/or pseudovirus neutralization test and/or surrogate virus 
neutralization test (sVNT) and/or microneutralization test.  Testing using other SARS-CoV-2 
isolates may also be performed.   
Total IgG against the full-length SARS-CoV-2 recombinant spike protein and/or spike protein 
subunits will be assessed using an immune-Luminex and/or ELISA assay.  
T-cell subclass responses will be tested by flow cytometry and ELISPOT assay using peptide 
pools from SARS CoV-2 spike protein. 
6.2.4 
Surveillance for SARS-CoV-2 Infection 
In concert with the collection of adverse events, at each visit study subjects will be interviewed 
for potential symptoms of COVID-19 disease, recent diagnosis of SARS-CoV-2 infection or 
COVID-19, and for potential exposure to confirmed COVID-19 or confirmed SARS-CoV-2 
infection from household/intimate contacts.  A standardized question list will be used for this 
process. 
Potential symptoms of COVID-19 disease include (at a minimum): 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 and diarrhoea. 
Subjects 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.   
Should a subject describe any of the following, or exposure to a confirmed case of COVID-19, 
the subject should receive a SARS-CoV-2 PCR test preferably within 72 hours (and repeated if 
clinically appropriate) to determine if he/she is positive for SARS-CoV-2 virus infection.   
• TWO of the following systemic symptoms:  
o If onset is not within 48 hours after injection with Study Drug: fever (≥ 38ºC), 
chills, myalgia, headache, congestion or runny nose, nausea, diarrhoea  
o With onset at any time:  sore throat, new olfactory and taste disorder(s)  
OR   
• ONE of the following respiratory signs/symptoms: cough, shortness of breath or 
difficulty breathing  
OR  
o Clinical or radiographical evidence of pneumonia 

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For subjects who terminate early from the study, the site will remind the subject to contact the 
site until 1 year post last dose of ARCT-021 if they experience any of the above symptoms of 
COVID-19 or if they receive a diagnosis of COVID-19 or SARS-CoV-2 infection (Section 3.9). 
If a subject reports symptoms of COVID-19, the Investigator will make reasonable efforts to 
perform a SARS-CoV-2 PCR test preferably within 72 hours to confirm diagnosis.  
Reporting requirements for confirmed COVID-19 are described in Section 9.5.5 
6.3 
Restriction on the Lifestyle of Subjects 
6.3.1 
Contraception Requirements 
All male subjects and women of childbearing potential (WOCBP) must refrain from sperm/egg 
donation and use highly effective contraception from the time of signing the informed consent 
form until at least 56 days after their last dose of Study Drug.  
For male subjects engaged in sexual relations with a WOCBP either the subject or their female 
partner must use highly effective contraception from the time of signing the informed consent 
until 56 days after the subject’s last dose of study treatment. 
For the purposes of this study, WOCBP are defined as any female who has experienced 
menarche, and who does not meet one of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, highly effective contraception is defined as follows: 
For male subjects: 
• Highly effective male contraception includes a vasectomy with negative semen analysis 
at follow-up, or the non-pregnant female partner of WOCBP uses a highly effective 
contraceptive method (defined below) 
• Male subjects with partners that are pregnant must use condoms until at least 56 days 
after the last dose of Study Drug to ensure that the fetus is not exposed to the Study Drug 
For female subjects and female partners of male subjects, highly effective female contraception 
methods comprise: 
• Surgical sterilization (e.g., bilateral tubal occlusion), hormonal contraception associated 
with inhibition of ovulation (combined estrogen and progestogen containing, or 
progestogen-only), intrauterine contraception device or intrauterine hormone-releasing 
system (IUS). 
Note: A female condom and a male condom should not be used together as friction 
between the two can result in either or both products failing. 
 

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7 
STUDY DRUG 
For additional information please refer to the Pharmacy Manual. 
7.1 
Study Drug Description 
The Study Drug is ARCT-021.  
ARCT-021 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 which must be stored frozen at 
-70°C (+/- 10°C). ARCT-021 is a white to off-white liquid when thawed with a nominal 
 
 and osmolality of approximately
 mOsm/kg. 
 
Table 3: ARCT-021 Characteristics 
Strength 
0.2 mg/ mL  
Volume/Formulation 
2.0 mL solution per vial  
Route of Administration 
IM* 
*IM = intramuscular 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged ARCT-021 labeled in accordance with 
specific country regulatory requirements.  
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction ARCT-021 
supplies provided by the Sponsor.  The Study Center must return all unused frozen vials of 
ARCT-021 to the Sponsor or designee.  Used or thawed vials of ARCT-021 should be destroyed 
by the Study Center after drug accountability has been done by the unblinded study monitor.  
 
8 
TREATMENT OF SUBJECTS 
8.1 
Treatment Precautions 
Adrenaline 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 injection is being 
performed. 
8.2 
Study Drug Preparation 
Please refer to the Pharmacy Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug preparation. 

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ARCT-021 (1 volume) must be diluted with 3 volumes of sterile water for injection (SWFI) to 
target an osmolality of approximately 
 mOsm/kg. 0.9% sterile saline should then be added to 
reach the final target volume as shown in Table 4. Following dilution, 0.5 mL of diluted ARCT-
021 should be drawn up into a 1.0 mL syringe for administration. The syringe of ARCT-021 can 
be stored at room temperature (≤25°C) but must be administered within 6 hours of first puncture 
of the drug vial. 
 
Table 4. Dilution Volumes for Preparation of ARCT-021 
Dose Level  
(mg) 
Amount of 
ARCT-021 
(mg) 
Volume of 
ARCT-021 
(mL) 
Volume 
of SWFI 
(mL) 
Volume of 
0.9% Sterile 
Saline (mL) 
Final 
Volume 
(mL) 
Final 
Concentration 
(mg/mL) 
7.5 
150 
0.75 
2.25 
7.0 
10.0 
15.0 
Note: ARCT-021 must first be added to the empty vial provided by the Sponsor and then 
the SWFI added to the ARCT-021, followed by 0.9% sterile saline. 
8.3 
Study Drug Administration 
Study Drug will be administered by injection into the lateral aspect of the deltoid muscle of the 
non-dominant arm. 
Subjects should remain at the center for at least 30 minutes for observation following vaccine 
administration.  
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. 
If the subject experiences a severe reaction following vaccine administration, the CRO Medical 
Monitor should be contacted as soon as feasible to discuss if additional assessments may be 
clinically warranted prior to the discharge of the subject from the study center.   
8.4 
Other Protocol-Required Treatment Procedures 
None 
8.5 
Safety Monitoring Rules 
Clinical safety parameters, including laboratory tests and vital signs will be monitored 
throughout the study.   
Confirmation Guidance: At any time during the study (Study Drug Administration or Post-
Treatment Periods), clinical laboratory results that are ≥ Grade 3 in severity or liver chemistry 
tests that meet the criteria presented below must be confirmed by performing measurements 
(ideally in the same laboratory that performed the initial measurement) on new specimens. All 
new specimen collections should take place as soon as possible (ideally within 3 days of the 
initial collection). For laboratory results that meet stopping rules, if the initial laboratory result is 

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observed during the Study Drug Administration Period, the results from the retest must be 
available prior to administering the next dose of Study Drug. 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the guidance for industry, “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation,” issued by the U.S. Department of Health and Human 
Services, Food and Drug Administration, July 2009.  
In the event of an ALT or AST measurement that is >3 x ULN at any time during the study, the 
initial measurement(s) should be confirmed as described above.  Additional, confirmatory 
measurements should also be performed if ALT or AST levels increase to 5 x ULN. 
Frequency of Repeat Measurements:  Subjects with confirmed ALT or AST levels > 3 x ULN 
should have their liver chemistry tests (ALT, AST, ALP, INR, and total bilirubin) retested at 
least once-weekly until ALT and AST levels become ≤ 1.2 x ULN or until clinically stable 
and/or an alternate underlying etiology is identified. 
Further Investigation into Liver Chemistry Elevations:  For subjects with confirmed ALT or AST 
levels > 3 x ULN, the following evaluations should be performed (these tests may be performed 
in local lab): 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody (ANA)) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, or if requested by the Sponsor 
Medical Monitor.  Repetition of the above evaluations should be considered if a subject’s ALT 
and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring Rules for Local and Systemic Reactogenic Events 
Monitoring and recording of solicited reactogenic adverse events will be performed according to 
Section 6.2.1 and Appendix 1.  
8.6 
Treatment Stopping Rules for Individual Subjects 
As subjects in this study receive a single dose administration of ARCT-021, stopping rules for 
subsequent doses of study vaccine do not apply. 
8.7 
Adjustment of Dose and/or Treatment Schedule 
Adjustment of dose is not permitted.  

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8.7.1 
Delay in Vaccination  
If any of the following events occur within 72 hours of the day planned for study vaccination, the 
subject experiencing these symptoms should not receive the study vaccine:   
• Acute illness, as determined by the Investigator, with or without fever  
• Fever, defined as temperature ≥ 38.0°C (100.4°F)  
As long as the subject remains eligible for study participation, the fever has subsided and/or the 
moderate or severe infection has resolved or reduced to mild severity for 48 hours, and the 
subject has been tested and confirmed to be negative for the SARS-CoV-2 virus, as appropriate 
(Section 6.2.4) the study vaccination may be rescheduled.   
8.8 
Withdrawal of Subjects from the Study Procedures 
Subjects must be withdrawn from study procedures for any of the following: 
• Withdrawal of consent 
• The subject is unwilling or unable to comply with the protocol in the judgement of the 
Investigator 
Other reasons for withdrawal of subjects from study procedures might include: 
• At the discretion of the Investigator for medical reasons 
• Significant protocol deviation 
• The subject is lost to follow-up 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the eCRF. 
For subjects who fail to show up for the final visit, or for three consecutive visits, study staff are 
encouraged to make at least three documented attempts to contact the subject by telephone and at 
least one documented written attempt to contact the subject or legal guardian to encourage the 
completion of study termination procedures. These efforts to contact the subject should be 
recorded in the source documentation. The termination date for the subject to be captured on the 
Study Termination eCRF page is the date of the last successful contact (clinic visit or telephone) 
with the subject. These subjects will be regarded as lost to follow-up. 
Any subject who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These subjects should be 
encouraged to complete the early termination study procedures and observations at the time of 
withdrawal (Appendix 1). 
For subjects withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination of study procedures and observations at the time of withdrawal 
(see Appendix 1).  

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The reason for withdrawal from the study will be entered in the EDC. If the reason for 
withdrawal includes one or more AEs then an AE will be entered as the primary reason for 
withdrawal.  
8.9 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject’s 
eCRF. Adverse events associated with administration of these therapies or procedures must also 
be documented on the appropriate eCRF. 
8.9.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
of the informed consent document and the subject’s last protocol-specified study visit. 
Disallowed Concomitant Therapy 
The use of the following concomitant medications and/or vaccines will not require withdrawal of 
the subject from the study but may determine a subject’s eligibility in the per-protocol analysis: 
• Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period.  
• 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. 
Subjects who receive ARCT-021 vaccine in this study should also be asked if they have taken 
any antipyretic or analgesic to prevent fever or pain within 24 hours prior to vaccine 
administration or if they have taken antipyretic or analgesics to treat fever or other solicited 
adverse events within 7 days after each study vaccine administration, including the day of 
dosing. These details should be specified on the Concomitant Medication CRF page. 
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 the dose of 
ARCT-021 (if relevant).  Otherwise, only concomitant medications associated with an SAE, 
CESI, NOCD or MAAE or for treatment of COVID-19 will be entered in the eCRF. 
 

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8.9.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of the informed consent document and the subject’s last protocol-specified study visit. 
All concomitant procedures must be recorded in the eCRF until 28 days after the last dose of 
Study Drug. Thereafter only concomitant medications associated with an SAE or medically 
attended AE (MAAE) will be entered in the eCRF. 
8.10 
Treatment Compliance 
Compliance with Study Drug dosing is to be monitored and recorded in the eCRF by Study 
Center staff.   
9 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING  
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee in 
accordance with the applicable SOPs throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting serious adverse 
events (SAEs), including suspected unexpected serious adverse reactions (SUSARs), to the 
Investigators per the International ICH guidelines E2A and ICH GCP, as outlined by ICH 
E6(R2) and subsequent amendments. Country-specific regulatory requirements will be followed 
in accordance with local country regulations and guidelines. 
The Independent Ethics Committee (IEC) or Institutional Review Board (IRB), as appropriate 
will be notified of any SAE according to applicable regulations.   
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of all reported SAEs and 
determine if there is a reasonable possibility that the Study Drug is causally related to a reported 
SAE.  While the Sponsor may upgrade an Investigator’s decision it is not permissible to 
downgrade the Investigator’s opinion for the purposes of determining whether the SAE meets the 
definition of a SUSAR. 
For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population.  For Study Drug “expected” AEs, refer to the Reference Safety Information in the 
Investigator’s Brochure. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event (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 
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An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an 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 (e.g., headache) not present at baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, 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 assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
9.3.2 
Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not have been established, ADR is defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. 
The phrase "responses to a medicinal product" means that a causal relationship between the 
medicinal product and the adverse event has been determined as at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 
Suspected Unexpected Adverse Drug Reaction  
A suspected unexpected ADR is any ADR, the nature or severity of which is not consistent with 
the Reference Safety Information in the applicable Investigator's Brochure. 
A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening: that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death.  It does not include an AE or suspected adverse reaction that, had it occurred in a 
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• Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in a congenital anomaly or birth defect in the offspring of the subject (whether 
the subject is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and 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. 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe or according to the criteria in Section 
9.4.4.2); the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded on 
the eCRF. 
9.3.4 
Medically Attended Adverse Event (MAAE) and New Onset of Chronic Disease 
(NOCD) 
An MAE is an AE that leads to an unscheduled visit (including a telemedicine visit) to a 
healthcare practitioner (HCP). This would include visits to a study site for unscheduled 
assessments (e.g., rash assessment, abnormal laboratory follow-up) and visits to or from HCPs 
external to the study site (e.g., urgent care, primary care physician).  
MAAE are adverse events with medically attended visits, such as visits for hospitalization, an 
emergency room or doctor’s clinic visit, or an otherwise unscheduled visit to or from medical 
personnel for any reason. They do not include routine study visits. 
Should an MAAE lead to the new diagnosis of a chronic medical condition that was not present 
or suspected prior to enrollment, this will be categorized as a new onset of chronic disease 
(NOCD). 
9.3.5 
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 
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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. 
9.3.6 
Targeted Medical Event 
Other targeted medical events (TMEs), or other adverse event of interest (OAEI), are AEs, 
including both serious or non-serious events, that may be defined in the study protocol or 
associated documents for further characterisation or evaluation of product specific adverse 
events.  
No TMEs are specified for this study. 
9.3.7 
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, this event will also be 
reported as an AE. 
To be considered as a CESI of COVID-19 the following case definition must be met: 
• The subject must have experienced at least TWO of the following systemic symptoms: 
Fever (≥ 38ºC), chills, myalgia, headache, sore throat, congestion or runny nose, nausea, 
diarrhoea, new olfactory and taste disorder(s), OR 
• The subject must have experienced at least ONE of the following respiratory 
signs/symptoms: cough, shortness of breath or difficulty breathing, OR  
• Clinical or radiographical evidence of pneumonia; AND 
• The subject must have at least one test positive for SARS-CoV-2 by PCR. 
To be considered as a CESI of asymptomatic SARS-CoV-2 infection, a subject 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.   
Reporting requirements for confirmed COVID-19 cases are described in Section 9.5.5.  
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the first 
injection of ARCT-021 should be recorded as Medical History and not recorded as AEs unless 
the pre-existing condition worsened.  The Investigator should always group signs and symptoms 
into a single term that constitutes a single unifying diagnosis if possible.  Before a diagnosis is 
confirmed, all symptoms should be reported as separate AEs.   
Any AE that includes a new diagnosis of a chronic medical condition that was not present or 
suspected prior to enrollment, will be categorized as a new onset of chronic disease (NOCD). 

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9.4.1 
Serious Adverse Events 
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.   
For subjects that received ARCT-021 in the parent study, the collection of SAE will begin at the 
Screening visit, when SAE (and MAAE) occurring since completion of the Parent Study will be 
solicited to ensure continuity of safety follow-up from the Parent Study to this study, and stop at 
the end of the subject’s follow-up period which is defined as the subject’s last protocol-specified 
study visit. 
For subjects who receive ARCT-021 in this study and who did not receive ARCT-021 in the 
Parent Study, the collection of SAEs will begin after the subject has received ARCT-021 and 
stop at the end of the subject’s follow-up period. SAEs that occur prior to administration of 
ARCT-021, including those that occurred between leaving the Parent Study and dosing in this 
Study,  will be recorded as medical history.  
SAEs considered to be related or possibly related to Study Drug and any deaths will continue to 
be reported for 30 days after the subjects last study visit.  SAEs will be reported within the 
electronic data capture system (EDC) whenever possible. If the EDC is not available, the SAE 
can be initially reported using a paper Initial Serious Adverse Event Form, which should be 
faxed or emailed to the Sponsor or designee. The SAE reporting instructions, including the fax 
number and email address for submitting paper forms can be found in the Investigator site file 
for the study.  If the Investigator is reporting by telephone, it is important to speak to someone in 
person versus leaving a message. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available. All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the subject’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
subject’s condition is unlikely to resolve, the Investigator and Sponsor will determine the follow-
up requirement.  
9.4.2 
Medically Attended Adverse Events 
For subjects that received ARCT-021 in the parent study, the collection of MAAE will begin at 
the Screening visit, when MAAE (and SAE) occurring since completion of the Parent Study will 
be solicited to ensure continuity of safety follow-up from the Parent Study to this study, and stop 
at the end of the subject’s follow-up period which is defined as the subject’s last protocol-
specified study visit. 
For subjects who receive ARCT-021 in this study and who did not receive ARCT-021 in the 
Parent Study, the collection of MAAEs will begin after the subject has received ARCT-021 and 
stop at the end of the subject’s follow-up period. MAAEs that occur prior to administration of 
ARCT-021, including those that occurred between leaving the Parent Study and dosing in this 
Study will be recorded as medical history.  
MAAEs that also fulfil the criteria of an SAE should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event (Section 9.4.1). 

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9.4.3 
Non-Serious Adverse Events 
For subjects who receive ARCT-021 in this study and who did not receive ARCT-021 in the 
Parent Study, the recording of non-serious AEs will begin after the subject has received 
ARCT-021 and will stop 28 days after the last dose of ARCT-021, with the exception of ongoing 
adverse events that worsen in severity and/or become serious, which will continue to be 
recorded. AEs that occur prior to administration of ARCT-021, including those that occurred 
between leaving the Parent Study and dosing in this Study will be recorded as medical history. 
For subjects who receive ARCT-021 in this study and who also received ARCT-021 in the 
Parent Study, the recording of non-serious AEs will begin from the time the subject received 
ARCT-021 in the Parent Study and will stop 28 days after the dose of ARCT-021 in this study, 
with the exception of ongoing adverse events that worsen in severity and/or become serious, 
which will continue to be recorded. Any AEs that occurred between leaving the Parent Study and 
entering this study will be recorded as AEs. 
For subjects who do not receive ARCT-021 in this study, only medically attended non-serious 
events will be recorded as described above (Section 9.4.2). The Investigator will monitor each 
subject closely and record all observed or volunteered AEs in the EDC. 
9.4.4 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following must be documented on the Adverse Event Case 
Report Form: 
9.4.4.1 
Relationship to the Study Drug 
Reactogenic events with onset within 7 days of injection of ARCT-021 will be regarded as 
related. 
For other events, the event’s relationship to the Study Drug is characterised by one of the 
following: 
• Related:  There is clear evidence that the event is related to the use of Study Drug, e.g., 
confirmation by positive re-challenge test 
• Possibly Related:  The event cannot be explained by the subject’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and Study Drug administration 
• Unlikely Related:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
Study Drug administration and/or exposure suggests that a causal relationship is unlikely 
(For reporting purposes, Unlikely/Remote will be grouped together with Not Related) 
• Not Related:  The event can be readily explained by the subject’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
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9.4.4.2 
Severity 
The severity of AEs and SAEs will be graded by the Investigator according to the Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, Sept 2007, where applicable.  
Any AE not listed in this scale will be graded as follows: 
• Mild:  The event is easily tolerated by the subject and does not affect the subject’s usual 
daily activities 
• Moderate:  The event causes the subject more discomfort and interrupts the subject’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
subject’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.4.3 
Action Taken with Study Drug 
Action taken with Study Drug due to the event is characterised by one of the following. 
• Not Applicable:  This applies to all AE occurring in subjects that do not receive 
ARCT-021 in this study.  For subjects who receive ARCT-021 in this study, this applies 
if a SAE/AE was reported during screening period prior to ARCT-021 administration or 
in the Post-Treatment Period following the Administration period 
• Dose Not Changed:  No changes were made to dose of ARCT-021 
• Drug Withdrawn:  ARCT-021 was discontinued and not restarted 
• Drug Interrupted:  Dosing frequency was temporarily interrupted/changed or delayed 
due to the AE and restarted at the same dose level 
9.4.4.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event eCRF. Treatment should also be recorded on the concomitant treatment or 
ancillary procedures eCRF, as appropriate. 

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9.4.4.5 
Outcome of the Adverse Event 
The AE’s outcome is characterised by one of the following: 
• Fatal: Subject died (the date of death should be entered as the SAE resolution date) 
• Not Recovered/Not Resolved:  Subject terminates from the trial and the AE continues 
• Recovered/Resolved:  Subject recovered completely from the AE 
• Recovered/Resolved with Sequelae: The signs/symptoms of the reported AE have 
improved but not completely resolved, and a new baseline for the subject is established 
since full recovery is not expected. 
• Recovering/Resolving: The signs/symptoms of the reported AE have improved but not 
completely resolved, but full recovery is expected. 
• Unknown:  The outcome of the reported is not available, e.g., subject is lost to follow-
up. 
9.4.4.6 
Follow-up of Adverse Events 
During the study period, the Investigator should follow each AE until the event has resolved to 
baseline grade or better, the event is assessed as stable, the subject is lost to follow-up, or the 
subject withdraws consent.  Every effort should be made to follow all SAEs until a final outcome 
can be reported (Section 9.4.1).  SAEs that remain ongoing past the subject’s last protocol-
specified follow-up visit will be evaluated by the Investigator and Sponsor.  If the Investigator 
and Sponsor agree the subject’s condition is unlikely to resolve, the Investigator and Sponsor 
will determine the follow-up requirement. 
Resolution of AE (with dates) should be documented on the Adverse Event eCRF and in the 
subject’s medical record to facilitate source data verification.  
Sponsor Follow-Up 
For SAEs and CESIs that have occurred in subjects who have been vaccinated with ARCT-021 
within the last 12 months, the Sponsor or a designee should follow-up by telephone, fax, email, 
and/or a monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. 
 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically significant abnormalities will be monitored by the Investigator until the parameter 

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returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor (or designee) that further follow-up is not required.  Laboratory abnormalities 
deemed not clinically significant (NCS) by the Investigator should not be reported as AEs.  
Similarly, laboratory abnormalities reported as AEs by the Investigator should not be deemed 
NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the subject’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Study Drug errors (including overdose, underdose, and administration error) should be 
documented as Protocol Deviations.  A brief description should be provided in the deviation, 
including whether the subject was symptomatic (list symptoms) or asymptomatic, and the event 
accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the subject receives a 
dose of Study Drug that exceeds protocol specifications and the subject is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
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.  All adverse events associated with an overdose or 
incorrect administration of Study Drug should be recorded on the Adverse Event eCRF.  If the 
associated adverse event fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event). 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 

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9.5.4 
Contraception and Pregnancy 
If a subject who received ARCT-021 in this study becomes pregnant or a pregnancy is suspected, 
or if a male subject who received ARCT-021 in this study makes or believes that  his sexual 
partner has become pregnant with his child during the study, then the Study Center staff must be 
informed immediately.  The pregnancy should be reported in the EDC within 24 hours of first 
learning of the occurrence of the pregnancy.  If the EDC is not available, the pregnancy can be 
initially reported using a paper Pregnancy Notification Form, which should be faxed or emailed 
to the Sponsor or designee. Follow-up information including delivery or termination should be 
reported in the EDC within 24 hours if the subject is still enrolled in the clinical trial or via a 
paper Pregnancy Follow-Up Form if the subject is no longer enrolled in the clinical trial.  
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. 
Payment for all aspects of obstetrical care, child or related care will be the subject’s 
responsibility.   
Female subjects:  If a suspected pregnancy occurs while on the study in a female subject that has 
received ARCT-021, a pregnancy test will be performed.  If the pregnancy test is positive, the 
subject will be encouraged to complete the post-treatment follow-up portion of the study to the 
extent that study procedures do not interfere with the pregnancy.  Regardless of continued study 
participation, the study physician will assist the subject in getting obstetrical care and the 
progress of the pregnancy will be followed until the outcome of the pregnancy is known (i.e., 
delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the birth of a 
child, the Study Center 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; e.g., pregnancy ICF may be required. 
Male subjects:  In the event that that the female partner of a male subject that has received 
ARCT-021 becomes pregnant, the progress of the pregnancy of the male subject’s partner should 
be followed until the outcome of the pregnancy is known (i.e., 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; e.g., partner informed consent form may be required. 
9.5.5 
Cases of PCR-confirmed COVID-19 or PCR/Serologically Confirmed 
SARS-CoV-2 Infection Without COVID-19 
Any case of PCR-confirmed COVID-19 will be regarded as a Clinical Event of Special Interest 
(Section 9.3.7) and must be reported to the Sponsor or designee within 24 hours of the site 
learning of this event.  
In addition, CESIs must be reported for all cases detected for up to one year after receipt of 
vaccination with ARCT-021, including events reported by participants who have early 

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terminated study ARCT-021-01 or study ARCT-021-02 and participants who did not roll over to 
the ARCT-021-02 study if these events fall within the 1 year timeframe.  
Whilst the subject is enrolled in the study reporting will be performed by completion of a 
‘COVID-19 and SARS-CoV-2 Infection Report Form’ in the EDC (Section 9.4.1).  For subjects 
that have terminated early from the study but not withdrawn consent, cases of PCR-confirmed 
COVID-19 and PCR/serologically confirmed SARS-CoV-2 infection without COVID-19 will be 
reported via a paper COVID-19 and SARS-CoV-2 Infection Report Form, which should be faxed 
or emailed to the Sponsor or designee. 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. 
The EDC and paper reporting forms will collect the following parameters: 
• Whether PCR test and/or anti-nucleocapsid antibody test are positive 
• COVID-19 symptoms 
• Oxygen saturation on air 
• Percent supplemental oxygen required (if any) 
• Type of assisted ventilation required (if any) 
o CPAP 
o External Ventilation 
o Invasive Ventilation 
o Other (specify) 
• Whether intensive care unit admission required 
• Investigations performed: 
o Chest X-ray 
o CT Scan 
o Bronchoscopy 
o Other (specify) 
• PCR confirmed COVID-19 disease will be graded as follows: 
o Mild:  No requirement for supplemental oxygen to maintain oxygen saturation ≥ 
93% 
o Moderate:  Oxygen supplementation at a concentration of < 50% required to 
maintain oxygen saturation ≥ 93% 
o Severe:  Oxygen supplementation at a concentration of > 50% or any form of 
mechanical ventilatory support required 
 
10 
STATISTICAL CONSIDERATIONS 
Full details of statistical analyses will be described in the Statistical Analysis Plan (SAP) for 
Study ARCT-021-01. The SAP will be finalized prior to final database lock. Any changes to the 
methods described in the final SAP will be described and justified as needed in the clinical study 
report (CSR). An overview is presented below. 

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10.1 
Sample Size Considerations 
As this is an open label follow-on study, the sample size is determined by the number of subjects 
enrolled in the Parent Study that consent to be followed up in this study; therefore, formal 
sample size calculations are not applicable. 
10.2 
Populations 
Safety Population:  All subjects who receive Study Drug in ARCT-021-02 only 
Longitudinal Safety Population: All subjects who receive Study Drug in either ARCT-021-01 or 
ARCT-021-02 
Immunogenicity Population: All subjects who receive Study Drug in either ARCT-021-01 or 
ARCT-021-02 and who have evaluable immunogenicity data following first vaccine 
administration. 
Additional populations may be defined for individual immunogenicity endpoints and will be pre-
specified in the SAP. 
Within these populations, analyses will also include Cohorts that combine relevant safety and 
immunogenicity assessments across ARCT-021-01 and ARCT-021-02 according to time since 
administration of last dose of ARCT-021 (See Table 5). These cohorts are defined as follows. 
Two primary cohorts will be defined: 
• Cohort 1: ARCT-021-02 vaccinated participants (those participants who receive ARCT-
021 in Study ARCT-021-02, including those who were assigned to receive placebo in the 
parent study (ARCT-021-01) and those who enter the ARCT-021-02 without detectable 
neutralising antibody responses at baseline) 
o This cohort will be further subdivided for an exploratory analysis of cohorts: 
▪ Cohort 1a: Primary vaccination (Those participants whose first ARCT-021 
vaccine administration occurs in the ARCT-021-02 study) and 
▪ Cohort 1b: Booster vaccination (Those participants who received primary 
vaccination in the ARCT-021-01 study and who receive an additional dose 
of ARCT-021 in the ARCT-021-02 study) 
• Cohort 2: ARCT-021-01 vaccinated participants (those participants who were vaccinated 
with ARCT-021 in the parent study and who do not receive subsequent vaccination with 
ARCT-021 in the current extension study). 
o This cohort will be further subdivided for an exploratory analysis of subcohorts: 
▪ Cohort 2a: Those participants who received ARCT-021 7.5 µg dose as a 
single dose administration in the parent study (Cohorts D1 and D2) 
▪ Cohort 2b: Those participants who received ARCT-021 10.0 µg dose as a 
single dose administration in the parent study (Cohort C) 
▪ Cohort 2c: Those participants who received alternate doses and schedules 
of ARCT-021 in the parent study (Cohorts A, B) 
▪ Cohort 2d: Those participants who receive two-dose schedules of ARCT-
021 in the parent study (Cohorts E, F, G, H) 
Additional analysis cohorts, if required, will be prespecified in the statistical analysis plan. 

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Table 5:  Grouping of Cohorts and Timepoints Across Studies ARCT-021-01 and  
ARCT-021-02 for Analysis  
 
15 days 
1 month 
2 months 
6 months 
12 months 
Cohorts 1a and 
1b (single dose 
of 7.5 µg in this 
Study) 
Day 15 in 
ARCT-
021-02 
Day 29 in 
ARCT-021-02 
Day 57 in 
ARCT-021-02 
Day 169 in 
ARCT-021-02 
Day 365 in 
ARCT-021-02 
Cohort 2a 
(single dose of 
7.5 µg in Parent 
Study only) 
Day 15 in 
ARCT-
021-01 
Day 29 in 
ARCT-021-01 
Day 57 in 
ARCT-021-01 
Day 29 in 
ARCT-021-02 
Day 197 in 
ARCT-021-02 
Cohort 2b 
(single dose of 
10 µg in Parent 
Study only) 
Day 15 in 
ARCT-
021-01 
Day 29 in 
ARCT-021-01 
Day 57 in 
ARCT-021-01 
Day 29 in 
ARCT-021-02 
Day 197 in 
ARCT-021-02 
Cohort 2c 
(alternate single 
dose schedules 
in Parent Study 
only) 
Day 15 in 
ARCT-
021-01 
Day 29 in 
ARCT-021-01 
Day 57 in 
ARCT-021-01 
Day 29 in 
ARCT-021-02 
Day 197 in 
ARCT-021-02 
Cohort 2d 
(alternate two 
dose schedules 
in Parent Study 
only) 
Day 43 in 
ARCT-
021-01 
Day 57 in 
ARCT-021-01 
Day 85 in 
ARCT-021-01 
Day 29 in 
ARCT-021-02 
Day 197 in 
ARCT-021-02 
 
10.3 
Definition of Baseline 
For the Safety Population baseline will be the last value prior to first administration of ARCT-
021 in Study ARCT-021-02. 
For the Longitudinal Safety Population baseline will be the last value prior to first administration 
of ARCT-021 as it occurred in either the ARCT-021-01 or ARCT-021-02 study. 
For the Immunogenicity Population: baseline will be defined as follows. 
▪ Baseline for Cohort 1a and 1b: Day 1 of ARCT-021-02 study 
▪ Baseline for Cohort 2a, 2b, 2c, 2d:  Day 1 of ARCT-021-01 
10.4 
Interim Analysis 
Interim analyses of the data may be performed by the Sponsor or designee after all subjects have 
reached at least Day 29. Additional interim analyses may also be performed at other timepoints 
after Day 29. 

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10.5 
Planned Methods of Analysis 
10.5.1 
General Approach 
Statistical analyses will be primarily descriptive; no formal hypothesis testing will be conducted. 
Analyses will be performed using SAS® (Version 9.4 or higher). 
In general, clinical data will be summarised separately by treatment group, by age group, dose 
level and visit (where applicable), using descriptive statistics (e.g. n, mean, standard deviation, 
standard error, median, minimum, maximum, first and third quartiles for continuous variables, 
and frequencies and percentages for categorical variables). When categorical data are presented, 
the percentages will be suppressed when the frequency count is zero. Non-zero percentages will 
be rounded to one decimal place, except 100% will be displayed without any decimal places. 
Statistical testing, if performed, will be prespecified in the final statistical analysis plan prior to 
unblinding of subject data.  
10.5.2 
Demographic and Baseline Characteristics 
The Safety Population and Longitudinal Safety Population will be used for analyses of 
disposition, demographics and baseline characteristics, which will be summarised using 
descriptive statistics. 
10.5.3 
Safety Analysis 
The primary objective of the study is the evaluation of the safety and tolerability of ARCT-021. 
The primary endpoints that align with this objective are: 
▪ Solicited AEs for 7 days after vaccination (Cohort 1), summarized by toxicity grade 
▪ Unsolicited AEs for 28 days after vaccination (Cohort 1), summarized by 
mild/moderate/severe and relationship to ARCT-021 
▪ SAEs through Day 197 (Cohort 2; 12 months after ARCT-021 vaccination in ARCT-021-
01 study), summarized by relationship to ARCT-021 
▪ SAEs through Day 365 (Cohort 1; 12 months after ARCT-021 vaccination in ARCT-021-
02 study), summarized by relationship to ARCT-021 
▪ MAAEs through Day 197 (Cohort 2; 12 months after ARCT-021 vaccination in ARCT-
021-01 study), summarized by relationship to ARCT-021 
▪ MAAEs through Day 365 (Cohort 1; 12 months after ARCT-021 vaccination in ARCT-
021-02 study), summarized by relationship to ARCT-021 
▪ NOCDs through Day 197 (Cohort 2; 12 months after ARCT-021 vaccination in ARCT-
021-01 study), summarized by relationship to ARCT-021 
▪ NOCDs through Day 365 (Cohort 1; 12 months after ARCT-021 vaccination in ARCT-
021-02 study), summarized by relationship to ARCT-021 
▪ Safety laboratory assessments through 28 days after vaccination (Cohort 1), summarized 
by toxicity grade (where relevant) 

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▪ Vital signs assessments through day 365 (Cohort 1; 12 months after ARCT-021 
vaccination in ARCT-021-02 study) summarized by toxicity grade 
To support the continued characterization of  ARCT-021 tolerability and safety when 
administered as a single dose, the following summaries will be provided: 
▪ Summary of solicited (7 days after vaccination) and unsolicited AEs 28 days after 
vaccination)  
▪ Summary of MAAEs, NOCDs, SAEs through 12 months after vaccination  
10.5.4 
Immunogenicity Analyses 
Assessment of the long-term neutralising and anti-spike protein IgG responses, including 
seroconversion rates, following vaccination with ARCT-021 is the secondary objective of the 
study. The assays and study endpoints for these analyses include:  
Assays: 
▪ Neutralising antibody responses based on hCoV-19/Singapore/2/2020 isolate: 
o Plaque reduction neutralising titers (PRNT) and/or 
o pseudovirus neutralization test and/or 
o surrogate virus neutralization test (sVNT) and/or 
o microneutralization test. 
o Exploratory: testing using other SARS-CoV-2 isolates may also be performed. 
▪ Binding antibody responses: Total IgG against the full-length SARS-CoV-2 recombinant 
spike protein and/or spike protein subunits will be assessed using an immune-Luminex 
and/or ELISA assay. 
Endpoints: 
▪ Neutralising and binding antibody responses at Day 29 (6 months after last dose of 
ARCT-021), Day 197 (12 months after last dose of ARCT-021), Day 281 (15 months 
after last dose of ARCT-021) for Cohort 2: 
▪ Neutralising and binding antibody responses at Day 1, Day 15, Day 29 (1 month after last 
dose of ARCT-021), Day 57 (2 months after last dose of ARCT-021), Day 169 (6 months 
after last dose of ARCT-021), Day 365 (12 months after last dose of ARCT-021) for 
Cohort 1 
▪ T cell responses (Flow cytometry and ELISpot assays) at Day 29 and Day 197 (Cohort 2) 
▪ T cell responses (Flow cytometry and ELISpot assays) at Day 1, Day 15, Day 29, Day 
169, Day 365 (Cohort 1: ARCT-021-02 vaccinated participants) 
 
Descriptive statistics, by assessment time point, will be used to describe all immunogenicity 
results and further specified in the SAP prior to data analysis.  Statistical testing, if performed, 
will be prespecified in the final SAP and will be exploratory in nature. 

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10.5.5 
Clinical Events of Special Interest Analyses 
Statistical analyses of CESIs will be descriptive over timepoint in the safety and longitudinal 
safety populations. These endpoints include confirmed COVID-19 (including severe cases) and 
asymptomatic SARS-CoV-2 infection over timepoint and also analyzed as pooled and separately 
for the younger and older adult groups. 
10.5.6 
Missing Data Handling 
Due to the exploratory nature of this study and the lack of statistical testing, missing data will not 
be imputed. Values that are below the level of quantification will be recoded to zero for analysis 
purposes.  
11 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
subject population and approved by the Sponsor or designee. 
Before a subject’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the subject after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific screening 
procedures or any Study Drug are administered. Explanation of the theoretical risks of enhanced 
COVID-19 disease as a consequence of ARCT-021 administration will be included as part of 
informed consent process for all subjects who will be receiving ARCT-021 in the study. The 
subject must be given sufficient time to consider whether to participate in the study.   
The acquisition of informed consent and the subject’s agreement or refusal to notify his/her 
primary care physician should be documented in the subject’s medical records and the informed 
consent form should be signed and personally dated by the subject and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
subject. 
11.2 
Ethical Conduct of the Study 
The study must be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCP), as outlined by ICH E6(R2), as well as the demands of national drug and data 
protection laws and all applicable local and national regulatory requirements. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent forms, other written subject information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor or designee before recruitment of subjects into the study and shipment of Study Drug.  
A copy of the written approval of any other items/materials that must be approved by the Study 
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subjects into the study and shipment of Study Drug.  The Investigator’s Brochure must be 
submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP, as outlined by ICH E6(R2).  The Investigator should also notify the IEC/IRB of SAEs 
occurring at the Study Center and other AE reports received from the Sponsor or designee, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor or designee. 
11.4 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor or designee, subjects should be identified by 
initials (if permitted by local law) and a subject identification number only.  Documents that are 
not for submission to the Sponsor or designee (e.g., signed informed consent forms) should be 
kept in strict confidence by the Investigator. 
In compliance with Federal and local regulations/ICH GCP, as outlined by ICH E6(R2) 
Guidelines, it is required that the Investigator and institution permit authorized representatives of 
the company, of the regulatory agency(s), and the IEC/IRB direct access to review the subject’s 
original medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study.  The Investigator is obligated to inform and obtain the 
consent of the subject to permit named representatives to have access to his/her study-related 
records without violating the confidentiality of the subject. 
12 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
Agreement from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent document.  The regulatory authority and IEC/IRB must be informed of 
all amendments and give approval for any amendments likely to affect the safety of the subjects 
or the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor or designee. 
12.2 
Study Termination 
The Sponsor or designee reserves the right to terminate the study.  The Investigator reserves the 
right to terminate their participation in the study, according to the terms of the site contract.  The 
Investigator should notify the IEC/IRB in writing of the trial’s completion or early termination 
and send a copy of the notification to the Sponsor or designee. 

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12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the subject’s case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, 
eCRF pages may not be used as source documents. 
The Investigator and Study Center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with ICH 
GCP, as outlined by ICH E6(R2), suitable for inspection at any time by representatives from the 
Sponsor or designee and/or applicable regulatory authorities.  Elements should include: 
• Subject files containing completed case report forms, informed consents, and supporting 
copies of source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor or designee 
• If drug supplies are maintained at the Study Center, proof of receipt, Study Drug Product 
Accountability Record, Return of Study Drug Product for Destruction, final Study Drug 
product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
designee and the Investigator.  Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify the Sponsor or designee. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., case report forms and other pertinent data) provided that 
subject confidentiality is respected. Remote monitoring may be used for some visits, but 100% 
source data verification will be performed. 
The Sponsor monitor or designee is responsible for inspecting the case report forms at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research.  
The monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the case report forms.  
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing case report forms, are resolved. 

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To ensure the quality of clinical data a clinical data management review will be performed on 
subject data received by the Sponsor or designee.  During this review, subject data will be 
checked for consistency, omissions, and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol and ICH GCP, as outlined by ICH E6(R2).  To resolve 
any questions arising from the clinical data management review process, data queries and/or 
Study Center notifications will be sent to the Study Center for completion and return to Sponsor 
or designee. 
The Principal Investigator will sign and date the indicated places on the case report form in the 
EDC.  These signatures will indicate that the Principal Investigator inspected or reviewed the 
data on the case report form, the data queries, and the Study Center notifications, and agrees with 
the content. 
12.5 
Site Audit 
In accordance with ICH GCP, as outlined by ICH E6(R2) and in accordance with the Sponsor’s 
audit plans, this study may be selected for audit by representatives (or designees) from the 
Sponsor.  Inspection of Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) 
and review of study-related records may occur to evaluate the trial conduct and compliance with 
the protocol, ICH GCP, as outlined by ICH E6(R2) and applicable regulatory requirements. 
12.6 
Language 
Case report forms must be completed in English.  Generic names and trade names are acceptable 
for concomitant medications.  Combination medications should be recorded using their trade 
name. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
12.7 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Subjects will be treated and/or compensated for any study-
related illness/injury in accordance with the information provided in the Compensation for Injury 
section of the Informed Consent document. 
 
 
 

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13 
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14 
APPENDICES 
.

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APPENDIX 1: SCHEDULE OF ASSESSMENTS 
 
 
 

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Appendix 1: Schedule of Assessments 
1. Screening 
Subjects who Received Placebo or a Single Injection of ARCT-021 in Parent Study 
 
Study Week/Day 
D –28 to D –1 
Visit Window (Days) 
0 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Body Weight 
X 
Physical Exam1 
X 
Vital Signs2 
X 
Pregnancy Test3 
X 
Chemistry Panel 
X 
Hematology 
X 
Coagulation 
X 
HbA1c 
X 
Urinalysis4 
X 
Immunogenicity5 
X 
Drug/Alcohol Screen6 
X 
SAE, CESI, NOCD and MAAE7 
X 
Concomitant Medications and Procedures8 
X 
SARS-CoV-2 questioning9 
X 
 
1 
Full physical exam  
2 
BP, HR, RR, temp 
3 
Women who are not surgically sterile or post-menopausal.  Dipstick acceptable 
4 
Dipstick test per local procedures. If abnormal send sample to laboratory for microscopy. 
5 
This is only PRNT50 for the screening visit 
6 
Urine test.   
7 
SAE, CESI, NOCD and MAAE that occurred since completion of the Parent Study and screening for this study will be 
recorded. For subjects that received ARCT-021 in the Parent Study, these will be entered as SAE/CESI/MAAE in the EDC. 
For subjects that received placebo in the Parent Study these will be recorded as medical history. 
8 
Concomitant medications and procedures since completion of the Parent Study and screening for this study will be recorded 
for all subjects. 
9 
Subjects will be questioned about symptoms of COVID-19 and exposure to confirmed COVID-19 or confirmed SARS-
CoV-2 infection cases amongst household contacts, friends, work contacts and other contacts. 
 

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Subjects who Received Two Injections of ARCT-021 in Parent Study 
 
Study Week/Day 
D –28 to D –1 
Visit Window (Days) 
0 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Body Weight 
X 
Physical Exam1 
X 
Vital Signs2 
X 
SAE, CESI,  NOCD and MAAE3 
X 
Concomitant Medications and Procedures4 
X 
SARS-CoV-2 questioning5 
X 
 
1 
Full physical exam (assessment of heart, lungs, abdomen, eyes, ears, nose and throat, head and neck, musculoskeletal, 
lymphatic, injection site, dermatologic, neurologic, extremities)  
2 
BP, HR, RR, temp 
3 
SAE, CESI, NOCD and MAAE that occurred since completion of the Parent Study and screening for this study will be 
recorded 
4 
Concomitant medications and procedures since completion of the Parent Study and screening for this study will be recorded  
5 
Subjects will be questioned about symptoms of COVID-19 and exposure to confirmed COVID-19 or confirmed SARS-
CoV-2 infection cases amongst household contacts, friends, work contacts and other contacts. 
 
 

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2. Assessments After the Screening Period 
Subjects Not Receiving ARCT-021 in This Study 
 
 
Observation Period  
(40 Weeks) 
Study Week/Day 
W1 
D1 
W5 
D29 
W13 
D85 
W29 
D197 
W41 
D281/or 
Early 
Term* 
Visit Window (Days) 
0 
±7 
±7 
±14 
+14 
Physical Exam1 
X 
 
X 
X 
X 
Vital Signs2 
X 
 
X 
X 
X 
Archived plasma sample3 
X 
X 
X 
X 
X 
Archived serum sample3 
X 
X 
X 
X 
X 
Archived PBMC sample3 
X 
X 
X 
X 
X 
Immunogenicity 
 
X 
 
X 
X 
T-cell responses 
 
X 
 
X 
X 
SAE, CESI, NOCD and MAAE4 
X 
X 
X 
X 
X 
SARS-CoV-2 questioning5 
X 
X 
X 
X 
X 
Counselling about long-term follow-
up for SARS-CoV-2 infection6 
 
 
 
 
X 
*Subjects that terminate early should complete all procedures for Study Day 281 
 
1 
Abbreviated physical exam (assessment of vitals, heart, lungs, lymphatic, abdomen and symptom directed examination, if 
any symptoms) to be given during observation period to assess changes from screening.  
2 
BP, HR, RR, temp 
3 
Stored at -70 °C for follow up immunological assessments or exploration of laboratory findings and/or adverse events  
4 
SAE, CESI, NOCD and MAAEs will be recorded.  
5 
At each visit, subjects will be questioned about symptoms of COVID-19 and exposure to confirmed COVID-19 or 
confirmed SARS-CoV-2 infection cases amongst household contacts, friends, work contacts and other contacts. 
6 
Subjects that terminate from the study before completion will be told to inform the study site staff if they develop symptoms 
compatible with COVID-19 (Section 6.2.4) or a diagnosis of SARS-CoV-2 infection or COVID-19 for one year after 
vaccination so that they can be adequately followed up. 
 
 

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Subjects Receiving a Single Injection of ARCT-021 in This Study 
 
Study Drug 
Administration 
Post-Treatment Period  
(52 Weeks) 
Study Week/Day 
W1 
D1 
W2 
D8 
W3 
D15 
W5 
D29 
W9 D57 
W25 
D169 
W37 
D253 
W53 
D365/ 
Early 
Term* 
Visit Window (Days) 
0 
±1 
±1 
0 
±7 
±14 
±14 
+14 
Physical Exam1 
Xa 
X 
X 
X 
X 
X 
X 
X 
Vital Signs2 
Xa 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test3 
Xa 
 
 
 
 
 
 
 
Chemistry Panel 
Xa 
X 
X 
X 
 
 
 
 
Hematology 
Xa 
X 
X 
X 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
Urinalysis4 
Xa 
X 
 
X 
 
 
 
 
Archived plasma sample5 
Xa 
 
 
X 
X 
X 
X 
X 
Archived serum sample5 
Xa 
 
 
X 
X 
X 
X 
X 
Archived PBMC sample5 
Xa 
 
X 
X 
X 
X 
X 
X 
Immunogenicity 
Xa 
 
 
X 
X 
X 
 
X 
T-cell responses 
Xa 
 
X 
X 
 
X 
 
X 
Drug/Alcohol Screen6 
Xa 
 
 
 
 
 
 
 
Study Drug Administration 
X 
 
 
 
 
 
 
 
Review of symptom diary7 
 
X 
X 
 
 
 
 
 
Unsolicited AE 
X 
X 
X 
X 
 
 
 
 
SAE, CESI, NOCD and MAAE8 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications and 
Procedures 
X 
X 
X 
X 
 
 
 
 
SARS-CoV-2 questioning9 
X 
X 
X 
X 
X 
X 
X 
X 
Counselling about long-term 
follow-up for SARS-CoV-2 
infection10 
 
 
 
 
 
 
 
X 
*Subjects that terminate early should complete all procedures for Study Day 365 
 
1 
Full physical exam to be given at Day 1 and Day 365/Early Termination; abbreviated physical exam (assessment of vitals, 
heart, lungs, lymphatic, abdomen and symptom directed examination, if any symptoms) to be given during treatment and 
follow-up period to assess changes from screening. Injection site to be inspected at all visits after injection until resolution of 
local reactogenicity event(s). 
2 
BP, HR, RR, temp 
3 
Women who are not surgically sterile or post-menopausal.  Dipstick acceptable 
4 
Dipstick test per local procedures. If abnormal send sample to laboratory for microscopy. 
5 
Stored at -70 °C for follow up immunological assessments or exploration of laboratory findings and/or adverse events  
6 
Can be done at the site using established methods, e.g., a breathalyzer or urine test. 

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7 
Symptom diary to be reviewed on Day 8. If subject has any unresolved local or systemic reactogenic events then they should 
be instructed to continue to complete the symptom diary for a further week and the symptom diary should be reviewed again 
at Day 15. This review includes specifically asking about injection site and systemic (fever, fatigue, headache, chills, 
nausea, vomiting, diarrhoea, new or worsened myalgia, and new or worsened arthralgia) events. If not being completed for 
the second week after injection, then the symptom diary will be collected on Day 8; otherwise symptom diary to be collected 
on Day 15.  
8 
Only SAE, CESI, NOCD and MAAE will continue to be recorded after Day 29.  
9 
At each visit, subjects will be questioned about symptoms of COVID-19 and exposure to confirmed COVID-19 or 
confirmed SARS-CoV-2 infection cases amongst household contacts, friends, work contacts and other contacts. 
10 Subjects that terminate from the study before completion will be told to inform the study site staff if they develop symptoms 
compatible with COVID-19 (Section 6.2.4), or a diagnosis of SARS-CoV-2 infection or COVID-19 for one year after 
vaccination so that they can be adequately followed up. 
 
Time (time is in reference to Study Drug administration): 
a 
Pre-dose  
If not specifically labeled, “X” means anytime 
 
 

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APPENDIX 2: LIST OF LABORATORY ANALYTES 
 
 
 

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Appendix 2: List of Laboratory Analytes 
 
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  
Coagulation Panel 
• aPTT 
• PT 
• INR 
Other Screening Tests 
• Serum βhCG 
• Drug/Alcohol screen 
• HbA1c 
 
Urine Dipstick Analysis 
• Color 
• Appearance 
• Specific gravity 
• pH 
• Protein 
• Blood 
• Ketones 
• Urobilinogen 
• Glucose 
• Bilirubin 
• Leukocyte esterase 
• Nitrite 
• Microscopic 
examination1 
Urine Laboratory Analysis 
• UPCR 
 
Immunogenicity 
• SARS CoV-2 
neutralising antibody 
titer by PRNT and/or 
pseudovirus 
neutralization test and or 
sVNT and/or 
microneutralization test 
• Anti-S full length protein 
and anti-RBD IgG 
• T-cell surface markers 
(CD3, CD4, CD8, 
CD45RA, CCR7) 
T-cell intracellular 
cytokines (IFN-γ, IL-2, 
TNFα, IL-4) 
SARS-CoV-2 
Confirmation 
• PCR2 
• Anti-nucleocapsid 
antibody2, 3 
 
 
1 
Will be performed on abnormal findings unless otherwise specified 
2 
May be performed in local lab 
3 
May be performed on retained serum samples if required to confirm SARS-CoV-2 infection 
 

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APPENDIX 3: LIST OF EXCLUSIONARY AUTOIMMUNE DISEASES 
 
 
 

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Appendix 3: List of Exclusionary Autoimmune Diseases  
The following list details the autoimmune diseases listed by the American Autoimmune Related 
Disease Association (https://www.aarda.org/diseaselist).  These autoimmune diseases represent 
exclusion criteria for the purpose of eligibility to participate in this study. 
• Achalasia 
• Addison’s disease 
• Adult Still's disease 
• Agammaglobulinemia 
• Alopecia areata 
• Amyloidosis 
• Ankylosing spondylitis 
• Anti-GBM/Anti-TBM nephritis 
• Antiphospholipid syndrome 
• Autoimmune angioedema 
• Autoimmune dysautonomia 
• Autoimmune encephalomyelitis 
• Autoimmune hepatitis 
• Autoimmune inner ear disease (AIED) 
• Autoimmune myocarditis 
• Autoimmune oophoritis 
• Autoimmune orchitis 
• Autoimmune pancreatitis 
• Autoimmune retinopathy 
• Autoimmune urticaria 
• Axonal & neuronal neuropathy (AMAN) 
• Baló disease 
• Behcet’s disease 
• Benign mucosal pemphigoid 
• Bullous pemphigoid 
• Castleman disease (CD) 
• Celiac disease 
• Chagas disease 
• Chronic inflammatory demyelinating polyneuropathy (CIDP) 
• Chronic recurrent multifocal osteomyelitis (CRMO) 
• Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA) 
• Cicatricial pemphigoid 
• Cogan’s syndrome 
• Cold agglutinin disease 
• Congenital heart block 
• Coxsackie myocarditis 
• CREST syndrome 
• Crohn’s disease 
• Dermatitis herpetiformis 

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• Dermatomyositis 
• Devic’s disease (neuromyelitis optica) 
• Discoid lupus 
• Dressler’s syndrome 
• Endometriosis 
• Eosinophilic esophagitis (EoE) 
• Eosinophilic fasciitis 
• Erythema nodosum 
• Essential mixed cryoglobulinemia 
• Evans syndrome 
• Fibromyalgia 
• Fibrosing alveolitis 
• Giant cell arteritis (temporal arteritis) 
• Giant cell myocarditis 
• Glomerulonephritis 
• Goodpasture’s syndrome 
• Granulomatosis with Polyangiitis 
• Graves’ disease 
• Guillain-Barre syndrome 
• Hashimoto’s thyroiditis 
• Hemolytic anemia 
• Henoch-Schonlein purpura (HSP) 
• Herpes gestationis or pemphigoid gestationis (PG) 
• Hidradenitis Suppurativa (HS) (Acne Inversa) 
• Hypogammalglobulinemia 
• IgA Nephropathy 
• IgG4-related sclerosing disease 
• Immune thrombocytopenic purpura (ITP) 
• Inclusion body myositis (IBM) 
• Interstitial cystitis (IC) 
• Juvenile arthritis 
• Juvenile diabetes (Type 1 diabetes) 
• Juvenile myositis (JM) 
• Kawasaki disease 
• Lambert-Eaton syndrome 
• Leukocytoclastic vasculitis 
• Lichen planus 
• Lichen sclerosus 
• Ligneous conjunctivitis 
• Linear IgA disease (LAD) 
• Lupus 
• Lyme disease chronic 
• Meniere’s disease 

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• Microscopic polyangiitis (MPA) 
• Mixed connective tissue disease (MCTD) 
• Mooren’s ulcer 
• Mucha-Habermann disease 
• Multifocal Motor Neuropathy (MMN) or MMNCB 
• Multiple sclerosis 
• Myasthenia gravis 
• Myositis 
• Narcolepsy 
• Neonatal Lupus 
• Neuromyelitis optica 
• Neutropenia 
• Ocular cicatricial pemphigoid 
• Optic neuritis 
• Palindromic rheumatism (PR) 
• PANDAS 
• Paraneoplastic cerebellar degeneration (PCD) 
• Paroxysmal nocturnal hemoglobinuria (PNH) 
• Parry Romberg syndrome 
• Pars planitis (peripheral uveitis) 
• Parsonage-Turner syndrome 
• Pemphigus 
• Peripheral neuropathy 
• Perivenous encephalomyelitis 
• Pernicious anemia (PA) 
• POEMS syndrome 
• Polyarteritis nodosa 
• Polyglandular syndromes type I, II, III 
• Polymyalgia rheumatica 
• Polymyositis 
• Postmyocardial infarction syndrome 
• Postpericardiotomy syndrome 
• Primary biliary cirrhosis 
• Primary sclerosing cholangitis 
• Progesterone dermatitis 
• Psoriasis 
• Psoriatic arthritis 
• Pure red cell aplasia (PRCA) 
• Pyoderma gangrenosum 
• Raynaud’s phenomenon 
• Reactive Arthritis 
• Reflex sympathetic dystrophy 
• Relapsing polychondritis 

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• Restless legs syndrome (RLS) 
• Retroperitoneal fibrosis 
• Rheumatic fever 
• Rheumatoid arthritis 
• Sarcoidosis 
• Schmidt syndrome 
• Scleritis 
• Scleroderma 
• Sjögren’s syndrome 
• Sperm & testicular autoimmunity 
• Stiff person syndrome (SPS) 
• Subacute bacterial endocarditis (SBE) 
• Susac’s syndrome 
• Sympathetic ophthalmia (SO) 
• Takayasu’s arteritis 
• Temporal arteritis/Giant cell arteritis 
• Thrombocytopenic purpura (TTP) 
• Thyroid eye disease (TED) 
• Tolosa-Hunt syndrome (THS) 
• Transverse myelitis 
• Type 1 diabetes 
• Ulcerative colitis (UC) 
• Undifferentiated connective tissue disease (UCTD) 
• Uveitis 
• Vasculitis 
• Vitiligo 
• Vogt-Koyanagi-Harada Disease 
 
 
 

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APPENDIX 4: PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
 

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Appendix 4:  Protocol Amendment 1 Summary of Changes 
In addition to the changes listed below, this amendment includes administrative changes for 
consistency of language and changes to the Synopsis for consistency with the changes outlined 
below. 
• Updated Version number, Date, and Amendment 
• Signatory updated from 
 
• Protocol Synopsis: 
o Study phase updated to 2a correcting typographical error 
o Study Population: Exclusion criterion 12: removed ‘each’ as multiple vaccinations is not 
applicable 
o Study Drug Dosage and Administration: Removed reference to 2 injection vaccinations 
and added 30 minute observation period following vaccination 
o Rationale for Dose and Schedule Selection: updated for single dose regimen based on 
study results observed in ARCT-021-01 Parent Study  
o Adjustment of Dose: removed reference to stopping rules for subsequent doses as it is no 
longer applicable 
o Study Visit Schedule and Procedures: removed reference to two injection cohort as it is 
no longer applicable  
o Study Visit Schedule and Procedures: clarified definition of subjects receiving ARCT-
021 vs receiving no injection  
o Study Visit Schedule and Procedures: clarified window for recording AEs in symptom 
diary  
o Primary Endpoint: provided additional details to primary endpoint for clarity 
o Statistical Considerations: Safety and Tolerability – included collection of any CESI, 
NOCDs following completion of Parent Study and Screening visit of this study 
• Glossary 
o Added ‘MAAE’ and ‘NOCD’ 
o Clarified definition of ‘enrolled’ 
• Section 1.2.1: provided additional details to primary endpoint to clarify major safety 
categories for analysis and to remove minor endpoints that fall under these categories 
• Section 2.1: updated current status of approved vaccine availability 
• Section 2.3: updated dosing rationale and revised dose regimen to single dose of 7.5 ug based 
on study results observed in ARCT-021-01 Parent Study 
• Section 3.2, 8.3: updated study design to remove reference to 2 injection cohort and added 
precautionary safety measures including a post-dose observation period 
• Section 3.5: clarified number of study centers  

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• Section 3.7, 3.8.2, 3.8.3: removed reference to subjects receiving 2 injections as it no longer 
applies 
• Section 3.8.1: added definition of screen failure 
• Section 3.8.2: reduced observation period from 1 hour to 30 minutes based on 
standardization of safety procedures across studies 
• Section 5.2: Exclusion criterion 12 - removed ‘each’ as multiple vaccinations is not 
applicable 
• Section 6.2 and 6.2.1: Clarified the collection of SAEs, NOCDs, CESIs and MAAEs and 
local and systemic solicited AEs 
• Section 8.2: clarified use of study drug must be within 6 hour of first puncture of the drug 
vial 
• Section 8.2: removed non-applicable dose levels (1.0, 3.0 and 5.0 µg) from Table 4 
• Section 8.6: clarified stopping rules for treatment are no longer applicable for single dose 
administration resulting in the removal of sections 8.6.1, 8.6.2, 8.6.3 
• Section 8.9.1: Disallowed Concomitant Therapy streamlined to focus on relevant therapies 
that may interfere with the evaluation of safety and immunogenicity and to remove 
unnecessary restrictions in a Phase 2 study 
• Section 9.3.4: Addition of New Onset Chronic Disease (NOCD) 
• Section 9.3.7: clarified Clinical Events of Special Interest definition 
• Section 9.4.1: added duration for follow up of SAE to resolution for clarity 
• Section 9.4.3: clarified reporting window for non-serious AEs 
• Section 9.4.4.6: Sponsor Follow up updated to include CESIs and remove follow up of 
pregnancy cases which are addressed in section 9.5.4. 
• Section 9.5.4: clarified pregnancy reporting and follow up for female subjects or partners of 
male subjects who received ARCT-021 only 
• Section 9.5.5: clarified reporting requirements for CESIs 
• Section 10.2, 10.3: added Immunogenicity population definition and elaborated on analyses 
plans; added Table 5: Grouping of Cohorts and Timepoints Across Studies ARCT-021-01 
and ARCT-021-02 for Analysis 
• Section 10.5.3: Safety analysis section updated to clarify the process for evaluating 
participants who received ARCT-021 vaccine in either the Parent study or in this study. 
• Section 10.5.4: Immunogenicity Analyses updated to clarify the evaluation of participants 
who received ARCT-021 vaccine in either the Parent study or in this study. 
• Section 10.5.5. added CESI analyses 
• Appendix 1: Schedule of Assessments 

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o Screening: updated footnotes to include body systems for full physical exam, 
Immunogenicity sample and recording of SAE, CESI, NOCD and MAAE for 
clarification 
o Subjects Not Receiving an Injection: removed measurement of body weight after 
Screening visit and clarified collection of SAE, CESI, NOCD and MAAE 
o Subjects Receiving a Single Injection of ARCT-021 in This Study: corrected Week 13 to 
Week 9, removed measurement of body weight after Screening visit,  clarified collection 
of SAE, CESI, NOCD and MAAE 
o Removed schedule of assessment for ‘Subjects Receiving Two Injections of ARCT-021 
in This Study as it is no longer applicable 
o For subjects receiving ARCT-021 injection, added: 
▪ HbA1c and Coagulation at Day 1 
▪ Lymphatic exam to  abbreviated physical exam 
• Appendix 2: List of Laboratory Analytes – updated to confirm which analytes are included in 
cell mediated immunity tests. 
• Appendix 4: Summary of Protocol Changes added for Amendment 1