A Phase 1/2 Randomized, Placebo-controlled, Observer-blind Trial to Assess the Safety and Immunogenicity of COVIVAC Vaccine Produced by IVAC in Adults Aged 18-60 Years in Vietnam
Phase: PHASE1
Conditions: COVID-19 Disease, SARS Pneumonia, Pneumonia, Viral, COVID-19 Vaccine
Sponsor: Institute of Vaccines and Medical Biologicals, Vietnam

A Phase 1/2 Randomized, Placebo-controlled, Observer-blind Trial
to Assess the Safety and Immunogenicity of COVIVAC Vaccine
produced by IVAC in Adults Aged 18-75 Years in Vietnam
Trial Registration: Registration in progress on clinicaltrials.gov
MOH Study Number (To-be-assigned by MOH)
CONFIDENTIAL
Version 1,0
February 05, 2021
Sponsored by:
Institute of Vaccines and Medical Biologicals (IVAC)
Nha Trang, Viet Nam
Principal Investigator:
Prof. Dang Duc Anh and Associate Prof. Vu Dinh Thiem
Ha Noi, Vietnam
Confidentiality Statement
This document contains confidential information that must not be disclosed to anyone or used
except as authorized by IVAC

Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
TABLE OF CONTENTS
TABLE OF CONTENTS........................................................................................................................2
LIST OF ABBREVIATIONS AND ACRONYMS ...............................................................................7
STATEMENT OF COMPLIANCE......................................................................................................10
PROTOCOL SIGNATURE PAGE ......................................................................................................11
KEY ROLES AND CONTACT INFORMATION..............................................................................12
1.     PROTOCOL SUMMARY............................................................................................................13
2.     BACKGROUND AND RATIONALE.........................................................................................19
2.1.     Burden of Disease ..................................................................................................................19
2.2.     Pathogen and Clinical Disease...............................................................................................19
2.3.     Transmission and Infectivity..................................................................................................20
2.4.     Vaccine Development ............................................................................................................20
2.5.     Risk of Immune Enhancement...............................................................................................21
2.6.     Introduction to COVIVAC Vaccine.......................................................................................22
2.7.     Summary of Nonclinical Studies............................................................................................23
2.8.     Study Design Rationale..........................................................................................................28
2.8.1.     Justification for Dose......................................................................................................29
2.9.     Overall Clinical Development Strategy .................................................................................30
3.     HYPOTHESES, OBJECTIVES AND ENDPOINTS...................................................................30
3.1.     Study Hypotheses...................................................................................................................30
3.1.1.     Primary Hypothesis:........................................................................................................30
3.1.2.     Secondary Hypothesis:....................................................................................................30
3.2.     Study Objectives ....................................................................................................................30
3.2.1.     Primary Objectives: ........................................................................................................30
3.2.2.     Secondary Objectives: ....................................................................................................31
3.2.3.     Exploratory Objectives: ..................................................................................................31
3.3.     Study Endpoints .....................................................................................................................32
3.3.1.     Primary Endpoints: .........................................................................................................32
3.3.2.     Secondary Endpoints: .....................................................................................................32
3.3.3.     Exploratory Endpoints:...................................................................................................33
4.     STUDY DESIGN..........................................................................................................................33
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
5.     STUDY POPULATION...............................................................................................................36
5.1.     Study Population ....................................................................................................................36
5.2.     Clinical Trial Site ...................................................................................................................36
5.3.     Inclusion Criteria....................................................................................................................38
5.4.     Exclusion Criteria...................................................................................................................38
5.5.     Screen Failures.......................................................................................................................40
6.     STUDY PRODUCT......................................................................................................................40
6.1.     Product Descriptions ..............................................................................................................40
6.2.     Stability and Storage ..............................................................................................................40
6.3.     Preparation and Administration .............................................................................................41
6.4.     Accountability and Disposal ..................................................................................................41
7.     STUDY PROCEDURES ..............................................................................................................42
7.1.     Recruitment............................................................................................................................42
7.1.1.     Initial and Continuing Informed Consent .......................................................................43
7.2.     Study Visits ............................................................................................................................43
7.2.1.     Screening (Day -42 to Day 1).........................................................................................45
7.2.2.     Visit 1 (Day 1) ................................................................................................................45
7.2.3.     Visit 2 (Day 8) and Visit 4 (Day 36)...............................................................................47
7.2.4.     Visit 3 (Day 29) ..............................................................................................................48
7.2.5.     Visit 5 (Day 43) ..............................................................................................................49
7.2.6.     Visit 6 (Day 57) ..............................................................................................................49
7.2.7.     Visit 7 (Day 197) ............................................................................................................50
7.2.8.     Visit 8 (Day 365, EOS)...................................................................................................50
7.2.9.     Unscheduled Contacts and Visits ...................................................................................51
7.3.     Subject Discontinuation .........................................................................................................51
7.4.     Concomitant Medications ......................................................................................................52
7.5.     Emergency Unblinding Procedure .........................................................................................52
7.6.     Management of Pregnancy.....................................................................................................53
7.7.     Clinical Procedures ................................................................................................................53
8.     SAFETY ASSESSMENT AND REPORTING............................................................................53
8.1.     Collection of Safety Events....................................................................................................54
8.2.     Definitions..............................................................................................................................54
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
8.2.1.
8.2.2.
8.2.3.
8.2.4.
8.2.5.
8.2.6.
8.2.7.
8.2.8.
8.2.9.
8.2.10.
8.2.11.
Adverse Event.................................................................................................................54
Solicited Adverse Event..................................................................................................54
Unsolicited Adverse Event .............................................................................................55
Medically-Attended Adverse Event................................................................................55
Adverse Event of Special Interest...................................................................................55
Protocol-Related Adverse Event.....................................................................................55
Treatment-Emergent Adverse Event...............................................................................55
Serious Adverse Event....................................................................................................55
Severity (Intensity) of Adverse Event.............................................................................56
Causal Relationship of an Adverse Event...................................................................57
Assessment of Outcome of Adverse Event.................................................................57
8.3.     Adverse Event Recording and Reporting...............................................................................57
8.4.     Serious Adverse Event Reporting ..........................................................................................58
8.5.     Unanticipated Problems .........................................................................................................58
9.     SAFETY MONITORING.............................................................................................................58
9.1.     Protocol Safety Review Team................................................................................................58
9.2.     Data and Safety Monitoring Board ........................................................................................59
9.3.     Pause Rules ............................................................................................................................59
9.4.     Protocol Deviation..................................................................................................................60
10.      STATISTICAL CONSIDERATIONS.......................................................................................60
10.1.       Overview and General Considerations...............................................................................60
10.2.       Randomization Procedures.................................................................................................61
10.3.       Sample Size and Power ......................................................................................................61
10.4.       Definitions of Populations to be Analyzed.........................................................................63
10.4.1.
10.4.2.
10.4.3.
10.4.4.
10.4.5.
Enrolled Population.....................................................................................................63
Exposed Population.....................................................................................................63
Safety Analysis Population .........................................................................................63
Full Analysis Population.............................................................................................63
Per Protocol Population...............................................................................................64
10.5.       Analysis Sequence and Analytical Methodology...............................................................64
10.5.1.
10.5.2.
Analysis of Demographic and Baseline Characteristics .............................................64
Analysis of Primary Objectives ..................................................................................65
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
10.5.3.
10.5.4.
Analysis of Secondary Objectives...............................................................................66
Analysis of Exploratory Objectives ............................................................................66
10.6.       Multiplicity.........................................................................................................................67
10.7.       Handling of Subject Discontinuations and Missing Data...................................................67
11.      LABORATORY EVALUATIONS...........................................................................................67
11.1.       Blood Sample Collection, Distribution, and Storage .........................................................67
11.2.       Safety Clinical Laboratory Assays .....................................................................................68
11.3.       Immunological Assays (Secondary Objectives).................................................................68
11.4.       Microbiological Assays ......................................................................................................68
11.5.       Assay Qualification, Standardization, and Validation........................................................69
11.6.       Biohazard Containment......................................................................................................69
12.      DATA MANAGEMENT...........................................................................................................69
12.1.       Case Report Form Development and Completion..............................................................69
12.2.       Record Archival..................................................................................................................70
12.2.1.
12.2.2.
Archiving Data at Study Site.......................................................................................70
Data Storage and Archival ..........................................................................................70
12.3.       Posting of Information on Clinicaltrials.gov ......................................................................71
12.4.       Confidentiality....................................................................................................................71
12.5.       Publication..........................................................................................................................71
13.      QUALITY ASSURANCE AND QUALITY CONTROL.........................................................71
13.1.       General Considerations.......................................................................................................71
13.2.       External Monitoring ...........................................................................................................71
13.3.       Independent Auditing .........................................................................................................72
13.4.       Regulatory Agency Auditing..............................................................................................72
14.      OBLIGATIONS AND ROLES OF THE SPONSOR, PI, AND STUDY PERSONNEL.........72
15.      ETHICAL CONSIDERATIONS AND INFORMED CONSENT............................................73
15.1.       Ethical Review....................................................................................................................73
15.2.       Informed Consent Process..................................................................................................74
15.3.       Study-Related Injury...........................................................................................................74
15.4.       Risk/Benefit........................................................................................................................74
15.5.       Subject Confidentiality.......................................................................................................75
15.6.       Reimbursement...................................................................................................................76
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
15.7.       Storage of Specimens .........................................................................................................76
16.      APPENDICES ...........................................................................................................................77
16.1.       Appendix 1: Solicited Injection Site and Systemic Reactions Toxicity Grading Table....77
16.2.       Appendix 2: Vital Signs Toxicity Grading Table..............................................................79
16.3.       Appendix 3: Serum and Hematology Toxicity Grading Table...........................................80
16.4.       Appendix 4: Potential Immune-Mediated Medical Conditions (PIMMC).........................81
16.5.       Appendix 5: Adverse Events Specific to COVID-19 Disease ...........................................83
16.6.       Appendix 6: Template of interim study report for transition to Phase 2............................84
16.7.       Appendix 7: References......................................................................................................85
List of tables and figures in the protocol:
-
Table 1. Summary of preclinical studies
-
Table 2. COVIVAC Treatment Groups (Toxicology Study)
-
Table 3. Treatment Groups
-
Table 4. Phase 1 Dose Escalation Steps
-
Table 5. Schedule of Study Visits and Procedures – Phase 1 and Phase 2
-
Table 6.
Severity Grading
-
Table 7. Probability to observe at least one serious or severe adverse event by sample size and
underlying event rate.
-
Table 8. Power to select the candidate with the highest true mean to progress to second phase and
overall for the Phase 1/2 overall by minimum fold-difference between the highest candidate mean
and the other means, assuming log10 variability of 0.5.
-
Table 9.
Blood Volume Requirements
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
LIST OF ABBREVIATIONS AND ACRONYMS
ABBREVIATION/
ACRONYM
Ab
ACE2
ADCC
ADE
ADR
AE
AESI
ALT
ANCA
ARDS
AST
ATC
BMI
BPL
C
CAPA
CBER
CDC
CI
Cm
CMI
COVID-19
CREST
CRF
CRO
CSR
D
DSMB
EC
EDC
ELISA
ELISpot
ELU
EOS
ER
EUA
F
FDA
FIPV
G
GCP
GLP
GMC
GMFR
GMP
GMT
DEFINITION
antibody
angiotensin-converting enzyme 2
antibody-dependent cellular cytotoxicity
antibody-dependent enhancement
adverse drug reaction
adverse event
adverse event of special interest
alanine transaminase
anti-neutrophil cytoplasmic antibody
acute respiratory distress syndrome
aspartate transaminase
anatomical therapeutic chemical
Body Mass Index
beta-propiolactone
Celsius
corrective action and preventive action
Center for Biologics Evaluation and Research
Centers for Disease Control and Prevention
confidence interval
Centimeter
cell-mediated immunity
coronavirus disease 2019 (disease caused by SARS-CoV-2)
calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly,
and telangiectasia
case report form
contract research organization
clinical study report
day(s)
Data and Safety Monitoring Board
Ethics Committee
electronic data capture
enzyme-linked immunosorbent assay
enzyme-linked immunospot
ELISA Units
end of study
Emergency Room
Emergency Use Authorization
Fahrenheit
US Food and Drug Administration
feline infectious peritonitis virus
Group
good clinical practice
good laboratory practice
geometric mean concentration
geometric mean fold rise
good manufacturing practice
geometric mean titer
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Study Protocol:
HBsAg
hCG
HCV Ab
Hgb
HIV 1/2 Ab
HMU
HN
HXP
IATA
IB
ICF
ICH
ID
IIV
IgG
IL
IM
IME
IN
INF
ISO
IP
ISMMS
IV
IVAC
IWRS
LMIC
LSLV
MAAE
MedDRA
MERS-CoV
MIS-C
mm
MoH
N
NAb
NDV
NICVB
NIHE
NT50
NT80
NTF
PBMC
PBS
PE
PI
PIMMC
Plt
PNA
PPE
Version: 1.0 dated February 05, 2021_ IVAC
hepatitis B surface antigen
serum human gonadotrophic hormone
hepatitis C virus antibody
hemoglobin
human immunodeficiency virus 1 and 2 antibody
Hanoi Medical University
hemagglutinin-neuraminidase
HexaPro
International Air Transport Association
Investigator’s Brochure
informed consent form
International Conference on Harmonisation
identification
inactivated influenza virus vaccine
immunoglobulin G
interleukin
intramuscular
important medical event
intranasal
interferon
International Organization for Standardization
investigational product
Icahn School of Medicine at Mount Sinai
intravenous
Institute of Vaccines and Medical Biologicals
Interactive Web Response System
low- and middle-income country
last subject last visit
medically-attended adverse event
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome coronavirus
multisystem inflammatory syndrome in children
millimeter
Ministry of Health
nucleocapsid
neutralizing antibody
Newcastle disease virus
National Institute for Control of Vaccines and Biological
National Institute of Hygiene and Epidemiology
50% neutralizing antibody titer
80% neutralizing antibody titer
note to file
peripheral blood mononuclear cell
phosphate-buffered saline
physical examination
principal investigator (the term is used throughout to indicate PI or
designee)
potential immune-mediated medical conditions
platelet
pseudovirus neutralization assay
personal protective equipment
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Study Protocol:
PP IMM
PSRT
qPCR
R
R0
RLU
RNA
RSV
RT-PCR
S
SAE
SAP
SARS-CoV
SARS-CoV-2
SC
SOC
SOP
SSP
SUSAR
TEAE
TEN
Th
TLR-9
TMF
US
USP
V
WBC
WHO
WMA
WOCBP
WT
Version: 1.0 dated February 05, 2021_ IVAC
per protocol immunogenicity population
Protocol Safety Review Team
quantitative polymerase chain reaction
recovery
reproduction number
relative luminescence units
ribonucleic acid
respiratory syncytial virus
reverse transcription polymerase chain reaction
Spike
serious adverse event
statistical analysis plan
severe acute respiratory syndrome coronavirus
severe acute respiratory syndrome coronavirus 2
subcutaneous
system organ class
standard operating procedure
study-specific procedure
suspected unexpected serious adverse reaction
treatment-emergent adverse event
toxic epidermal necrolysis
T-helper cell
toll-like receptor 9
trial master file
United States
United States Pharmacopeia
Visit number (e.g. V1 = first study visit)
white blood cell
World Health Organization
World Medical Association
Women of childbearing potential
wild-type
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
STATEMENT OF COMPLIANCE
I am Principal Investigator of the study “A Phase 1/2 Randomized, Placebo-controlled, Observer-
blind Trial to Assess the Safety and Immunogenicity of COVIVAC Vaccine produced by IVAC in
Adults Aged 18-75 Years in Vietnam”; signing below ensures that the study will be carried out on
schedule, according to the content of approved protocol, and in accordance with Good Clinical
Practice (GCP) as required by applicable rules of Vietnam: Decision No. 799/2008/QD-BYT dated
07 Mar, 2008, on “Guidance on Good Clinical Practice,” Circular No. 29/2018/TT-BYT dated 29
Oct, 2018 on “Regulation on Clinical Trial” and the Circular No. 32/2018/TT/BYT dated 12 Nov,
2018 on “Regulation on Medical Product Registration and Input Materials,” Decision 1248/QD BYT
dated 11 Jan, 2013, on the National Guidelines on ethical issues in biomedical research; Circular
04/2020/TT-BYT dated 05 Mar, 2020 on the Establishment, Functions and Responsibilities of
Biomedical Ethics Committee, and Dispatch No 62/QĐ-K2ĐT dated 02 Jun, 2017, on the guidelines
on recording/reporting SAEs in a clinical trial. And the Decision No 3659/QĐ-BYT dated 21 Aug,
2020 on “Guidance on Research, Clinical Trial, Licensing and Use of COVID-19 vaccine”.
The study informed consent documents will embody the elements of consent as described in the
Declaration of Helsinki.
The study will also be carried out in accordance with Good Clinical Practice (GCP) as required by the
following:
·
International Conference on Harmonisation (ICH) Guidance for GCP E6(R2)
·
World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Research
Involving Human Subjects (Oct 2013 or subsequent amendments)
All key personnel (all individuals responsible for the design and conduct of this study) have
completed Human Subjects Protection Training and ICH-GCP training prior to interaction with any
participants or to have access to their confidential study data.
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
PROTOCOL SIGNATURE PAGE
The signature below constitutes the approval of this protocol and the attachments, and provides the
necessary assurances that this trial will be conducted according to all stipulations of the protocol,
including all statements regarding confidentiality, and according to local legal and regulatory
requirements and ICH-GCP guidelines as outlined in the ‘Statement of Compliance.’
Site Investigator:
Signed:
Date:
Name: Associate Prof. Vu Dinh Thiem, MD
Title: Director of Clinical Trial Center, NIHE
Signed:
Date:
Name: Prof. Dang Duc Anh, MD
Title: Director of NIHE
Sponsor’s Representative:
Signed:
Date:
Name:
Title:
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
KEY ROLES AND CONTACT INFORMATION
Sponsor
Clinical Trial Center
Principal Investigator
Co- Principal Investigator
Vaccine Manufacturer
Contract Research Organization for
clinical monitoring
Contract Research Organization for
data management
Clinical site
Immunology Laboratory
Clinical Laboratory
Microbiology Laboratory
Ethics Committees
National Regulatory Agency
Sponsor Medical Monitor:
Technical support
Institute of Vaccines and Medical Biologicals (IVAC)
National Institute of Hygiene and Epidemiology (NIHE)
Prof. Dang Duc Anh
Associate Prof. Vu Dinh Thiem, MD
IVAC
Vietstar
Local CRO with experience and collaboration with
international CRO on data management will be contracted in
order to meet the requirements in the ICH E6-R2 and
electronic data security.
Hanoi Medical University (HMU) for Phase 1.
Vu Thu District Hospital, Thai Binh province for Phase 2
Nexelis
525 Cartier West Blvd
Laval, Quebec
Canada, H7V 3S8
Clinical lab of HMU’s Hospital.
No 1, Ton That Tung Street, Hanoi, Vietnam
Laboratory of virus transmitted from animal to human, Virus
Lab Department of NIHE
NIHE’s IRB and Independent Ethics Committee of MoH
Ministry of Health (MoH) in Vietnam
Associate Prof. Le Van Be
PATH Vietnam office
11th Floor, Hanoi Towers
49 Hai Ba Trung
Hoan Kiem District
Hanoi, Vietnam
PATH US office
2201 Westlake Avenue, Suite 200.
Seattle, WA 98121, USA
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
1. PROTOCOL SUMMARY
TITLE
STUDY NUMBER
PROJECT PHASE
INVESTIGATIONAL
PRODUCT(S)
STUDY HYPOTHESES
A Phase 1/2 Randomized, Placebo-controlled, Observer-blind Trial to Assess
the Safety and Immunogenicity of COVIVAC Vaccine produced by IVAC in
Adults Aged 18-75 Years in Vietnam
Phase 1/2
Investigational Vaccine:
Inactivated Newcastle Disease Virus (NDV) chimera expressing a trimeric pre-
fusion form of the SARS-CoV-2 Spike (S) protein that contains six proline
mutations (HexaPro, HXP); for intramuscular (IM) administration. One
formulation of COVIVAC evaluated in this study includes 1.5 mg of the adjuvant
CpG 1018 (a 22-mer phosphorothioate-linked oligodeoxynucleotide).
Placebo:
Phosphate-buffered saline (PBS); for IM administration
Safety, Tolerability:
·
COVIVAC will have an acceptable safety profile and be well-tolerated at all
dose levels when administered as a two-dose regimen either without adjuvant
(at 1 µg, 3 µg, and 10 µg of S protein per 0.5 ml dose), or with the adjuvant
CpG 1018 (at 1 µg of S protein per 0.5 ml dose).
Immunogenicity:
·
COVIVAC will elicit a measurable and dose-dependent neutralizing antibody
response.
STUDY OBJECTIVES
– PHASE 1
Primary Objective:
Safety, Tolerability:
1. To assess the safety and tolerability of each of four formulations of COVIVAC
(at 1, 3 and 10 µg without adjuvant; and at 1 µg with CpG 1018) after the first
and second dose of a two-dose regimen administered at a 28-day interval to
adults aged 18-59 years
Secondary Objectives:
Immunogenicity:
1. To assess the functional (neutralizing) humoral immune response elicited by
each formulation of NDV-HXP-S, as measured by a SARS CoV-2 pseudovirus-
based neutralization assay (PNA), at baseline, 28 days after the first
vaccination, and 14 days after the second vaccination (to inform the selection of
two formulations for evaluation in Phase 2), and at 6 months and 12 months
after the second vaccination, in adults aged 18-59 years
2. To assess the Immunoglobulin G (IgG) immune response elicited by each
formulation of COVIVAC against the S protein of SARS-CoV-2, as measured
by enzyme-linked immunosorbent assay (ELISA), at baseline, 28 days after the
first vaccination, and 14 days, 6 months and 12 months after the second
vaccination, in adults aged 18-59 years
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
STUDY OBJECTIVES
– PHASE 2
Primary Objective:
Safety, Tolerability:
1. To assess the safety and tolerability of two selected formulations of COVIVAC
(based on Phase 1 safety and immunogenicity) after the first and second dose of
a two-dose regimen administered at a 28-day interval to adults aged 18-75 years
2. To assess the safety and tolerability of two selected formulations of COVIVAC
after the first and second dose of a two-dose regimen administered at a 28-day
interval to adults aged 18-59 years and 60-75 years
Secondary Objectives:
Immunogenicity:
1. To assess the functional (neutralizing) humoral immune response elicited by
each of two selected COVIVAC formulations, as measured by PNA, at
baseline, 28 days after the first vaccination, and 14 days, 6 months and 12
months after the second vaccination, in adults aged 18-75 years
2. To assess the functional (neutralizing) humoral immune response elicited by
each of two selected COVIVAC formulations, as measured by PNA, at
baseline, 28 days after the first vaccination, and 14 days, 6 months and 12
months after the second vaccination, in adults aged 18-59 years and 60-75 years
3. To assess the IgG immune response elicited by each of two selected COVIVAC
formulations against the S protein of SARS-CoV-2, as measured by ELISA, at
baseline, 28 days after the first vaccination, and 14 days, 6 months and 12
months after the second vaccination, in adults aged 18-75 years
4. To assess the IgG immune response elicited by each of two selected COVIVAC
formulations against the S protein of SARS-CoV-2, as measured by ELISA, at
baseline, 28 days after the first vaccination, and 14 days, 6 months and 12
months after the second vaccination, in adults aged 18-59 years and 60-75 years
Exploratory Objectives (Immunogenicity):
1. To assess the S protein-specific T cell response elicited by each of two selected
COVIVAC formulations, as measured by enzyme-linked immunospot assay
(ELISpot), at baseline, and 14 days and 6 months after the second vaccination,
in adults aged 18-75 (subset of subjects)
2. To assess the S protein-specific T cell response elicited by each of two selected
COVIVAC formulations, as measured by ELISpot, at baseline, and 14 days and
6 months after the second vaccination, in adults aged 18-59 years and 60-75
years (subsets of subjects)
3. To assess the IgG immune response elicited by each of two selected COVIVAC
formulations against the hemagglutinin-neuraminidase (HN) protein of NDV,
as measured by ELISA, at baseline, 28 days after the first vaccination, and 14
days and 12 months after the second vaccination, in adults aged 18-59 years
STUDY ENDPOINTS        Primary Endpoints:
Safety, Tolerability:
·
Number and severity of solicited local and systemic adverse events (AEs)
during the first 7 days after each vaccination
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
·
Number, severity, and relatedness of clinically significant hematological and
biochemical measurements at 7 days post each vaccination
·
Number, severity and relatedness of all unsolicited AEs during the first 28 days
after each vaccination
·
Number, severity and relatedness of serious adverse events (SAEs) throughout
the entire study period
·
Number, severity and relatedness of medically-attended AEs (MAAEs)
throughout the entire study period
·
Number, severity and relatedness of adverse events of special interest (AESI)
throughout the entire study period, including AESI relevant to COVID-19, and
potential immune-mediated medical conditions (PIMMC)
Secondary Endpoints:
Immunogenicity:
For Secondary Objective 1 (Phase 1), and Objectives 1 and 2 (Phase 2):
·
50% and 80% neutralizing antibody (NT50 and NT80) geometric mean titer
(GMT) against SARS-CoV-2 pseudovirus at 28 days after the first vaccination,
and 14 days, 6 months and 12 months after the second vaccination in subjects
who are anti-S IgG seronegative at baseline
·
Geometric mean fold rise (GMFR) (from baseline) in NT50 and NT80 against
SARS-CoV-2 pseudovirus at 28 days after the first vaccination, and 14 days, 6
months and 12 months after the second vaccination
·
Percentage of subjects with NT50 and NT80 seroresponses against SARS-CoV-2
pseudovirus as defined by (1) a ≥ 4-fold increase from baseline, and (2) a ≥ 10-
fold increase from baseline at 28 days after the first vaccination, and 14 days, 6
months and 12 months after the second vaccination
For Secondary Objective 2 (Phase 1), and Objectives 3 and 4 (Phase 2):
·
Anti-S IgG GMT at 28 days after the first vaccination, and 14 days, 6 months
and 12 months after the second vaccination in subjects who are anti-S IgG
seronegative at baseline
·
GMFR (from baseline) in anti-S IgG GMT at 28 days after the first vaccination,
and 14 days, 6 months and 12 months after the second vaccination
·
Percentage of subjects with seroresponses in anti-S IgG titer as defined by (1) a
≥ 4-fold increase from baseline, and (2) a ≥ 10-fold increase from baseline, at
28 days after the first vaccination, and 14 days, 6 months and 12 months after
the second vaccination
For Exploratory Objectives 1 and 2 (Phase 2):
·
Magnitude, functionality, and T-helper cell (Th) polarization of S protein-
specific T cells relative to baseline at 14 days and 6 months after the second
vaccination
For Exploratory Objective 3 (Phase 2):
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
·
Anti-NDV HN IgG GMT at baseline, 28 days after the first vaccination, and 14
days and 6 months after the second vaccination
STUDY DESIGN
This prospective, single-center, randomized, placebo-controlled, observer-blind
Phase 1/2 study includes two separate parts.
Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability
and immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3,
and 10 µg) without adjuvant, and at one dose level (1 µg) with the adjuvant CpG
1018, in a total of 120 subjects aged 18-59 years. Eligible subjects will be randomly
assigned to receive study vaccine or placebo as an IM injection in the deltoid
muscle at Visit [V]1 as part of one of four sequential groups of escalating antigen
dose level or added adjuvant. Each group will be divided into two sequential
subgroups, a sentinel subgroup (n=6) and a larger subgroup (n=24) that includes the
remaining subjects to be evaluated at that dose level (or for that formulation in the
case of the one adjuvanted treatment group). Initially, a sentinel subgroup of 6
subjects will be randomized to receive COVIVAC 1 µg or placebo in a 5:1 ratio.
Sentinel subjects will be monitored for reactogenicity and safety through Day 8
(Visit 2), including for the initial 24 hours post-injection in clinic. If the Protocol
Safety Review Team (PSRT) has no safety concerns based on blinded review of all
safety data, including clinical laboratory results, through Visit 2, the second
subgroup of 24 subjects will be randomized to receive COVIVAC 1 µg or placebo
at the same ratio; on the same day, the sentinel subgroup (n=6) for the second dose
level to be evaluated (COVIVAC 3 µg) can be randomized to receive study vaccine
or placebo in a 5:1 ratio, and so on for the subsequent dose level and formulation
(see Table 4).
The PSRT will review blinded safety, reactogenicity and clinical laboratory data
accrued on a weekly basis until D43 of the last subject in each phase, then at least
once monthly until the end of the study. Subjects will receive 2 doses of assigned
investigational product (IP) on D1 and D29 (V1 and V3), and be assessed in clinic
for safety and reactogenicity at 7 days after each vaccination (V2 and V4), for
safety at 28 days after the second vaccination (V6), and for safety and
immunogenicity assessments at baseline (V1), 28 days after the first vaccination
(V3) and 14, 168 and 336 days after the second vaccination (V5, V7, and V8, end-
of-study [EOS] Visit) (see Visit Schedule Table below).
An interim analysis of Phase 1 data conducted after the last subject last visit for V6
(D57) will serve as the basis for decisions about down-selection and advancing to
Part 2 of the study (Phase 2). Down selection and advancement to Part 2 (Phase 2)
will be based on the following parameters:
·
Post-dose 2 immunogenicity results at the aggregate treatment level
o A threshold immune response at Day 43 will be required: the observed
seroresponse rate in a treatment group (defined as the percentage of
subjects with at least a 4-fold rise from baseline in 80% neutralizing
antibody titers) will need to be ≥52% at the LL of the 95% CI for that
treatment (vaccine formulation) to be considered for advancement to Phase
2.
·
Post-dose 1 and post dose 2 safety results including all solicited and unsolicited
adverse events, serious adverse events, and clinical laboratory results.
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The following process will be followed for the decision about down selection and
advancing to Part 2 (Phase 2):
·
The DSMB will review the unblinded safety data and provide a
recommendation to the Sponsor on whether the safety profile is acceptable for
advancing a formulation to Phase 2.
·
The Sponsor will review the DSMB recommendation in conjunction with the
immunogenicity data and select two formulations to advance to Phase 2.
o If multiple formulations achieve the threshold immune response (as well as
have an adequate safety and tolerability profile per the DSMB), the
Sponsor will select two formulations to advance to Phase 2 based on
consideration of such factors as the relative functional immunogenicity of
these formulations, opportunity for dose sparing, and opportunity to limit
cost and possible supply constraints associated with use of the CpG
adjuvant.
·
The selection and recommendation to advance to Phase 2 along with the interim
report will be jointly reviewed by NIHE’s IRB and MoH prior to Phase 2
enrollment.
In Part 2 of this combined Phase 1/2 study, 300 adults aged 18-75 years will be
randomized (2:5:5) to placebo, or one of two selected formulations of COVIVAC
being evaluated in Phase 1. At least one-third of the subjects in Phase 2 will be aged
≥60 years to ensure that adequate safety and immune data will be available from
older and elderly adults to inform the selection of the COVIVAC formulation to
advance to Phase 3 studies. The Phase 2 cohort will follow the same visit schedule,
and undergo the same procedures and assessments, as in Phase 1. In addition, as
exploratory objectives, the anti-NDV HN IgG response will be assessed at V1, V3,
V5, and V8 in all subjects, and 36 subjects (equally distributed between the two age
strata) will be randomly selected in a 1:1:1 ratio to provide additional blood at V1,
V5 and V7 to be used to isolate peripheral blood mononuclear cells (PBMCs) for
assessment of T-cell-mediated immunity (CMI).
An interim analysis of Phase 2 data (combined with immunogenicity and safety
data generated for the placebo group and two selected COVIVAC formulations
from Phase 1) will be conducted after the last subject of the Phase 2 cohort
completes V6 (D57) as the basis for selecting the optimal formulation of
COVIVAC to advance to Phase 3 studies. As was the case for the Phase 1 interim
analysis at the same timepoint, the data generated will include unblinded post-dose
1 and dose 2 safety results for review by the DSMB, and immunogenicity results
aggregated by treatment group for review by the Sponsor. The DSMB will consider
all accumulated safety data from both phases of the study prior to making any
recommendation to the Sponsor that it not advance a formulation based on safety
concerns. The Sponsor will ultimately select the formulation to advance to Phase 3
that, in addition to having been judged by the DSMB to have an adequate safety and
tolerability profile, is optimal based on relative functional immunogenicity and
other programmatic considerations such as those noted above.
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
TREATMENT GROUPS
Phase
Group
1                      1
2
3
4
5
2                      1
2
3
Sample Size
20
25
25
25
25
50
125
125
Study Product
Placebo
COVIVAC 1 µg
COVIVAC 3 µg
COVIVAC 10 µg
COVIVAC 1 µg + CpG 1018 1.5 mg
Placebo
Formulation A
Formulation B
VISIT SCHEDULE – PHASE 1 AND PHASE 2
Day
(+ window)
Screening
Vaccination
Immune labs
Pseudovirus
ELISAs*
CMI
#
V1
-42 to 1
1
X
1
X
X
V2
V3
V4
V5
8
29
36
43
(+3)            (+3)            (+3)            (+3)
2
X
X
X
X
V6
V7
V8
57
197
365
(+7)           (+14)         (+28)
X
X
X
Safety data collection:
Safety visits
Clinical labs
Reactogenicity
AEs
MAAEs
AESI
SAEs
X
X
X
X
X
X
X
X
X
X
X
X
* Anti-NDV ELISA in Phase 2 only, at V1, V3, V5, and V8
# Phase 2 only, in subset of subjects
STUDY POPULATION
STUDY DURATION
A total of 420 male and female adults aged 18-75 (both inclusive) will receive
Investigational Product (IP) and be evaluated for safety and immunogenicity as
part of this combined Phase 1/2 study. At least one-third of the subjects evaluated
in Phase 2 will be ≥60 years old. Phase 1 of the study will be conducted at Hanoi
Medical University (HMU) and Phase 2 of the study will be conducted at Vu Thu
district health center, Thai Binh province.
Subjects will be followed for approximately 13 months after randomization (12
months following the 2nd dose of IP).
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2. BACKGROUND AND RATIONALE
On 7 January 2020, a novel coronavirus was identified as the cause of a cluster of pneumonia cases
first detected in December 2019 in Wuhan, the capital of China’s Hubei province,1 marking the third
documented zoonotic transmission event of a coronavirus within the last two decades. Two other
highly pathogenic coronaviruses,1 both of the genus Betacoronavirus, also crossed the species barrier
during this period: severe acute respiratory syndrome virus (SARS-CoV), which emerged in
Guangdong province, China in November 2002, and ultimately led to 8,096 reported cases and 774
deaths in 27 countries before the last infection was detected in July 2003; and the Middle East
respiratory syndrome coronavirus (MERS-CoV), which was first detected in Saudi Arabia in June
2012 (where it still circulates in camels) and has led to 2494 laboratory-confirmed cases and 858
deaths.2 Phylogenic analysis from full-genome sequencing of the novel coronavirus (which became
publicly available on 12 January 2020 [GenBank accession no. MN908947.2] indicated that it was
also a Betacoronavirus, and that it belonged to the same subgenus (subgenus Sarbecovirus [subgroup
B]) as SARS-CoV, with which it shares 79% nucleotide identity.3 Given its taxonomic relationship to
SARS-CoV, the novel coronavirus was designated severe acute respiratory syndrome virus 2
(SARS-CoV-2) by the International Committee on Taxonomy of Viruses. By 30 January 2020, the
international outbreak of SARS-CoV-2 was declared a Public Health Emergency of International
Concern by the World Health Organization (WHO), which on 11 February 2020 named the disease
caused by the virus COVID-19 (coronavirus disease 2019). By March 11, 2020, WHO officially
declared the outbreak of COVID-19 a global pandemic.
2.1.
Burden of Disease
As of 06 January, 2021, the confirmed global case count of COVID-19 has risen to over 87 million,
and deaths directly due to SARS-CoV-2 infection have surpassed 1.85 million.4 The large majority of
deaths have occurred among the elderly in the United States, Brazil, India and Mexico, which may be
largely attributable to poorly implemented control measures (such as surveillance, border closure,
quarantine and social distancing) in those countries.5 While there have been significantly fewer cases
to date in most low- and middle-income countries (LMICs), there is great concern about the potential
impact of easing of containment efforts, particularly in countries where robust and functioning public
health infrastructure is lacking.6 In addition to the potentially devastating direct disease burden of
SARS-CoV-2 in LMICs, the disruptions to routine health services and economic systems due to the
pandemic may result in an indirect disease burden of equal or even greater magnitude – a burden that
would be borne by all demographic groups. One study has estimated that disruptions to health
systems and access to food in LMICs as a result of the COVID-19 pandemic would result in a
minimum of 253,500 children under 5 child deaths and 12.200 maternal deaths over a 6-month
period. In the worse scenario, there would be 1,157,000 additional under-five child deaths and 56.700
maternal deaths over a 6-month period.7 In Vietnam, as of 06 January 2021 there have been 1.504
confirmed cases and 35 deaths.
2.2.
Pathogen and Clinical Disease
Like all viruses in the Coronaviridae family, SARS-CoV-2 is an enveloped, positive-sense, single-
stranded RNA virus, with a genome that (in addition to a replicase and accessory proteins) encodes
four major structural proteins: the spike surface glycoprotein (S), small envelope protein, matrix
protein, and nucleocapsid (N) protein. The diagnosis of COVID-19 is made by detection of
SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR), with a common
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
gene target being one of the structural proteins. The coronavirus S protein plays the essential role of
mediating cell entry by binding to the host-cell receptor, and thus is the primary determinant of viral
tropism.8 The S proteins of SARS-CoV and SARS-CoV-2 bind to the same primary host receptor, the
angiotensin-converting enzyme 2 (ACE2) receptor, whereas MERS-CoV (which belongs to a
different coronavirus lineage) uses dipeptidyl peptidase 4.
As is the case for both SARS-CoV and MERS-CoV, the median incubation period of SARS-CoV-2 is
approximately four to five days after exposure.9 Similar to SARS-CoV, pneumonia is the most
frequent serious manifestation of SARS-CoV-2 infection, with dry cough, fever, myalgia, headache,
dyspnea and sore throat being the most common presenting clinical features.10 Diarrhea,
nausea/vomiting, abdominal pain,11 smell and taste disorders (i.e., anosmia and dysgeusia),12 and
rhinorrhea are also associated with COVID-19, though less commonly. While the spectrum of
symptomatic SARS-CoV-2 infection ranges from mild to critical, most cases of COVID-19 are mild
(approximately 80%).13 In addition, multiple studies now suggest that asymptomatic infection may be
very common – as high as 88% by one report.14 This is in contrast to SARS-CoV, which uncommonly
caused mild or asymptomatic disease.15
In patients with severe to critical disease (approximately 15% and 5% of total cases, respectively),13
dyspnea, hypoxia, cytokine release syndrome, acute respiratory distress syndrome, shock,
thromboembolic complications, sudden cardiac death and multiorgan failure have been reported.16
Most patients who die from COVID-19 are older persons (~80% of deaths occur in those > 65 years
old)17 and/or persons with underlying medical comorbidities (obesity, cardiovascular disease,
diabetes, chronic lung disease, cancer, chronic kidney disease, hypertension),18 although severe illness
can occur in otherwise healthy persons of any age. In rare cases children can be severely affected,
manifesting clinically as a hyperinflammatory syndrome similar to Kawasaki disease (a rare acute
pediatric vasculitis)19 or toxic shock syndrome;20 this syndrome has been termed multisystem
inflammatory syndrome.21 In multiple cohort studies, male gender is strongly associated with death
from COVID-19.22,23
2.3.
Transmission and Infectivity
Like SARS-CoV, there is considerable evidence that SARS-CoV-2 originated in bats, and was
transmitted to humans after amplification in an intermediate host such as the pangolin.24 Human-to-
human transmission is thought to occur as a result of direct contact of virus with the mucous
membranes of the infected person, primarily via infected respiratory droplets and aerosols. The risk of
transmission from an individual with SARS-CoV-2 infection varies by the type and duration of
exposure, factors such as the amount of virus in respiratory secretions, and the use of preventive
measures. The interval during which an individual with COVID-19 is infectious appears to be highly
variable, with duration of viral shedding dependent upon the severity of the illness.25 However, it is
known that SARS-CoV-2 can be transmitted prior to, or in the absence of the development of
symptoms, and throughout the course of illness, with highest levels of virus in the upper respiratory
tract – and thus perhaps highest infectivity – soon after symptom onset.26 It is not known to what
extent asymptomatic infection has contributed to the pandemic spread of the virus.27
2.4.
Vaccine Development
Based on a basic reproduction number (R0) of ~2-3,28 60% to 70% of the population would need to
develop immunity to SARS-CoV-2 for pandemic spread to be contained in the absence of significant
control measures. Recent seroprevalence surveys indicate that population immunity remains well
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
below this threshold in countries with the highest burden of COVID-19.29 These results make clear
that herd immunity cannot be achieved through natural infection without incurring very significant
additional costs to society in terms of mortality, morbidity, and ongoing economic and social
disruption, and that the only acceptable route to achieving herd immunity is widespread – and ideally
rapid – deployment of an effective vaccine.
Studies conducted previously in support of SARS-CoV and MERS-CoV vaccine development were
instrumental in accelerating development of SARS-CoV-2 candidates. The fact that many COVID-19
vaccine programs have moved quickly with selection of the S protein as target antigen was due to
prior preclinical and human immunology studies on SARS-CoV demonstrating that the S protein of
SARS-CoV elicits neutralizing antibodies that are protective against SARS-CoV challenge (by
blocking virus attachment and fusion, as well as possibly by triggering FcR-mediated cytolysis or
phagocytosis), and that these antibodies persist in convalescent serum of patients who have recovered
from SARS.30 Not long after the onset of the COVID-19 pandemic it was similarly demonstrated that
the S protein of SARS-CoV-2 induces anti-S IgG antibodies in infected humans that neutralize the
virus in animal models,31 and that these antibodies persist for many months in convalescent sera.32
While it is likely that induction of CD8+ T-cells against S as well as other viral proteins 33 plays a
complementary role in protection after natural infection, the importance of a robust anti-S IgG
neutralizing antibody response in protection against disease after natural infection34 or experimental
vaccination35 is now incontrovertible.,
While there is currently no licensed vaccine to prevent COVID-19, a large number of vaccine
candidates employing a large diversity of vaccine platforms (mRNA, DNA, subunit, viral vectors,
nanoparticle) are in development, including 11 candidates that are currently in late stage Phase 3
development.36 Two of these vaccines, Pfizer/BioNTech’s and Moderna’s mRNA-based vaccines that
encode the full-length S protein with two stabilizing proline mutations (S-2P) have recently been
shown in interim analyses to have an efficacy against COVID-19 of greater than 90% after a two-dose
regimen. These results, along with supportive early-phase study results from multiple other S-protein-
based candidate vaccines that have elicited high-titer neutralizing antibodies further validate the
selection of the S protein as target antigen.37
2.5.
Risk of Immune Enhancement
In addition to facilitating target antigen selection, preclinical studies of SARS-CoV and MERS-CoV
vaccines have also highlighted the potential risk of a SARS-CoV-2 vaccine exacerbating disease
caused by subsequent SARS-CoV-2 infection. An inactivated SARS-CoV vaccine was shown to
induce disease enhancement in rhesus monkeys subsequently challenged with SARS-CoV, as a result
of non-neutralizing antibodies generated by the vaccine against the SARS-CoV S protein.38 Such
antibody-dependent enhancement (ADE) also occurred in cats infected with the Alphacoronavirus
feline infectious peritonitis virus (FIPV), after being vaccinated with an inactivated FIPV vaccine.39
Vaccine-induced non-functional antibodies cause ADE by facilitating viral entry into host cells, by
increasing binding efficiency of virus-antibody complexes to host cells via Fc receptors on those
cells.40
A second mechanism by which immune enhancement of disease may occur is via vaccine-induced
inflammation.41 Apart from activating Fc-receptor mediated endocytosis, vaccine-induced antibodies
may elicit Fc-mediated responses, such as complement activation and antibody-dependent cellular
cytotoxicity (ADCC), that may contribute to immunopathology. This phenomenon was observed in
ferrets and Cynomolgus monkeys challenged with SARS-CoV following vaccination with an
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
inactivated whole SARS-CoV vaccine;42 the animals developed lung immunopathology characterized
by eosinophilic recruitment, increased mucus production and airway hyperresponsiveness. The same
immunopathology was observed in 1966 in children given formalin-inactivated respiratory syncytial
virus (RSV) vaccine who subsequently were infected by RSV.43 Enhancement of RSV disease in that
study led to frequent hospitalizations and, in the youngest cohort, two deaths.44 The prominence of
eosinophils with such lung immunopathology has often been interpreted as signifying that this
immune enhancement was the result of Th2-biased immune responses.
To date, there has been no evidence of antibody-dependent disease enhancement or
immunopathology in animal studies and human trials of SARS-CoV-2 candidate vaccines. This is
likely due to the fact that these candidates, including an inactivated SARS-CoV-2 vaccine,45 have
been shown to elicit high-titer anti-S neutralizing antibody responses. SARS-CoV-1 vaccines that
elicit neutralizing antibodies against the SARS-CoV S protein were similarly able to protect animals
from SARS-CoV challenge without evidence of acute lung injury and immunopathology.46 In
addition, many SARS-CoV-2 vaccine candidates include Th1-polarizing adjuvants to minimize the
risk of disease enhancement. Nevertheless, disease enhancement remains a theoretical risk,
particularly after waning of antibody responses, and therefore needs to be closely monitored in human
clinical trials of SARS-CoV-2 vaccines.
2.6.
Introduction to COVIVAC Vaccine
Given the global scope of the COVID-19 pandemic, there is an urgent need for a safe and effective
vaccine against COVID-19 that will be affordable and able to be manufactured at a sufficient scale to
supply Vietnam and other low- and-middle-income countries. To achieve this aim, IVAC and two
other consortium manufacturers – Government Pharmaceutical Organization (GPO), Thailand, and
Instituto Butantan, Brazil – are independently developing an inactivated whole chimeric virion
vaccine based on a Newcastle Disease Virus (NDV) that has been modified to also express the
SARS-CoV-2 S protein on its surface. This technology was invented at the Icahn School of Medicine
at Mount Sinai (ISMMS) (New York, New York, USA). Since NDV grows well in embryonated
chicken eggs, the NDV chimeric vaccine can be manufactured using the same inexpensive egg-based
process employed for inactivated influenza virus vaccine (IIV).47 In addition to taking advantage of
the cost-effectiveness of the manufacturing process, an inactivated chimeric NDV vaccine propagated
in eggs (prior to being inactivated by beta-propiolactone [BPL]) is also expected to be as safe as egg-
based IIV, which has an excellent safety profile, including in infants, pregnant women, and elderly
adults.
As in the case of many COVID-19 vaccines currently in development, the inactivated chimeric NDV
vaccine expresses the ectodomain of the SARS-CoV-2 S protein – which is fused to the F protein
transmembrane domain of NDV, resulting in abundant expression of membrane-bound S antigen (see
Figure 1). While many candidate COVID-19 vaccines are targeting the S protein as antigen, the S
protein expressed on the surface of the chimeric NDV virion is a much more stable construct than that
utilized in other COVID-19 vaccines as it contains six stabilizing proline substitutions – four more
than are introduced in the S protein antigen (S-2P) used in a number of COVID-19 candidate
vaccines, including the Pfizer/BioNTech and Moderna vaccines. The resulting protein, called
“HexaPro” (HXP) and developed by the University of Texas (Austin, TX, USA),48 is more
immunogenic (>10-fold higher) than S-2P in mice (data unpublished), and also provides higher yields
than S-2P when expressed recombinantly. As a result of these properties it is expected that significant
dose-sparing will be possible with the COVIVAC vaccine candidate relative to other vaccine
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
candidates expressing the earlier-developed S-2P antigen. Dose-sparing translates to higher
production volumes and lower cost of vaccine. Finally it is important to note that HexaPro has also
been shown to be more thermostable than S-2P.48 The fact that COVIVAC is expected to be
thermally stable at 2-8 °C is a major advantage of the vaccine over other COVID-19 candidates in
development that will require storage at -20°C or even lower temperature.
Figure 1. Electron micrograph of COVIVAC (courtesy of GPO Thailand)
While it is likely that the whole virion COVIVAC vaccine alone will prove to be highly
immunogenic in healthy adults due to endogenous adjuvanticity of the NDV virion, use of exogenous
adjuvant may further increase the functional immune response to the vaccine – which may be
important to ensure adequate protection in older adults, or possibly provide additional opportunity for
dose-sparing. For this reason, the first part of this combined Phase 1/2 study is a first-in-human,
Phase 1 evaluation of a 2-dose regimen of both unadjuvanted COVIVAC (at 1 µg, 3 µg, and 10 µg
dose levels) and COVIVAC adjuvanted with CpG 1018 (at the 1 µg dose level) in healthy adults.
CpG 1018, the adjuvant in the US-licensed HEPLISAV-B® vaccine (Dynavax Technologies
Corporation, Emeryville, CA, USA), is a synthetic 22-mer oligodeoxynucleotide that exerts its action
by targeting toll-like receptor 9 (TLR-9) expressed on a few key immune-cell types. When used as a
vaccine adjuvant, CpG 1018 increases antibody concentrations to co-administered antigen, stimulates
helper (CD4+) and cytotoxic (CD8+) T cell populations and generates robust T and B cell memory
responses. Additionally, CpG 1018 strongly favors development of the Th1 subset of helper T cells,
the type of helper T cell that is essential for protection from infections with viruses and intracellular
bacteria. HEPLISAV-B was well-tolerated and shown to have an adequate safety profile in clinical
trials in adults.49 Interim analyses of an ongoing post-marketing study of over 30,000 HEPLISAV-B
recipients and more than 35,000 active comparator recipients have raised no safety concerns.
2.7.
Summary of Nonclinical Studies
A complete summary of the COVIVAC preclinical development program is provided in the
Investigator’s Brochure (IB).
In brief, a pilot immunogenicity study in BALB/c mice and challenge study in golden Syrian
hamsters (the latter evaluating multiple adjuvants including CpG 1018) have been conducted using
bench-scale vaccine. Preliminary data show that a 2-dose vaccine regimen (21 days apart) in BALB/c
mice and golden Syrian hamsters induces potent protective immunity, as reflected by the level of
anti-S IgG antibody (see Figure 2), prevention of weight-loss post-challenge with SARS-CoV-2
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
(hamsters, Figure 3), and the reduction of SARS-CoV-2 in the lung on Days 2 and 5 post-challenge
(hamsters, Figure 3). This protective effect is particularly notable in hamsters, as they are known to
develop COVID-19 lung disease much like humans.50
Figure 2. Induction of anti-S after vaccination of mice (top) and hamsters (bottom) with NDV-HXP-S
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
Figure 3. Data from a pilot study showing protection of golden Syrian hamsters from infection by wild-
type (WT) SARS-CoV-2.
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
Additional preclinical studies (see Table 1) are described in brief below.
Table 1. Summary of preclinical studies
Purpose
Cell-mediated
immunity
Protection against
challenge with
WT SARS-CoV-2
GLP-Toxicology
Species
Mice
Hamsters
Rat
Groups
NDV only (control)
NDV-HXP-S
NDV-HXP -S+CpG 1018
Mock challenge (control)
NDV only (control)
NDV-HXP-S
COVIVAC +CpG 1018
Saline control
COVIVAC 10µg
COVIVAC 3µg+1.5mg
CpG 1018
Endpoints
Anti-CoV2 S
ELISA
CD4, CD8 T cell,
Th1, Th2 cytokine
Anti-CoV2 S
ELISA
Weight loss x 5d,
virus titer in lung
Assess potential
local and systemic
toxicity of vaccine
with and without
CpG 1018
Challenge virus
None
USA WA1/2020,
105 pfu, IN (non-
lethal) on D36 or
D43
None
Institution
ISMMS
ISMMS
Bioneeds India
(GLP
toxicology
CRO, India)
Evaluation of cell-mediated immunity in mouse study with GMP lot vaccine
Vaccine candidates that elicit strong T-cell responses with a Th1 bias may provide durable protection
against COVID-19, as well as minimize risk of disease enhancement. To characterize the induction of
cell-mediated immunity by COVIVAC vaccine with and without CpG 1018, each consortium
manufacturer’s vaccine will be evaluated in mice. Groups of mice (n=8) will be administered two
doses of vaccine intramuscularly on day 0 and 21. Post dose 1 and 2, mice will be euthanized to
isolate splenic T cells. T cells will be cultured overnight with peptide pools derived from S protein as
the source of antigen stimulation, then immune-profiled to determine antigen specific CD4+ and
CD8+ T-cell populations. The proportion of T cells secreting IFNγ or IL-4 cytokines will be
estimated by ELISpot to assess Th polarization.
Comparing protective efficacy of GMP lots of vaccine in hamsters
A study is currently being conducted by ISMMS to evaluate the efficacy of each manufacturer’s
COVIVAC vaccine with and without CpG 1018 adjuvant against wild-type (WT) SARS-CoV-2 virus
challenge in golden Syrian hamsters. Briefly, golden Syrian hamsters of 7-8 weeks of age (n =
8/group) will be immunized twice, three weeks apart using the GMP lot of COVIVAC vaccine from
each manufacturer. A dose of 1 µg S antigen will be used, which corresponds to the low human dose
planned for Phase 1. The adjuvanted vaccine group will also receive 100 µg of CpG 1018. The
controls will be NDV vector only and mock challenged animals. Animals will be bled on Days 1, 21
and 33. Serum samples will be tested for anti-S IgG by ELISA. On Day 35, hamsters will be
challenged with WT SARS-CoV-2. Body weight will be measured daily from all surviving animals.
On Days 2 or 5 post-challenge, hamsters will be euthanized, and lung tissues collected to measure
viral titers in the upper and lower lobes of the lung.
Repeat-dose toxicology study
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A GLP non-clinical toxicology evaluation is being conducted to evaluate COVIVAC vaccine from
each consortium manufacturer; interim results from this study have been reported, as detailed below.
Per guidance provided by the World Health Organization (WHO), a repeat-dose toxicology study was
designed to test COVIVAC (including CpG 1018) at the human dose level. Since COVIVAC will be
evaluated in clinical trials as a two-dose vaccination schedule, the toxicology study evaluated IM
administration of three doses, following the n+1 rule.
A total of 210 Sprague Dawley rats (105 Males and 105 Females) were randomly allocated to seven
main groups (G) and seven recovery groups (R). Each main group consisted of 10 rats/sex and each
recovery group consisted of 5 rats/sex. The animals allocated to group G1/G1R were administered
0.9% normal saline. COVIVAC was administered to the other groups as shown in Table 2.
Table 2. COVIVAC Treatment Groups (Toxicology Study)
Antigen groups:                   Groups
Antigen 1                         G2/G2R
(IVAC)                          G5/G5R
Antigen 2                         G3/G3R
(Instituto Butantan)                 G6/G6R
Antigen 3                         G4/G4R
(GPO)                           G7/G7R
G = Group, R = Recovery group
Dose
COVIVAC 10 µg
COVIVAC 3 µg + CpG 1.5 mg
COVIVAC 10 µg
COVIVAC (3 µg +
CpG 1.5 mg
COVIVAC 10 µg
COVIVAC 3 µg + CpG 1.5 mg
Doses were administered IM in the thigh muscle of the animals on Days 1, 15 and 29. The total
volume administered was 0.4 mL/animal, with 0.2 mL administered to each thigh. After treatment on
Day 29, the main group animals (G1 to G7) were sacrificed on Day 32; the animals in the recovery
groups (G1R to G7R) were not given any treatment and observed for reversibility or persistence of
toxic effects, and sacrificed on Day 43. Animals were observed for clinical signs of toxicity twice
daily, with detailed clinical examination weekly; local reactions at the site of injection were evaluated
approximately 24, 48 and 72 hours after each dose. Rectal temperature was recorded pre-treatment
and at approximately 6 hours (± 10 min) and 24 hours (± 20 min) after each dose on Days 1, 15 and
29. Body weight was recorded once on Day 1 prior to dosing, 3 hours post dose and on Day 2 and
weekly thereafter. Feed consumption was measured daily. Blood was collected from all animals prior
to treatment, on Day 3, 8 and at necropsy (Day 32 for main groups and Day 43 for recovery groups)
from overnight-fasted animals. Urine was collected on Day 32 from main groups and on Day 43 from
recovery groups and analysed. All animals were subjected to necropsy and detailed gross pathological
examination at termination. Organs specified in the study plan were collected, weighed and
preserved. Haptoglobin and alpha2-macroglobulin were analysed from main group animals (5
rats/sex) prior to treatment (pre-dose), on Days 8 and 32 using a kit-based ELISA method. Serum
samples collected from all rats during pre-dose, Day 32 (main groups) and Day 43 (recovery groups)
were assessed for immunogenicity.
Interim Results:
All three GMP lots of vaccine drug substance from GPO, IVAC and Butantan were well tolerated in
rats with no morbidity/mortality found in any of the groups throughout the experimental period.
There were no clinical signs of toxicity observed during the experimental period. A few statistically
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significant variations in percent change in body weight with respect to Day 1 were noted during the
experimental period across groups that received any of the three vaccines; these were inconsistent and
minimal in nature and hence considered as incidental. Also, there were no concomitant variations in
mean body weights and/or feed consumption and hence these variations in body weight not
considered to be related to vaccine administration.
No adverse treatment-related variations in body temperature after any dose were noted in groups of
either sex. A few statistically significant variations of body temperature were noted during different
measurement periods; however these were considered incidental as the variations were less than 2%
and all the values were within 37±2°C. No skin reactions at the site of injection were noted after any
administration of vaccine. Haptoglobin and alpha2-macroglobulin were increased on Day 8 and Day
32 when compared to pre-dose levels; this increase was also noted in the saline control group and
hence considered not be related to treatment with vaccine. No adverse treatment-related changes were
observed in hematology, coagulation, clinical chemistry and urinalysis parameters. Statistically
significant changes were noted in hematology parameters on Days 3 and/or 8 when compared with
pre dose sampling due to repeated blood withdrawal for clinical pathology analysis and hence not
considered to be due to vaccine administration.
There were no adverse treatment-related changes in fasting body weights. However, in the main
groups, statistically significant increases in absolute and relative organ weight of the liver (G5M,
G6M, G5F, G6F and G7F), and decreases in relative weight of ovaries (G2F, G4F, G6F and G7F),
heart (G5F, G6F) and brain (G6F) were noted. Further data from the recovery group animals and the
histopathology data is necessary to interpret these data.
2.8.
Study Design Rationale
The Phase 1/2 combined study has been designed to rigorously evaluate the safety, tolerability
(primary objective) and immunogenicity (secondary objective) of COVIVAC vaccine across a range
of S-antigen dose levels – one with CpG 1018 as adjuvant – with the aim of expeditiously selecting a
single candidate to advance to Phase 3 studies. Phase 1 will provide justification for advancement to
the Phase 2 segment based on safety evaluations during an initial sentinel dose-escalation stage, and
later an interim analysis of safety and immunogenicity (the latter primarily based on pseudovirus
neutralization) through 28 and 14 days after the second dose, respectively. An independent Data and
Safety Monitoring Board (DSMB) will review unblinded safety data through Day 57, and on the basis
of this review provide a recommendation for advancing to Phase 2 (the DSMB will also be convened
at any time during conduct of the study in the event that a study pause rule is triggered; see Section
9.3). In addition to this process for assessing adequate safety for advancing to Phase 2, a threshold
immune response at Day 43 will be required for a vaccine formulation to be considered for
advancement to Phase 2: namely, the observed seroresponse rate (defined as the percentage of
subjects in a treatment group with at least a 4-fold rise from baseline in NT80 titers) will need to be at
least 52% at the lower limit (LL) of the 95% confidence interval (CI) . Based on this criterion, there is
less than 10% chance of incorrectly rejecting a vaccine candidate with a true seroresponse rate of
85% or higher, which is estimated to be the minimum response rate that would be consistent with
further investment in an additional second-wave COVID-19 vaccine.
If warranted based on safety and immunogenicity, the two optimal COVIVAC formulations will be
selected for ongoing evaluation in Part 2 of the study based on results of the Phase 1 interim analysis.
The Phase 2 segment of the study will include a sufficient number of older adults aged 60-75
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(including those with stable chronic co-morbidities) to determine whether safety and immunogenicity
of the vaccine may differ in this older population. It is critical that evaluation of COVIVAC in older
adults informs the selection of the COVIVAC candidate to advance to Phase 3 studies (based on
safety and immunogenicity through 14 days post-second vaccination in Phase 2), given the higher
risk of severe COVID-19 in this age group, and the potential need for a higher dose level of antigen
and/or use of adjuvant to achieve a comparable functional immune response as younger adults. Phase
2 immunogenicity and safety data through Day 43 and Day 57, respectively, will determine the
vaccine composition to advance to Phase 3, registration, and commercialization. Cell-mediated
immunity will also be evaluated in a subset of subjects in the Phase 2 segment as an exploratory
objective to assess the S protein-specific T cell response including Th polarization. An exploratory
evaluation of the IgG immune response against the NDV HN protein will also be conducted in all
Phase 2 subjects to generate hypotheses about the utility of administering a booster dose of
COVIVAC vaccine.
In addition to standard safety monitoring throughout the study, subjects will be evaluated for specific
adverse event of special interest (AESI); these include potential immune-mediated medical
conditions, which may be associated with vaccination. In addition subjects will be closely monitored
for adverse events associated with COVID-19 to identify, and treat if indicated, potential cases of
COVID-19 during the trial, and to assess for possible vaccine-induced immune enhancement of
disease. In addition to mandatory use of masks and other exposure control measures by staff and
subjects during clinic visits, study subjects will be instructed to contact the Principal Investigator (PI)
if they meet criteria for COVID-19 testing based on specified signs and symptoms; these criteria will
be provided to subjects in the form of a fact sheet.
2.8.1.
Justification for Dose
As shown above, the COVIVAC vaccine candidate elicits similar post-dose 2 titers of anti-S IgG
antibody in mice over a 100-fold dilution (from 1 µg to 0.01 µg of total protein). The S protein of the
vaccine content is estimated to be 10% of total protein. COVIVAC vaccine (5 µg total protein)
administered twice to hamsters afforded excellent protection against virus challenge. These results
suggest that relatively low doses of COVIVAC may be immunogenic in human subjects, despite the
uncertainty of translating rodent doses to human doses. Consequently, 3 µg of S protein has been
selected for unadjuvanted COVIVAC as the mid-dose range for clinical evaluation, with a high dose
of 10 µg and a low dose of 1 µg. Evaluating this full dose range of COVIVAC in subjects aged 18-75
will provide the necessary safety and immunogenicity data to determine whether increasing the dose
level of COVIVAC in elderly subjects in Phase 3 may be desirable.
Furthermore, the low dose level of COVIVAC vaccine will be evaluated ± CpG 1018 in the current
study. CpG 1018 is approved for use in the US by the Food and Drug Administration (FDA) at a dose
of 3 mg/ml in HEPLISAV-B. A dose of 1.5 mg/ml has been selected with COVIVAC for the
following reasons:
·
CpG 1018 has shown a dose-dependent adjuvant effect with other vaccines. Dynavax has
shown that 1.5 mg/ml of CpG 1018 has an acceptable adjuvant effect with protein subunit
vaccine.51 Given that COVIVAC is an inactivated whole virion, it is expected that it will have
intrinsic adjuvant effects that will complement the adjuvant effects of CpG 1018.
·
Advanced adjuvants, such as CpG 1018, add considerable cost per dose of vaccine. Keeping
the level of adjuvant relatively low but still effective, will assist in controlling the cost of
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goods of the final product.
·
CpG 1018 is being tested in multiple vaccine candidates. This may put significant pressure on
the supply/availability of CpG 1018 for approved products. Formulating COVIVAC with a
lower dose of CpG 1018 may be beneficial when manufacturing at commercial scale.
2.9.
Overall Clinical Development Strategy
The ultimate aim of developing COVIVAC vaccine for the prevention of COVID-19 is to obtain local
registration of the vaccine in Vietnam, followed by prequalification by the WHO, with the goal of
providing affordable access to a life-saving COVID-19 vaccine for Vietnam and other LMICs.
Assuming this Phase 1/2 study results in advancement of an COVIVAC vaccine candidate for further
evaluation, IVAC will likely conduct one Phase 3 trial to confirm lot-to-lot consistency and generate
expanded safety data for that candidate. The nature of a second Phase 3 study to confirm vaccine
effectiveness will be determined in discussions with the MoH of Vietnam. As COVID-19 vaccines
become available and SARS-CoV-2 transmission rates decline due to population immunity and
public health control measures, conducting placebo-controlled studies may be challenging if not
infeasible. As a result, it may be the case that effectiveness can only be demonstrated by conducting
an immunogenic non-inferiority trial that includes an approved comparator with a similar mechanism
of protection.
3. HYPOTHESES, OBJECTIVES AND ENDPOINTS
3.1.
Study Hypotheses
3.1.1.
Primary Hypothesis:
Safety, Tolerability:
·
The COVIVAC vaccine (NDV-HXP-S) will have an acceptable safety profile and be well-
tolerated at all dose levels when administered as a two-dose regimen either without adjuvant (at
1 µg, 3 µg, and 10 µg of S protein per 0.5 ml dose), or with the adjuvant CpG 1018 (at 1 µg of S
protein per 0.5 ml dose).
3.1.2.
Secondary Hypothesis:
Immunogenicity:
·
COVIVAC will elicit a measurable and dose-dependent neutralizing antibody response.
3.2.
Study Objectives
3.2.1.
Primary Objectives:
Safety, Tolerability:
For Phase 1:
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1. To assess the safety and tolerability of each of four formulations of COVIVAC (at 1, 3 and 10
µg without adjuvant; and at 1 µg with CpG 1018) after the first and second dose of a two-dose
regimen administered at a 28-day interval to adults aged 18-59 years
For Phase 2:
1. To assess the safety and tolerability of two selected formulations of COVIVAC (based on Phase
1 safety and immunogenicity) after the first and second dose of a two-dose regimen
administered at a 28-day interval to adults aged 18-75 years
2. To assess the safety and tolerability of two selected formulations of COVIVAC after the first
and second dose of a two-dose regimen administered at a 28-day interval to adults aged 18-59
years and 60-75 years
3.2.2.
Secondary Objectives:
Immunogenicity:
For Phase 1:
1. To assess the functional (neutralizing) humoral immune response elicited by each formulation
of NDV-HXP-S, as measured by a SARS-CoV-2 PNA, at baseline, 28 days after the first
vaccination, and 14 days after the second vaccination (to inform the selection of two
formulations for evaluation in Phase 2), and at 6 months and 12 months after the second
vaccination, in adults aged 18-59 years
2. To assess the IgG immune response elicited by each formulation of COVIVAC against the S
protein of SARS-CoV-2, as measured by ELISA, at baseline, 28 days after the first vaccination,
and 14 days, 6 months and 12 months after the second vaccination, in adults aged 18-59 years
For Phase 2:
1. To assess the functional (neutralizing) humoral immune response elicited by each of two
selected COVIVAC formulations, as measured by PNA, at baseline, 28 days after the first
vaccination, and 14 days, 6 months and 12 months after the second vaccination, in adults aged
18-75 years
2. To assess the functional (neutralizing) humoral immune response elicited by each of two
selected COVIVAC formulations, as measured by PNA, at baseline, 28 days after the first
vaccination, and 14 days, 6 months and 12 months after the second vaccination, in adults aged
18-59 years and 60-75 years
3. To assess the IgG immune response elicited by each of two selected COVIVAC formulations
against the S protein of SARS-CoV-2, as measured by ELISA, at baseline, 28 days after the first
vaccination, and 14 days, 6 months and 12 months after the second vaccination, in adults aged
18-75 years
4. To assess the IgG immune response elicited by each of two selected COVIVAC formulations
against the S protein of SARS-CoV-2, as measured by ELISA, at baseline, 28 days after the first
vaccination, and 14 days, 6 months and 12 months after the second vaccination, in adults aged
18-59 years and 60-75 years
3.2.3.
Exploratory Objectives:
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Immunogenicity:
For Phase 2:
1. To assess the S protein-specific T cell response elicited by each of two selected COVIVAC
formulations, as measured by ELISpot, at baseline, and 14 days and 6 months after the second
vaccination, in adults aged 18-75 (subset of subjects)
2. To assess the S protein-specific T cell response elicited by each of two selected COVIVAC
formulations, as measured by ELISpot, at baseline, and 14 days and 6 months after the second
vaccination, in adults aged 18-59 years and 60-75 years (subset of subjects in each age stratum)
3. To assess the IgG immune response elicited by each of two selected COVIVAC formulations
against the NDV HN protein, as measured by ELISA, at baseline, 28 days after the first
vaccination, and 14 days and 12 months after the second vaccination, in adults aged 18-59 years
Note: other exploratory studies to further characterize the immune response to COVIVAC may be
conducted in Phase 1 or Phase 2. This includes evaluation of the functional response to COVIVAC as
measured by a wild-type neutralization assay, which will be conducted if a collaboration for
performing the assay is established. The collaborator for evaluation of the cell-mediated immune
response to COVIVAC in Phase 2 is also yet to be determined.
3.3.
Study Endpoints
3.3.1.
Primary Endpoints:
Safety, Tolerability:
·
Number and severity of solicited local and systemic AEs during the first 7 days after each
vaccination
·
Number, severity, and relatedness of clinically significant hematological and biochemical
measurements at 7 days post each vaccination
·
Number, severity and relatedness of all unsolicited AEs during the first 28 days after each
vaccination
·
Number, severity and relatedness of SAEs throughout the entire study period
·
Number, severity and relatedness of MAAEs throughout the entire study period
·
Number, severity and relatedness of AESI throughout the entire study period, including AESI
relevant to COVID-19, and potential immune-mediated medical conditions (PIMMC)
3.3.2.
Secondary Endpoints:
Immunogenicity:
For Secondary Objective 1 (Phase 1), and Objectives 1 and 2 (Phase 2):
·
NT50 and NT80 GMT against SARS-CoV-2 pseudovirus at 28 days after the first vaccination,
and 14 days, 6 months and 12 months after the second vaccination in subjects who are anti-S
IgG seronegative at baseline
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·
GMFR (from baseline) in NT50 and NT80 against SARS-CoV-2 pseudovirus at 28 days after the
first vaccination, and 14 days, 6 months and 12 months after the second vaccination
·
Percentage of subjects with NT50 and NT80 seroresponses against SARS-CoV-2 pseudovirus as
defined by (1) a ≥ 4-fold increase from baseline, and (2) a ≥ 10-fold increase from baseline at
28 days after the first vaccination, and 14 days, 6 months and 12 months after the second
vaccination
For Secondary Objective 2 (Phase 1), and Objectives 3 and 4 (Phase 2):
·
Anti-S IgG GMT at 28 days after the first vaccination, and 14 days, 6 months and 12 months
after the second vaccination in subjects who are anti-S IgG seronegative at baseline
·
GMFR (from baseline) in anti-S IgG GMT at 28 days after the first vaccination, and 14 days, 6
months and 12 months after the second vaccination
·
Percentage of subjects with seroresponses in anti-S IgG titer as defined by (1) a ≥ 4-fold
increase from baseline, and (2) a ≥ 10-fold increase from baseline, at 28 days after the first
vaccination, and 14 days, 6 months and 12 months after the second vaccination
3.3.3.
Exploratory Endpoints:
Immunogenicity
For Exploratory Objectives 1 and 2 (Phase 2):
·
Magnitude, functionality, and Th polarization of S protein-specific T cells relative to baseline at
14 days and 6 months after the second vaccination
For Exploratory Objective 3 (Phase 2):
Anti-NDV HN IgG GMT at baseline, 28 days after the first vaccination, and 14 days and 6 months
after the second vaccination.
Note: In this protocol one month in this study context is defined as 4 weeks or 28 days; then 6
months means 24 weeks or 168 days, and 12 months means 48 weeks or 336 days.
4.
STUDY DESIGN
This prospective, single-center, randomized, placebo-controlled, observer-blind Phase 1/2 study
includes two separate parts. The treatment groups to be evaluated in each part of the study (and their
corresponding sample size) are presented in Table 3.
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Table 3. Treatment Groups
Phase
Group
1                      1
2
3
4
5
2                      1
2
3
Sample Size
20
25
25
25
25
50
125
125
Study Product
Placebo
COVIVAC 1 µg
COVIVAC 3 µg
COVIVAC 10 ug
COVIVAC 1 µg + CpG1018 1.5 mg
Placebo
Formulation A
Formulation B
Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability, and
immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, and 10 µg) without
adjuvant, and at one dose level (1 µg) with the adjuvant CpG 1018, in a total of 120 subjects aged 18-
59 years. Eligible subjects will be randomly assigned to receive study vaccine or placebo as an IM
injection in the deltoid muscle at Visit [V]1 as part of one of four sequential groups of escalating
antigen dose level or added adjuvant. Each group will be divided into two sequential subgroups, a
sentinel subgroup (n=6) and a larger subgroup (n=24) that includes the remaining subjects to be
evaluated at that dose level (or for that formulation in the case of the one adjuvanted treatment
group). Initially, a sentinel subgroup of 6 subjects will be randomized to receive COVIVAC 1 µg or
placebo in a 5:1 ratio (subjects within a sentinel subgroup will receive the first injection only after
immediate reactogenicity assessments of the prior subject in the subgroup are completed). Sentinel
subjects will be monitored for reactogenicity and safety through Day 8 (Visit 2), including for the
initial 24 hours post-injection in clinic. If the PSRT has no safety concerns based on blinded review
of all safety data, including clinical laboratory results, through Visit 2, the second subgroup of 24
subjects will be randomized to receive COVIVAC 1 µg or placebo at the same ratio; on the same day,
the sentinel subgroup (n=6) for the second dose level to be evaluated (COVIVAC 3 µg) can be
randomized to receive study vaccine or placebo in a 5:1 ratio, and so on for the subsequent dose level
and formulation (see Table 4).
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Table 4. Phase 1 Dose Escalation Steps
Subgroup
Escalation Steps
Dose 1µg &
Placebo (5+1)
Dose 1µg &
Placebo (20+4)
Dose 3µg &
Placebo (5+1)
Dose 3µg &
Placebo (20+4)
Dose 10µg &
Placebo (5+1)
Dose 10µg &
Placebo (20+4)
Dose 1µg+CpG
& Placebo (5+1)
Dose 1µg+CpG
& Placebo (20+4)
Review
V1
V2
V1
V2
V1
V2
V1
V1
PSRT
PSRT
V2
V2
V1
V2
V1
V2
V1
V2
PSRT
PSRT
V1 = Visit 1 (Day 1)
V2 = Visit 2 (Day 8)
PSRT = Protocol Safety Review Team meeting
The PSRT will review blinded safety, reactogenicity and clinical laboratory data accrued on a weekly
basis until D43 of the last subject in each phase of the study, then at least once monthly until the end
of the study. Subjects will receive 2 doses of assigned IP on D1 and D29 (V1 and V3), and be
assessed in clinic for safety and reactogenicity at 7 days after each vaccination (V2 and V4), for
safety at 28 days after the second vaccination (V6), and for safety and immunogenicity assessments at
baseline (V1), 28 days after the first vaccination (V3) and 14, 168 and 336 days after the second
vaccination (V5, V7, and V8, EOS Visit).
An interim analysis of Phase 1 data conducted after the last subject last visit for V6 (D57) will serve
as the basis for decisions about down-selection and advancing to Part 2 of the study (Phase 2). Down
selection and advancement to Part 2 (Phase 2) will be based on the following parameters:
· Post-dose 2 immunogenicity results at the aggregate treatment level
o A threshold immune response at Day 43 will be required: the observed seroresponse rate in a
treatment group (defined as the percentage of subjects with at least a 4-fold rise from
baseline in 80% neutralizing antibody titers) will need to be ≥52% at the LL of the 95% CI
for that treatment (vaccine formulation) to be considered for advancement to Phase 2.
· Post-dose 1 and post dose 2 safety results including all solicited and unsolicited adverse events,
serious adverse events, and clinical laboratory results.
The following process will be followed for the decision about down selection and advancing Part 2
(Phase 2):
· The DSMB will review the unblinded safety data and provide a recommendation to the Sponsor
on whether the safety profile is acceptable for advancing a formulation to Phase 2.
· The Sponsor will review the DSMB recommendation in conjunction with the immunogenicity
data and select two formulations to advance to Phase 2.
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o If multiple formulations achieve the threshold immune response (as well as have an adequate
safety and tolerability profile per the DSMB), the Sponsor will select two formulations to
advance to Phase 2 based on consideration of such factors as the relative functional
immunogenicity of these formulations, opportunity for dose sparing, and opportunity to limit
cost and possible supply constraints associated with use of the CpG adjuvant.
· The selection and recommendation to advance to Phase 2 along with the interim report will be
jointly reviewed by NIHE’s IRB and MoH prior to Phase 2 enrollment.
In Part 2 of this combined Phase 1/2 study, 300 adults aged 18-75 years will be randomized (2:5:5) to
placebo, or one of two selected formulations of COVIVAC being evaluated in Phase 1. At least one-
third of the subjects in Phase 2 will be aged ≥60 years to ensure that adequate safety and immune data
will be available from older and elderly adults to inform the selection of the COVIVAC formulation
to advance to Phase 3 studies. The Phase 2 cohort will follow the same visit schedule, and undergo
the same procedures and assessments, as in Phase 1. In addition, as exploratory objectives, the anti-
NDV HN IgG response will be assessed at V1, V3, V5, and V8 in all subjects, and 36 subjects
(equally distributed between the two age strata) will be randomly selected in a 1:1:1 ratio to provide
additional blood at V1, V5 and V7 to be used to isolate PBMCs for assessment of T-cell-mediated
immunity. Other exploratory assays to characterize the immune response to COVIVAC may also be
performed.
An interim analysis of Phase 2 data (combined with immunogenicity and safety data generated for the
placebo group and two selected COVIVAC formulations from Phase 1) will be conducted after the
last subject of the Phase 2 cohort completes V6 (D57) as the basis for selecting the optimal
formulation of COVIVAC to advance to Phase 3 studies. As was the case for the Phase 1 interim
analysis at the same timepoint, the data generated will include unblinded post-dose 1 and dose 2
safety results for review by the DSMB, and immunogenicity results aggregated by treatment group
for review by the Sponsor. The DSMB will consider all accumulated safety data from both phases of
the study prior to making any recommendation to the Sponsor that it not advance a formulation based
on safety concerns. The Sponsor will ultimately select the formulation to advance to Phase 3 that, in
addition to having been judged by the DSMB to have an adequate safety and tolerability profile, is
optimal based on relative functional immunogenicity and other programmatic considerations such as
those noted above.
5. STUDY POPULATION
5.1.
Study Population
The study population will consist of eligible, Vietnamese male and female adults aged 18-75 years
old, inclusive.
5.2.
Clinical Trial Site
·     Phase 1:
Phase 1 of the study will be conducted at Hanoi Medical University (HMU), where facilities are
available to conduct intensive in-clinic safety monitoring for 24 hours after the 1st study product
administration, and for 4 hours after the 2nd study product administration. Hanoi Medical
University is experienced in the conduct of clinical trials. Study subjects in Phase 1 will be
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recruited via advertisement in mass media, and websites of NIHE, HMU and IVAC; volunteers
will contact the study team for registration. The advertisement materials will be reviewed by
relevant Ethics Committees before going live.
As of 6 January 2021, Hanoi has recorded 198 COVID-19 cases. For approximately the last 4
months, there has been no case of COVID-19 in Vietnam resulting from community transmission;
new cases have been imported from outside of Vietnam and quarantined upon arrival. As a result
exposure to SARS-CoV-2 is likely to be limited during conduct of the study, thus limiting
censoring of subjects from immunogenicity analyses requiring baseline seronegativity.
·
Phase 2:
Phase 2 of the study will be conducted at Vu Thu district health center, Thai Binh province in
Vietnam. National Institute of Hygiene and Epidemiology (NIHE) will collaborate with staff of
the commune health centers, district health center, district hospital, as well as the staff of the
Provincial Center for Disease Control for conduct of this study. Thai Binh CDC and district
health center have collaborated with NIHE for several vaccine clinical trials funded by
international sponsors and monitored by contract research organizations (CROs).
According to the health system in Vietnam, the district hospitals and their corresponding district
health centers, the provincial general hospital, and the CDC are all managed by the Provincial
Health Services; so it is straightforward to coordinate care among them should a serious adverse
event occur. The staff of commune and district health centers conduct routine vaccinations in the
community and have the capacity to handle serious vaccine reactions. The district hospitals also
have good capacity in terms of both personnel and equipment to provide medical care, including
emergency care. The district health center is only approximately 7 kilometers (10 minute drive)
from provincial general hospitals that would be engaged to manage higher grade and serious
adverse events requiring hospitalization or referred events requiring consultation with a specialist.
This will assure rapid patient transport and referral to tertiary care hospitals at provincial levels in
case such referral is necessary. The study documents will be stored at the provincial CDC where
data entry will occur, and will be moved to the district health center when a study visit is
occurring there. The study samples will also be stored at the provincial CDC lab. The study team
will recruit subjects for this study from the communes around the Vu Thu district health center.
Subjects will be seen at the Vu Thu district health center for scheduled study visits, and receive
routine medical care at Vu Thu district hospital. Subjects will be encouraged to contact the study
team if they have any new onset medical conditions, medically attended events, notable signs
and/or symptoms of COVID-19, or other concerns during their period of enrollment in the study
to ensure all safety data are collected in a complete, accurate and timely manner.
As of 6 January 2020, there has been no confirmed case of COVID-19 in the Vu Thu district. In
daily life, people living in Vu Thu district do not often have contact with people outside of their
community, as travel outside the district – and migration into the district – is rare. This is
expected to facilitate compliance with study visits and safety monitoring generally. Also,
exposure to SARS-CoV-2 is likely to be very limited during conduct of the study, thus limiting
censoring of subjects from immunogenicity analyses requiring baseline seronegativity.
Regardless of estimated exposure risk, HMU and Vu Thu district health center will follow the
policies and procedures implemented by Ministry of Health to minimize risk of SARS-CoV-2
transmission at these facilities, including mandatory use of masks by all staff, social distancing,
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and frequent handwashing/sanitizing. This policy will be extended to include study subjects (and
prospective subjects) during clinic visits, and will be strictly enforced. Study subjects will also be
instructed on how to minimize risk of exposure to SARS-CoV-2 while outside of the study clinic,
including during transit to and from study visits at HMU and Vu Thu district health center.
Prospective subjects who are consented to participate (i.e., enrolled) in this Phase 1/2 study will only be
eligible for randomization if, during screening, they meet all of the inclusion criteria, and none of the
exclusion criteria, as follows:
5.3.
Inclusion Criteria
Phase 1 Only:
1. Adult 18 through 59 years of age inclusive at the time of randomization.
2. Healthy, as defined by absence of clinically significant medical condition, either acute or chronic,
as determined by medical history, physical examination, screening laboratory test results, and
clinical assessment of the investigator.
Phase 2 Only:
1.
Adult 18 through 75 years of age inclusive at the time of randomization.
2. Having no clinically significant acute medical condition, and no chronic medical condition that
has not been controlled within 90 days of randomization, as determined by medical history,
physical examination, screening laboratory test results, and clinical assessment of the investigator.
Both Phase 1 and Phase 2:
3. Has provided written informed consent prior to performance of any study-specific procedure.
4. Has a body mass index (BMI) of 17 to 40 kg/m2, inclusive, at screening.
5. Resides in study site area and is able and willing to adhere to all protocol visits and procedures.
6. If a woman is of childbearing potential, must not be breastfeeding or be pregnant (based on a
negative urine pregnancy test at screening and during the 24 hours prior to receipt of the first dose
of IP), must plan to avoid pregnancy for at least 28 days after the last dose of IP, and be willing to
use an adequate method of contraception consistently and have a repeated pregnancy test prior to
the second (last) dose of IP.
5.4.
Exclusion Criteria
1. Use of any investigational medicinal product within 90 days prior to randomization or planned
use of such a product during the period of study participation.
2. History of administration of any non-study vaccine within 28 days prior to administration of study
vaccine or planned vaccination within 3 months after enrolment.
Note: receipt of any COVID-19 vaccine that is licensed or granted Emergency Use Authorization
in Vietnam during the course of study participation is not exclusionary if administered after Visit
5.
3. Previous receipt of investigational vaccine for SARS or MERS, or any investigational or licensed
vaccine that may have an impact on interpretation of the trial results
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4. History of hypersensitivity reaction to any prior vaccination or known hypersensitivity to any
component of the study vaccine
5. History of egg or chicken allergy
6. History of angioedema
7. History of anaphylaxis
8. Acute illness (moderate or severe) and/or fever (body temperature measured orally ≥38°C)
9. Any abnormal vital sign deemed clinically relevant by the PI
10. Abnormality in screening laboratory test deemed exclusionary by the PI in consultation with the
Sponsor
11. A positive serologic test for hepatitis B (HBsAg) or hepatitis C (HCV Ab)
12. History of confirmed HIV
13. History of laboratory-confirmed COVID-19
14. History of malignancy, excluding non-melanoma skin and cervical carcinoma in situ
15. Any confirmed or suspected immunosuppressive or immunodeficient state
16. Administration of immunoglobulin or any blood product within 90 days prior to first study
injection or planned administration during the study period.
17. Administration of any long-acting immune-modifying drugs (e.g., infliximab or rituximab) or the
chronic administration (defined as more than 14 days) of immunosuppressants within six months
prior to first study injection, or planned administration during the study period (includes systemic
corticosteroids at doses equivalent to ≥ 0.5 mg/kg/day of prednisone; the use of topical steroids
including inhaled and intranasal steroids is permitted).
18. History of known disturbance of coagulation or blood disorder that could cause anemia or excess
bleeding. (e.g, thalassemia, coagulation factor deficiencies).
19. Recent history (within the past year) or signs of alcohol or substance abuse.
20. Any medical, psychiatric or behavior condition that in the opinion of the PI may interfere with the
study objectives, pose a risk to the subject, or prevent the subject from completing the study
follow-up.
21. Employee of any person employed by the Sponsor, the contract research organization (CRO), the
PI, study site personnel, or site.
Note: specific exclusion criteria (e.g., ≥Grade 2 acute illness, or abnormal vital sign deemed
clinically relevant by the PI/designee) will be reassessed at both vaccination visits. Any subject who
cannot be vaccinated due to an acute abnormality assessed at a vaccination visit (Visit 1 or Visit 3)
may return once the acute issue has resolved, if deemed appropriate by the PI/designee. A minimum
of 48 hours must have passed after a documented fever before a subject can be vaccinated. This safety
requirement will not be deemed a protocol deviation should the visit fall outside the vaccination
window; however, it will be encouraged to maintain the vaccination window whenever possible in
these situations. Clinical laboratory test results and vital signs used to determine subject eligibility
will be those obtained at screening. These tests may be repeated once if deemed appropriate by the
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investigator and determined to be due to a transient condition that has resolved. In addition, a test
may also be repeated for test results determined to be spurious by the investigator (e.g., following
improper specimen collection). The last measurement will be taken as the baseline for purposes of
analysis.
5.5.
Screen Failures
Prospective subjects who are enrolled in the study, and who subsequently do not meet one or more
criteria required for participation in the study during the screening period, are considered screen
failures. Any individual deemed a screen failure may not be rescreened. All screen failures will be
recorded in the Case Report Form (CRF). Any individual deemed a screen failure due to a previously
undiagnosed medical condition will be provided with appropriate referral within the health care
system.
6. STUDY PRODUCT
6.1.
Product Descriptions
COVIVAC is an inactivated NDV chimera expressing a trimeric pre-fusion form of the SARS-CoV-2
S protein that contains six proline mutations (HexaPro). The vaccine is a clear and slightly opalescent
liquid.
All study vaccine products to be administered on a given day (based on the study stage) will be
formulated separately by the assigned site staff under aseptic conditions at the start of the clinic day.
A detailed mixing procedure will be provided in the Pharmacy Manual or SOP for study product
preparation. Each vaccine product will be formulated by filling a 4 ml (4R) [with the height of 46 mm
and diameter of 16/1 mm] USP Type I glass vial with bulk drug substance, bulk adjuvant (if indicated
based on formulation) and phosphate-buffered saline (PBS) to allow for five 0.5 ml doses per vial, as
well as sufficient residual volume for possible dose verification. Each vial label will include the
following information: name of the medicinal product, composition, fill volume, route of
administration, lot number, manufacturing date, storage condition, and a cautionary statement (“For
Clinical Trial Use Only”).
The placebo control is PBS (pH 7.2), manufactured by IVAC and tested by National Institute for
Control of Vaccines and Biological (NICBV).
6.2.
Stability and Storage
The temperature of bulk COVIVAC drug substance and CpG 1018 will be monitored during
shipment to and storage at the clinical site to ensure that temperature deviations do not occur. The
temperature of shipments will be monitored throughout transit using a continuous temperature
monitoring system. Vaccine and adjuvant will not be used until their temperature throughout transit
has been confirmed to be within acceptable limits. Upon receipt at HMU (for Phase 1) and the Thai
Binh CDC (for Phase 2), bulk COVIVAC vaccine, CpG 1018 adjuvant, and PBS will be stored at 2°C
to 8°C in a dedicated refrigerator that is safe, locked, and not accessible to unauthorized staff –
including study team personnel blinded for study conduct purposes. The refrigerator will be under
continuous temperature monitoring with maintenance of daily temperature logs and connected to a
power source with a reliable back-up system. COVIVAC vaccine, CpG 1018 and PBS must not be
frozen.
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
It is the responsibility of designated unblinded site staff to ensure that study products have not been
exposed to temperatures outside the allowed range during transport or storage at HMU and Thai Binh
CDC prior to being dispensed for vaccination. Should there be a deviation outside the allowed
temperature range, the affected vaccine will be quarantined. The temperature deviation will be
reported to the Sponsor and CRO within 24 hours of awareness who will advise the unblinded
investigator team of the action to be taken based on the magnitude and duration of the temperature
deviation. All drug accountability procedures will be documented and are the responsibility of the
unblinded study staff.
6.3.
Preparation and Administration
A limited number of appropriately trained, unblinded study staff, including the site pharmacist, will
be responsible for preparing study products (in accordance with the randomly determined
assignment), administering the study vaccine, and handling all drug accountability procedures. These
personnel will not participate in the other aspects of the clinical trial, to help ensure the integrity of
the blind at the site. The unblinded staff will not reveal subjects’ randomization assignments to
subjects, or staff associated with the Sponsor, CRO, or site.
Unblinded staff will retrieve a subject’s randomization assignment via secure Interactive Web
Response System (IWRS) or alternative approach (randomization envelope) after being informed by
the PI or designee that a subject is eligible for randomization. They will prepare the 0.5 ml dose of
study product based on the subject’s randomization assignment in a setting distinct from the clinic
staff. Since COVIVAC vaccine may appear opalescent, the syringe barrels of study product will be
masked to maintain the observer-blind study design. A total of five doses of study product may be
drawn from each vial of formulated study vaccine prepared for clinic on the same day; however, in no
circumstance may a dose be prepared and administered more than 6 hours after a vial of study
product has been formulated (the vials will be stored between 2°C and 8°C during this interval). To
be prepared for the highest level of possible medical risk, vaccination will take place in a clinical
setting in which there is immediate access to the medical personnel, equipment, and medications
required for emergency resuscitation.
Since COVIVAC vaccine is a suspension, study vaccine must be shaken gently immediately prior to
use, in order to obtain a uniform homogenous suspension (clear to opalescent in color). Inspection of
each vial will occur immediately prior to use. If a vial or its contents appear unusual in any way, the
vial will not be used, and procedures detailed in the Pharmacy Manual for documentation and
disposal will be followed.
COVIVAC vaccine or PBS placebo will be administered as an IM injection into the mid-deltoid
muscle of the subject’s non-dominant arm. Should the non-dominant arm not be acceptable based on
clinical assessment (e.g., local infection or pre-existing swelling) the dominant arm may be used and
the reason for the change documented. The site at which study vaccine is administered will be
documented in the CRF for all subjects. A detailed account of procedures related to preparation and
administration of study vaccine will be included in the Pharmacy Manual or SOP for study product
preparation.
6.4.
Accountability and Disposal
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The site pharmacist is required to maintain complete records of all study products received from the
Sponsor and will be responsible for maintaining an accurate record of the randomization codes,
inventory, and an accountability record of vaccine and placebo supplies for the study. The site
pharmacist will also be responsible for ensuring the security of these documents. All used vials of
study product will be stored in a dedicated space that is accessible only to the unblinded site staff and
the unblinded CRO monitor, who is responsible for the monitoring and final accountability of all
study products. Partially used vials after the completion of a clinic day will not be used for human
administration or for any other investigational purpose. After final drug accountability is completed,
all used and unused study products must be disposed of according to the Sponsor’s instructions. Due
to the need to maintain blinding, no drug accountability records will be sent to the Sponsor or
included in the trial master file (TMF) until after database lock.
7. STUDY PROCEDURES
7.1.
Recruitment
Details on recruitment and retention of subjects will be outlined in a Recruitment and Retention Plan
prior to study initiation.
In Phase 1 of the study, subjects will be recruited via advertisement in mass media, and websites of
NIHE, HMU and IVAC; volunteers will contact study team for registration. The advertisement
materials will be reviewed by relevant Ethics Committees before going live. Potential subjects who
are interested in study participation will be invited to Hanoi Medical University to attend an ICF
meeting and then a one-to-one consultation with the investigator to address questions and concerns
before being consented and signing the ICF.
In Phase 2 of the study, the study staff will work together with the appropriate district health and
commune health staff to recruit study participants, using IRB-approved recruitment strategies.
The commune staff will work with population collaborators/village health workers to develop a list of
potential study participants based on the existing Village Population Register Books. After that they
will go household to household to introduce the study and eligibility criteria to potential study
participants using information from the “Information Sheet” of the consent document.
Once a potential study participant confirms their interest, they will be invited to Vu Thu District
Hospital to attend an ICF meeting and participate in screening if they are consented.
At the ICF meeting, there will be an information session presented by the PI/designee to provide all
necessary information related to the study. After the information session, each potential participant
will have a one-and-one meeting with one of the assigned study investigators to further discuss the
trial and ask any questions they may have. The investigator will assess the potential participant’s
understanding of key aspects of the study, such as the voluntary nature of study participation and
potential risks and benefits, using an assessment of understanding. The investigator will review with
the participant any answers they did not understand in order to clarify any misunderstandings. Only
after that, if participant provided consent and signed the ICF, can the screening procedures be started.
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The study staff will follow inclusion/exclusion criteria to determine eligibility. Screening will be
conducted on all people who have signed the study consent, and their results will be reviewed with
them, regardless of eligibility.
7.1.1.
Initial and Continuing Informed Consent
Informed consent is the process of ensuring that study subjects fully understand the purpose of the
study and what will and may happen to them while participating in the study. Initial written informed
consent is required before any study procedures are performed. The informed consent process
continues throughout the study. If any new information becomes available that, in the judgement of
the PI or Sponsor, may affect subjects’ decision to continue in the trial, such information will be
shared with subjects, who may be asked to sign a new consent form.
7.2.
Study Visits
Procedures to be performed at each study visit are shown in Table 5 as follows:
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Table 5.
Schedule of Study Visits and Procedures – Phase 1 and Phase 2
VISIT
Study Day
(allowed window in days)
Informed consent
Demographics
Medical History
Concomitant medicationsA
Eligibility check
Vital signs
Complete physical exam
Targeted physical examB
Clinical chemistryC
HematologyD
Viral serology testsE
Urine pregnancy testF
Unsolicited AEsG
Concomitant medicationsH
Randomization
Blood for humoral immunity
Blood for CMII
Administer study product
Observation/solicited AEs
Provide Diary Card
Review Diary Card
Exit study
Blood volumes (mL):
Safety laboratory tests
(Phase 1 only)
HBV and HCV screening
Humoral immunity
Cell-mediated immunity
Screen
V1
V2
V3
V4
-28 to 1
1
 8
29
36
(+3)         (+7)         (+3)
ü
ü
ü
ü 
ü 
ü 
ü 
ü
ü
~
ü 
ü^ü 
ü 
ü^ü 
ü
ü
ü 
ü 
ü 
ü
ü
ü
ü
ü
ü
ü
ü
ü 
ü
ü
ü 
ü 
ü 
ü 
ü
ü 
ü 
ü 
ü 
ü
ü       ~
ü       ü
ü
ü
ü
ü
ü
ü
ü
ü
ü
4
4
4
2
0
0
10                           10
16
V5
V6
43
57
(+3)         (+7)
ü 
ü
ü 
ü
ü 
ü
ü 
ü
ü 
ü
ü
ü
10
16
V7
V8
197
365
(+14)       (+28)
ü 
ü
ü 
ü
ü 
ü
ü 
ü
ü 
ü
ü 
ü
ü
ü
10
10
16
~ Confirmation
^ Evaluations will be conducted twice – before and after vaccination
A After Visit 6, only medications associated with an AESI, MAAE or SAE will be recorded.
B Targeted PE will be conducted only in the event of new symptom, sign or, until Visit 6, any new AE; or, after Visit
6, any new AESI, MAAE or SAE.
C Serum creatinine, ALT, AST, total bilirubin; only in Phase 1.
D WBC count, hemoglobin, platelets; only in Phase 1.
E HBsAg, HCV Ab
F Women of childbearing potential (WOCBP) only
G After Visit 6, only AESI, MAAEs, and SAEs will be recorded.
H After Visit 6, only concomitant medications associated with a newly reported MAAE or SAE will be recorded I
Only in subset of subjects in Phase 2
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7.2.1.
Screening (Day -42 to Day 1)
Once informed consent has been documented, the prospective subject will be considered to be
enrolled in the trial and may be screened to determine study eligibility. All inclusion/exclusion
criteria must be assessed from data obtained within the screening period, unless otherwise specified in
the eligibility criteria. After informed consent has been obtained, the following screening procedures
will be performed:
1. Subject identification (ID)/screening number will be assigned.
2. The following information will be obtained from the subject:
a. Demographic and contact information, including home address, telephone number(s),
and email address
b. Complete medical history of relevance to study eligibility
c. History of medication use in the past 30 days, and of medications taken that are of
specific relevance to study eligibility (e.g., immunosuppressive medications)
d. Vaccination history
3. Height and weight will be measured, BMI calculation.
4. A full physical examination (PE) will be performed, including vital signs (temperature, pulse
rate, and respiratory rate) and assessment of the major organ systems.
5. A urine pregnancy test will be performed for all women of childbearing potential (WOCBP).
6. Venous blood samples (approximately 6 mL in phase 1, and 2 mL in phase 2) will be obtained
(non fasting) for clinical laboratory tests, as follows:
a. White blood cell (WBC) count, hemoglobin (Hgb), platelets (Plt)
b. Serum creatinine, alanine transaminase (ALT), aspartate transaminase (AST), total
bilirubin (t bili)
c. HBsAg, HCV Ab
Grade 1 vital sign and safety laboratory abnormalities (see Appendix 2 and 3) will not be considered
to be exclusionary at screening nor an AE for the study unless judged to be clinically significant by
the PI/designee, in consultation with the Sponsor. Prospective subjects may return for repeat
assessments once during the screening period to be reassessed for eligibility. The last measurement
will be taken as the baseline for purposes of analysis. The PI/designee will use good clinical judgment
in considering a prospective subject’s overall eligibility.
7.2.2.
Visit 1 (Day 1)
At Visit 1, the following procedures will be performed:
1.
Subject ID, addresses and telephone number(s) will be confirmed.
2.
A urine pregnancy test will be performed for all WOCBP.
3.
Unsolicited AEs will be recorded, including assessment of severity and outcome. Ongoing
unsolicited AEs will be reviewed.
4.
Concomitant medications will be recorded.
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5.
Vital signs will be measured prior to dosing.
6.
Targeted PE will be performed to evaluate any symptom, sign or reported AE, and to confirm
absence of exclusionary acute illness or abnormality of the extremity (skin and lymph nodes)
targeted for vaccination.
7.
Eligibility for vaccination will be confirmed based on review of inclusion/exclusion criteria.
Any subject who cannot be vaccinated due to an acute abnormality (e.g., ≥ Grade 2 acute
illness, or abnormal vital sign deemed clinically relevant by the PI) may return once the
acute issue has resolved, if deemed appropriate by the PI. A minimum of 48 hours must have
passed after a documented fever (oral temperature of ≥ 38°C) before a subject can be
vaccinated.
8.
The subject will be randomized if eligibility is confirmed by the PI.
9.
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing.
For participants in the CMI subset of phase 2, additional 16 mL will be collected.
10. The randomization ID will be recorded by unblinded study staff, who will maintain a list
documenting the study vaccine assigned and administered to given randomization IDs in a
secure location that is not accessible to blinded study staff. The subject will be referred to by
subject ID for the remainder of the study. The randomization ID will be required on select
CRFs.
11. The assigned study product will be administered.
12. After the study product is administered, the subject will be observed by blinded study staff
for at least 30 minutes post-injection.
13. Vital signs and any solicited AEs will be recorded at 30 (+10) minutes post-injection. See
Appendices 1 and 2 for relevant severity grading scales.
14. During the observation period, the subject will be provided with a ruler, thermometer, and
Diary Card, and given instructions on how to complete the Diary Card. The subject will be
instructed to collect solicited AEs daily for seven days (the day of Visit 1 and the following
six days) by recording them in the Diary Card, preferably at approximately the same time
each day. The subject will also be instructed to record unsolicited AEs and concomitant
medications on the Diary Card. Finally the subject will be instructed to call the PI in the
event of any severe (Grade 3) symptoms, or any other health issues that require medical care.
15. The subject will also be provided with a fact sheet on COVID-19 that will include contact
details for the PI, and instructions to contact the PI in the event of COVID-19-associated
symptoms that meet the following criteria:
At least ONE of the following:
· Fever (≥38°C)
· Shortness of breath
· Difficulty breathing
OR
TWO of the following for TWO or more days:
· Chills
· Cough
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
· Fatigue
· Muscle or body aches
· Headache
· New loss of smell or taste
· Sore throat
· Nausea or Vomiting or Diarrhea
The fact sheet will be reviewed with the subject in clinic prior to discharge.
16. Finally, the subject will be reminded to contact the study team to report any MAAE or SAE.
17. The subject will be scheduled for Visit 2 (Day 8).
18. Safety monitoring within 7 days post study vaccination will be as follows:
·
For Phase 1: The study subject will be monitored for safety on site of HMU for 24 hours
after study vaccination. The subject will then be discharged for home and will be
contacted on Day 4 by telephone or home visit to allow the subject to report any solicited
or unsolicited AEs, to address any questions or concerns, and to remind the subject to
complete the Diary Card. On Day 6, she/he will be contacted again by telephone or home
visit for the same purpose and as a reminder to attend Visit 2 (D8).
·
For Phase 2: On the third day (48 hours) post-injection (Day 3), the subject will be
contacted by telephone or home visit for a health check, to address any questions or
concerns, and to remind the subject to complete the Diary Card. On Day 5, she/he will be
contacted again by telephone or home visit for the same purpose and as a reminder to
attend Visit 2.
7.2.3.
Visit 2 (Day 8) and Visit 4 (Day 36)
At Visit 2 and Visit 4, the following procedures will be performed:
1.
Subject ID, addresses and telephone number(s) will be confirmed.
2.
Unsolicited AEs will be recorded, including assessment of relatedness to vaccination, severity,
and outcome. Ongoing unsolicited AEs will be reviewed.
3.
Concomitant medications will be recorded.
4.
Vital signs will be measured.
5.
Targeted PE will be performed to assess the injection site and draining lymph nodes, and to
evaluate any new or ongoing AE.
6.
The completed Diary Card will be reviewed with the subject for completeness and accuracy.
Possible inaccuracies will be clearly documented. Then completed pages of the Diary Card
will be collected, and blank pages and/or additional pages will be returned to subjects for
recording any health issue and concomitant medications until the next visit (V3/D29 and
V7/D57 respectively).
7.
Venous blood samples (approximately 4 mL, only in Phase 1) will be obtained for clinical
laboratory tests (non-fasting), as follows:
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
a.
WBC count, Hgb, Plt
b.
Serum creatinine, ALT, AST, total bilirubin
8.
The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed),
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met.
9.
The subject will be reminded to contact the study team to report any MAAE or SAE.
10. The date of the subsequent clinic visit will be established.
7.2.4.
Visit 3 (Day 29)
At Visit 3, the following procedures will be performed:
1.
Subject ID, addresses and telephone number(s) will be confirmed.
2.
A urine pregnancy test will be performed for all WOCBP.
3.
Unsolicited AEs will be recorded, including assessment of relatedness to vaccination,
severity, and outcome. Ongoing unsolicited AEs will be reviewed.
4.
Concomitant medications will be recorded.
5.
Vital signs will be measured prior to dosing.
6.
Targeted PE will be performed to evaluate any new or ongoing AE, and to confirm absence
of exclusionary acute illness or abnormality of the extremity (skin and lymph nodes) targeted
for vaccination.
7.
Eligibility for vaccination will be confirmed based on review of inclusion/exclusion criteria.
Any subject who cannot be vaccinated due to an acute abnormality (e.g., ≥ Grade 2 acute
illness, or abnormal vital sign deemed clinically relevant by the PI/designee) may return once
the acute issue has resolved, if deemed appropriate by the PI/designee. A minimum of 48
hours must have passed after a documented fever (oral temperature of ≥ 38°C) before a
subject can be vaccinated.
8.
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing.
9.
The subject’s randomization ID will be recorded by unblinded study staff, who will prepare a
dose of the assigned study product.
10. The assigned study product will be administered.
11. After the study product is administered, the subject will be observed by blinded study staff
for at least 30 minutes post-injection.
12. Vital signs and any solicited AEs will be recorded at 30 (+10) minutes post-injection. See
Appendices 1 and 2 for relevant severity grading scales.
13. During the observation period, the subject will be provided with a ruler, thermometer, and
Diary Card, and given instructions on how to complete the Diary Card. The subject will be
instructed to collect solicited AEs daily for seven days (the day of Visit 3 and the following
six days) by recording them in the Diary Card, preferably at approximately the same time
each day. The subject will also be instructed to record unsolicited AEs and concomitant
medications on the Diary Card. Finally the subject will be instructed to call the PI/designee in
the event of any severe (Grade 3) symptoms, or any other health issues that require medical
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care.
14. The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed),
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met.
15. The subject will be reminded to contact the study team to report any MAAE or SAE.
16. The subject will be scheduled for Visit 4 (Day 36).
17. Safety monitoring within 7 days post study vaccination will be as follows:
For Phase 1: The study subject will be monitored for safety on site of HMU’s hospital for 4
hours after study vaccination. The subject will then be discharged for home and will be
contacted on Day 32 by telephone or home visit for a health check, to address any questions
or concerns, and to remind the subject to complete the Diary Card. On Day 34, she/he will be
contacted again by telephone or home visit for the same purpose and as a reminder to attend
Visit 4 (D36).
For Phase 2: On the third day (48 hours) post-injection (Day 31), the subject will be
contacted by telephone or home visit for a health check, to address any questions or
concerns, and to remind the subject to complete the Diary Card. On Day 33, she/he will be
contacted again by telephone or home visit for the same purpose and as a reminder to attend
Visit 4.
7.2.5.
Visit 5 (Day 43)
At Visit 5, the following procedures will be performed:
1.
Subject ID, addresses and telephone number(s) will be confirmed.
2.
Unsolicited AEs will be recorded, including assessment of relatedness to vaccination,
severity, and outcome. Ongoing unsolicited AEs will be reviewed.
3.
Concomitant medications will be recorded.
4.
Vital signs will be measured.
5.
Targeted PE will be performed to evaluate any new or ongoing AE.
6.
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing.
For participants in the CMI subset of phase 2, additional 16 mL will be collected.
7.
The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed),
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met.
8.
Finally the subject will be reminded to contact the study team to report any MAAE or SAE.
9.
The subject will be scheduled for Visit 6 (Day 57).
7.2.6.
Visit 6 (Day 57)
At Visit 6, the following procedures will be performed:
1.
Subject ID, addresses and telephone number(s) will be confirmed.
2.
Unsolicited AEs will be recorded, including assessment of relatedness to vaccination,
severity, and outcome. Ongoing unsolicited AEs will be reviewed.
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3.
Concomitant medications will be recorded.
4.
Vital signs will be measured.
5.
Targeted PE will be performed to evaluate any new or ongoing AE.
6.
The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed),
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met.
7.
Finally the subject will be reminded to contact the study team to report any MAAE or SAE.
8.
The subject will be scheduled for Visit 7 (Day 197).
9.
The subject will receive a text or email every two weeks as a reminder to contact the site to
report any MAAE or SAE.
7.2.7.
Visit 7 (Day 197)
At Visit 7, the following procedures will be performed:
1.
Subject ID, addresses and telephone number(s) will be confirmed.
2.
MAAEs or SAEs that have not previously been reported will be recorded, including
assessment of relatedness to vaccination, severity, and outcome. Ongoing MAEs and SAEs
will be reviewed.
3.
Concomitant medications associated with a newly reported MAAE or SAE will be recorded,
and ongoing concomitant medications reviewed.
4.
Vital signs will be measured.
5.
Targeted PE will be performed to evaluate any new or ongoing AE, and intervening MAAE
or SAE.
6.
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing.
For participants in the CMI subset, additional 16 mL will be collected.
7.
The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed),
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met.
8.
The subject will be reminded to contact the study team to report any MAAE or SAE.
9.
The subject will be scheduled for Visit 8 (Day 365).
10. The subject will receive a text or email every two weeks as a reminder to contact the site to
report any MAAE or SAE.
7.2.8.
Visit 8 (Day 365, EOS)
At Visit 8, the following procedures will be performed:
1.
Subject ID, addresses and telephone number(s) will be confirmed.
2.
MAAEs or SAEs that have not previously been reported will be recorded, including
assessment of relatedness to vaccination, severity, and outcome. Ongoing MAEs and SAEs
will be reviewed.
3.
Concomitant medications associated with a newly reported MAAE or SAE will be recorded,
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and ongoing concomitant medications reviewed.
4.
Vital signs will be measured.
5.
Targeted PE will be performed to evaluate any new or ongoing AE, and intervening MAAE
or SAE.
6.
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing.
7.
The subject will exit the study after completion of the EOS CRF.
7.2.9.
Unscheduled Contacts and Visits
Unscheduled contacts and visits may take place at subject request or as deemed necessary by the PI or
site staff at any time during the study. Subjects will be instructed to contact the PI/designee if clinical
criteria for COVID-19 are met (as specified on the COVID-19 fact sheet) throughout the entire study
period. Subjects will also be instructed to contact the site to report any MAAE or SAE throughout the
entire study period. All unscheduled contacts and visits will be documented in the subject’s study
records and on applicable CRFs.
7.3.
Subject Discontinuation
Subject discontinuation from study procedures prior to completion of the last study visit may occur
for any of the following reasons:
·
Withdrawal (defined as discontinuation initiated by a subject): Participation in the study is
strictly voluntary. Subjects have the right to withdraw their consent from study participation at
any time and for any reason, without penalty. The subject may also withdraw due to an
adverse event.
·
PI-initiated: The PI/designee may, at her discretion, discontinue a subject from the study if it
is considered to be in the subject’s best interest to do so (e.g., for safety concerns), or if the
subject does not comply with the study requirements. Any subject who is determined to be
infected with SARS-CoV-2 prior to Visit 3 (Day 29) will be discontinued from the study (i.e.,
will not receive the second study injection) but will continue to be followed for safety
assessments through Visit 8 (EOS).
·
Lost to follow-up: For subjects who fail to attend scheduled visits, study staff are to make at
least three attempts to contact the subject prior to considering the subject as lost to follow-up.
These attempts should be recorded in the source documents.
·
Sponsor-initiated: For example, if the Sponsor is obliged to end the study for administrative or
any other reason, such as a recommendation by the DSMB based upon safety review.
Subjects who discontinue prior to first administration of the study product will be replaced, whereas
those withdrawn after first administration of the study product will not be replaced.
The reason for and date of subject discontinuation will be recorded in the source documents and
relevant CRF. Before concluding the reason for the subject’s discontinuation from the
study, the investigator should make every effort to investigate whether an AE may have been
related to the subject’s discontinuation from the study. For subjects considered lost to follow-up, the
discontinuation date for the subject to be captured on the discontinuation CRF page is the date of
the subject’s last completed study visit.
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In the event of subject discontinuation from the study, reasonable efforts should be made to conduct
the following procedures (unless subject consent to do so has been withdrawn):
·
Update subject contact information.
·
Review the Diary Card if still in use prior to discontinuation.
·
Update any AEs that remained ongoing at the time of the subject’s last visit prior to
discontinuation.
·
Collect any new reportable AEs and concomitant medications since the subject’s last visit,
based on the protocol-defined reporting period at the time of discontinuation.
·
Perform a targeted PE to evaluate any newly reported AEs since the subject’s last visit.
7.4.
Concomitant Medications
All concomitant medications will be recorded in source documents from Visit 1 (Day 1) through Visit
5 (Day 57). After Visit 5, only those concomitant medications associated with MAAEs and SAEs will
be recorded. Details on concomitant medications to be recorded include the generic and/or trade
name, indication, dosage, regimen, route of administration, and start and end dates of the medication.
The following concomitant medications are prohibited during the study; however, they must not be
withheld by the treating physician if clinically indicated to treat a subject:
·
Any investigational medicinal product other than the study product
·
Administration of immunoglobulins or any blood products
·
Administration of any long-acting immune-modifying drugs (e.g., infliximab or rituximab) or
the chronic administration (defined as more than 14 days) of immunosuppressive medications
(includes systemic corticosteroids at doses equivalent to ≥ 0.5 mg/kg/day of prednisone; the
use of topical steroids including inhaled and intranasal steroids is permitted).
Use of any prohibited medication must be recorded in the CRF. Whether a subject who uses a
prohibited medication will be included in the Per Protocol Population will be evaluated on a case-by-
case basis.
7.5.
Emergency Unblinding Procedure
In the event of a medical emergency, the PI/designee may require that the blind be broken for the
subject experiencing the emergency when knowledge of the subject’s treatment assignment may
influence the subject’s clinical care. Every effort will be made not to unblind the subject unless it is
considered
absolutely necessary for the welfare of the subject. Prior to unblinding, the investigator is
encouraged (to the extent possible, without jeopardizing the subject’s health) to contact the Sponsor
(or designee) to discuss the decision to break the blind.
Unblinding will occur through the secure IWRS or according to the emergency unblinding SOP, to
which there will be 24-hour access. Documentation of the unblinding event will be captured by the
IWRS or unblinded staff. In the unlikely event that the IWRS cannot be accessed, a backup process
(such as contacting the unblinded pharmacist) will be provided. The PI/designee will be expected to
provide a rationale for the necessity of unblinding, based on the expectation that knowledge of the
subject’s treatment assignment will have a meaningful impact on the subject’s medical care in the
short term. If a subject’s treatment assignment is unblinded, the subject will remain in the study and
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continue with protocol-defined study visits and procedures, unless there is another reason for subject
discontinuation. The decision to unblind will be communicated to all regulatory bodies as required.
At the end of the study, documentation of all unblinded subjects (and the rationale for unblinding)
will be incorporated into the TMF.
7.6.
Management of Pregnancy
All WOCBP will be monitored for pregnancy during the study and for the use of adequate
contraception until completion of Visit 6 (Day 57).
If a female subject becomes pregnant after Visit 1 (Day 1) but prior to Visit 3 (Day 29) no further
study product will be administered. The subject will be encouraged to complete all remaining study
visits for safety assessments alone, and if possible and agreed to by the subject, continue to be
followed through the pregnancy outcome. The pregnancy and its outcome will be documented, even
if birth occurs after the scheduled end of the study for the subject. The PI/designee is required to
notify the Sponsor (or designee) within 24 hours of knowledge of a pregnancy.
7.7.
Clinical Procedures
Vital Signs
·
Temperature will be measured in degrees Celsius (recorded to the nearest 0.1 degree) by oral
(sublingual) thermometer following at least 20 minutes of avoidance of food and drink.
·
Respiratory rate will be measured in breaths per minute.
·
Blood pressure will be measured in millimeters (mm) of mercury and heart rate in beats per
minute by automated device or manually on the arm not used for study product
administration.
·
Vital signs will be graded according to the toxicity grading scale in Appendix 2.
Height and Weight
·
Height will be measured in centimeters (cm) and recorded to the nearest 0.1 cm.
·
Weight will be measured in kilograms (kg) and recorded to the nearest 0.1 kg.
Complete Physical Examination
·
A complete physical examination will include head, eyes, ears, nose, oropharynx, neck, chest
(auscultation), lymph nodes (neck, supraclavicular, axillary), back, abdomen (auscultation and
palpation), musculoskeletal, skin (especially hands, arms, injection sites), and nervous system.
Injection Site Examination
·
Erythema will be examined under standard lighting conditions and measured based on the
maximum diameter and recorded to the nearest 0.1 cm.
·
Swelling/induration will be examined by palpation and visual inspection under standard
lighting conditions; the examiner may temporarily mark the skin at the margins of visible
swelling/induration, then measure at the maximum diameter and record the distance to the
nearest 0.1 cm.
·
Local reactions will be graded according to the toxicity grading scale in Appendix 1.
8. SAFETY ASSESSMENT AND REPORTING
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The PI/designee is responsible for the detection and documentation of events meeting the criteria and
definition of an AE or SAE as provided in this protocol for the duration of the study.
8.1.
Collection of Safety Events
AEs will be systematically collected at all clinic visits. Solicited AEs will be assessed in all
subjects immediately (30 minutes) after each injection. Subjects will record solicited AEs daily in
Diary card for the seven days following each injection, as well as record unsolicited AEs during this
period. If a solicited AE is ongoing at a 7-day post-injection follow-up visit (Visit 2 or 4), it will be
continued to be followed as per AE monitoring requirements. All unsolicited AEs and Solicited AEs,
but occurs after 7 days post-injection and clinically significant safety lab tests will be recorded on the
AE CRF.
All AEs, including MAAEs, SAEs and AESI, will be collected through the 28-day post-second-
injection follow-up visit (Visit 6). After Visit 6, only MAAEs, SAEs, and AESI will be recorded.
8.2.
Definitions
8.2.1.
Adverse Event
An adverse event is any untoward, undesired, or unplanned event in the form of signs, symptoms,
disease, or laboratory or psychological/physiologic observations occurring in a subject enrolled in the
clinical trial. This includes all subjects from whom consent has been obtained whether or not they
have yet been randomized and received a study product. The event does not need to be causally
related to trial participation or receipt of a study product. An AE is temporally related to participation
in the study and will be documented as to whether or not it is considered to be related to vaccine. An
AE includes, but is not limited to, the following:
·
An intercurrent illness or injury during the course of the study
·
Any clinically significant worsening of a preexisting condition
8.2.2.
Solicited Adverse Event
Solicited adverse events are pre-specified injection-site-specific local and systemic AEs that occur
relatively more frequently, or are known to be associated with, immunization, and which are
monitored actively as potential indicators of vaccine reactogenicity. Investigators will not be required
to assess causality of solicited AEs if the onset is during the solicitation period.
The following specific solicited AEs will be monitored for this study:
Local solicited AEs assessed at the injection site:
·
Pain or tenderness
·
Swelling or induration
·
Erythema
Systemic solicited AEs:
·
Fever (defined as oral temperature ≥ 38°C)
·
Headache
·
Fatigue or malaise
·
Myalgia
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·
Arthralgia
·
Nausea or vomiting
8.2.3.
Unsolicited Adverse Event
An unsolicited adverse event is any AE reported spontaneously by the subject, observed by the study
staff during study visits or those identified during review of medical records or source documents.
Solicited AEs with an onset after the seven-day solicitation period will be considered unsolicited
AEs. In the absence of a diagnosis, abnormal physical examination findings or abnormal clinical
safety laboratory test results that are assessed by the investigator to be clinically significant will be
recorded as an AE.
8.2.4.
Medically-Attended Adverse Event
A medically-attended adverse event is an unsolicited AE for which the subject received medical
attention, such as during an emergency room visit or a visit to or from medical personnel (e.g.,
medical doctor).
8.2.5.
Adverse Event of Special Interest
An adverse event of special interest (AESI) is an AE 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 can be appropriate. Such an event might warrant further investigation in
order to characterize and understand it.
The AESI to be monitored in this study include the following:
·
Potential immune-mediated medical conditions (PIMMC), given that vaccination has been
associated with autoimmunity (See Appendix 4)
·
AEs associated with COVID-19, given the importance to subject safety of managing any
occurrence of COVID-19, and the possible association of vaccination with enhancement of
COVID-19 (See Appendix 5)
There may be additional PIMMC, AEs associated with COVID-19, or other AESI not included in
Appendices 4 and 5 that are established by the Sponsor or regulatory authorities prior to or during
conduct of the study.
8.2.6.
Protocol-Related Adverse Event
A protocol-related adverse event is an AE that occurs from the time of enrollment until the EOS visit
that is not considered to be related to receipt of the study vaccine, but is considered by the
PI/designee or the Sponsor to be related to the research conditions, i.e., related to the fact that a
subject is participating in the study. For example, a protocol-related AE may be an untoward event
occurring during blood sampling or other protocol-specified activity.
8.2.7.
Treatment-Emergent Adverse Event
A treatment-emergent AE is defined as an AE that is not present prior to administration of the study
product, or, if present prior to the administration of the study medication, increases in intensity after
administration of the study medication during the course of the study.
8.2.8.
Serious Adverse Event
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An SAE is a specific AE that:
·
Results in death.
·
Is life-threatening.*
·
Requires inpatient hospitalization or prolongation of an existing hospitalization.**
·
Results in a persistent or significant disability or incapacity.***
·
Results in a congenital anomaly or birth defect.
*Life-threatening refers to immediate risk of death as the event occurred per the reporter. A life-
threatening event does not include an event that, had it occurred in a more severe form, might have
caused death but, as it actually occurred, did not create an immediate risk of death.
For example, hepatitis that resolved without evidence of hepatic failure would not be considered life-
threatening, even though hepatitis of a more severe nature can be fatal. Similarly, an allergic reaction
resulting in angioedema of the face would not be life-threatening, even though angioedema of the
larynx, allergic bronchospasm, or anaphylaxis can be fatal.
**Hospitalization is an admission to a health facility in the situation where there is an AE. A period
of observation at a clinical trial site is not considered to represent hospitalization for the purposes of
SAE reporting. Hospitalization or prolongation of a hospitalization constitutes a criterion for an AE to
be serious; however, it is not in itself considered an SAE. In absence of an AE, a hospitalization or
prolongation of a hospitalization should not be reported as an SAE by the PI/designee on a SAE form.
Such situations include, but are not limited to, the following:
·
A hospitalization for a preexisting condition that has not worsened.
·
Hospitalization for social reasons.
***Disability is defined as a substantial disruption in a person’s ability to conduct normal life
functions. If there is any doubt about whether the information constitutes an SAE, the information is
treated as an SAE.
Medical and scientific judgment should be exercised in deciding whether expedited reporting is
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require
intervention to prevent one of the other outcomes listed in the definition above. These should also
usually be considered serious. Examples of such events are intensive treatment in an emergency room
or at home for allergic bronchospasm, or blood dyscrasias or convulsions that do not result in
hospitalization.
8.2.9.
Severity (Intensity) of Adverse Event
The severity of all solicited AEs will be graded from Mild (Grade 1) to Potentially Life Threatening
(Grade 4), based on the criteria given in Appendix 1. All AEs leading to death are Grade 5 events.
Adverse events are graded based on the worst severity grade during the illness/symptoms. All other
unsolicited AEs will be classified as an AE and graded based on the AE severity scale in Error!
Reference source not found. 6 below. The grading scales for solicited and unsolicited AEs have
been derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and
Pediatric Adverse Events (Version 2.1, July 2017), from the US National Institutes of Health.
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Table 6.
Severity Grading
Grade 
Description
1
2
3
4
8.2.10.
Causes no or minimal interference with normal daily activities;
intervention not indicated
Interferes with but does not prevent normal daily activities;
intervention indicated
Prevents normal daily activities; intervention or hospitalization indicated
Causes inability to perform basic self-care activities; intervention
indicated to prevent permanent impairment, persistent disability, or death
Causal Relationship of an Adverse Event
A suspected adverse drug reaction (ADR) means any AE for which there is a reasonable possibility
that the study vaccine caused the AE. A reasonable possibility means there is evidence to suggest a
causal relationship between the vaccine and the AE. All cases judged by either the PI/designee or
the Sponsor as having a reasonable suspected causal relationship to the study vaccine will qualify
as ADRs. Medical judgment will be used to determine the relationship, considering all relevant
factors, including pattern of reaction, temporal relationship, confounding factors such as
concomitant medication, concomitant diseases, and relevant history.
The likelihood of the relationship of the AE to study vaccine is to be recorded as follows:
·
Related: There is a reasonable causal relationship between the vaccine administered and the
AE.
·
Not Related: There is no reasonable causal relationship between the vaccine administered
and the AE.
Note: solicited reactogenicity events will not be judged for relatedness.
8.2.11. Assessment of Outcome of Adverse Event
The outcome of the AE will be assessed and recorded as per the following categories:
·
Ongoing.
·
Recovered/resolved.
·
Recovered/resolved with sequelae.
·
Fatal.
·
Unknown.
8.3.
Adverse Event Recording and Reporting
Recording and reporting of all AEs will occur from signing of the ICF (enrollment) through 28 days
post-second injection (Visit 6) for each study subject receiving study product. SAEs, MAAEs, and
AESI will be recorded throughout the study period. The Study staff must completely and promptly
record each AE in the source documentation and on the AE CRF, regardless of relationship to the
vaccine administered/procedure as determined by the PI/designee. The PI/designee will attempt, if
possible, to establish a diagnosis based on the signs and symptoms. When a diagnosis for the reported
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signs or symptoms is known, the PI/designee will report the diagnosis as the AE, not the signs and
symptoms. Adverse events will be classified by MedDRA term and by severity/intensity, relatedness,
and outcome.
Enrolled subjects who subsequently screen fail (i.e., who never underwent randomization) or
withdraw consent will have any AEs recorded from enrollment until the time they are determined to
be ineligible for randomization or withdraw consent. These AEs will be listed in separate appendices
from those subjects randomized and vaccinated. For the purposes of data capture they will be closed
at the point the subject is deemed ineligible.
Reporting of AEs will follow the regulatory guidelines of the Ministry of Healthand NIHE’s EC in
regard to requirements, processes and forms.
8.4.
Serious Adverse Event Reporting
If an AE is classified as serious, an SAE form will be completed and submitted within 24 hours of the
PI/designee becoming aware of the SAE, including information on the location, severity, relatedness,
and clinical summary of the event to the Sponsor to initiate any PSRT evaluation and any additional
reporting requirements. In addition, the SAE submission will follow the regulatory guidelines of the
Ministry of Health andNIHE’s IRB in regards to requirements, processes and forms. It is the
responsibility of the Sponsor to ensure that Dynavax Technologies Corporation (manufacturer of the
adjuvant CpG 1018) and the other Consortium manufacturers are notified of SAEs and other notable
safety events per agreed procedures and timelines. Any SAE deemed related to study vaccine that is
ongoing at the time of last subject last visit (LSLV) will continue to be followed until it is resolved,
assessed to be resolved with sequelae, or assessed to be stable/chronic. SAEs deemed not related to
study vaccine that are unresolved at the time of LSLV will be classified as ongoing.
8.5.
Unanticipated Problems
All unanticipated problems will be reported in the continuing review report submitted to the Ministry
of Healthand NIHE’s IRB per reporting requirements of each regulatory body. All serious
unanticipated problems involving risk to participants or others will be promptly (within 48 hours)
reported by telephone, by email, or by facsimile to the Sponsor. Follow-up reports will be submitted
as soon as additional information becomes available.
9. SAFETY MONITORING
The PI/designee will be responsible for continuous monitoring of all study subjects’ safety. In case of
urgent need, subjects will have the means to get in contact with study staff at any time (24 hours per
day). The PI/designee will also be available by cell phone 24-hours per day for medical emergencies.
9.1.
Protocol Safety Review Team
Safety will be monitored routinely throughout the study by the PSRT, which includes the PI/designee
and other site investigators, the IVAC Clinical Lead, and the Medical Monitor. The PSRT will be
continuously involved in safety monitoring and be available to address any urgent medical queries or
safety concerns related to any subject’s participation in the study. Data management personnel will
ensure that the PSRT receives immediate notification of all reported SAEs and any other predefined
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AEs (e.g., Grade 3 AEs). The PSRT will convene to review blinded safety data on a weekly basis until
D43 of the last subject in each phase, then at least once monthly until the end of the study.
During meetings the PSRT will review blinded safety reports and review any outstanding medical or
safety queries from the previous review. The blinded safety reports will contain at a minimum,
subject disposition and discontinuations, all new Grade 3 and persistent (beyond 6 days post-IP
administration) solicited AEs, and all new unsolicited AEs. Cumulative safety data reports will also
be made available continuously for review by PSRT members. In addition, the PSRT will review all
major protocol deviations in an expedited manner and all other protocol deviations at least on a
monthly basis to assess for any potential safety implications, and will provide guidance in the
preparation of corrective action plans. The PSRT may also discuss any other study conduct issues that
impact study integrity and subject safety, including but not limited to data quality and critical
monitoring findings. The PSRT may refer any safety concerns to the DSMB. The full responsibilities
and procedures of the PSRT will be detailed in the Safety Management Plan.
9.2.
Data and Safety Monitoring Board
A DSMB, composed of at least three independent members with expertise in vaccine clinical trials,
will be convened to provide additional safety oversight. In Phase 1, the DSMB will meet to review
unblinded safety data through Day 57 (V6), and on the basis of this review provide a recommendation
for advancing to Phase 2 (i.e. the DSMB will indicate whether advancement to Phase 2 is warranted
based on the reviewed safety data, and whether specific COVIVAC formulations should not be
considered for advancement due to safety concerns). In the Phase 2 segment, the DSMB will again
meet to review unblinded safety data through Day 57 (V6), and on the basis of this review provide a
recommendation for advancing to Phase 3 (i.e. the DSMB will indicate whether there are any safety
concerns with one or the other selected COVIVAC formulation evaluated in Phase 2).
The DSMB will also meet if a study pause rule is met, or the PSRT elects to implement a study
pause. If this occurs, no further enrollment will occur, and no study product will be administered until
the DSMB approves lifting the pause based on unblinded review of all safety data accrued during the
trial. If the study is permanently terminated, subjects who have already received study product will
continue with all scheduled protocol visits and assessments; however, they will not receive any
further study product.
DSMB reviews will indicate whether or not safety concerns were identified, and whether the trial
should continue without change, be modified, or be terminated. The Sponsor will carefully consider
the DSMB recommendations. If the Sponsor does not agree with these recommendations, a meeting
will be held between the Sponsor, PI, and DSMB to reach consensus on the appropriate action(s) to
take in regard to the trial. However, if attempts to reach consensus fail, the Sponsor’s opinion will
prevail. In such situations, the Sponsor will inform the MoHand NIHE’s EC of the Sponsor’s
perspective, and any changes to the trial. The PSRT, PI or IVAC Clinical Lead may also seek
additional guidance from the DSMB as dictated by the occurrence of certain events that do not
warrant a study pause.
The composition, responsibilities and procedures of the DSMB will be detailed in the DSMB Charter.
9.3.
Pause Rules
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The DSMB will be convened if it is established that any of the following study pause rules has been
met during the conduct of the trial:
·
Rule 1: Occurrence of any SAE attributed to study vaccine in ≥ 1 subject
·
Rule 2: Occurrence of the following Grade 3 or greater injection site solicited AE in ≥ 1
subject: ulceration, necrosis, or sterile abscess at the injection site requiring drainage or
surgical intervention.
·
Rule 3: Occurrence of the same Grade 3 solicited AE, unsolicited AE attributed to study
vaccine, or laboratory abnormality in ≥ 10.0% of unique subjects. In the case of fever, pain
and tenderness, the episode must last longer than 24 hours, and, in the case of fever, be
confirmed by the PI/designee without evidence of other medical causes. Note: for the first
20 randomized subjects, this pause rule will only be met if the grade 3 AE or laboratory
abnormality occurs in ≥ 2 unique subjects.
9.4.
Protocol Deviation
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, site SOP
requirements, or departure from applicable regulatory requirements. The noncompliance may be
either on the part of the subject or the site team/PI.
Major protocol deviations are a subset of protocol deviations that may significantly impact the
completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject's
rights, safety, or well-being. Examples of major protocol deviations may include: failure to obtain
informed consent, failure to report SAEs, enrolling subjects in violation of key eligibility criteria
designed to ensure a specific subject population, or failing to collect data necessary to interpret
primary endpoints, as this may compromise the scientific value of the trial..
When appropriate, corrective actions and preventive actions (CAPAs) will be developed by the site to
address deviations, and will be implemented promptly. These practices will be consistent with ICH
E6 Guidelines.
10. STATISTICAL CONSIDERATIONS
10.1. Overview and General Considerations
This is a randomized, placebo-controlled, observer-blind, two-stage Phase 1/2 trial in healthy male
and non-pregnant female subjects of age 18-75 years old, inclusive. A maximum of 120 eligible
subjects will be accrued in the first stage (Phase 1), and a maximum of 300 eligible subjects will be
accrued in the second stage (Phase 2).
The first stage is a first-in-human study in 120 healthy subjects of age 18-59 years old designed to
evaluate the COVIVAC vaccine at three different dose levels (1 µg, 3 µg, 10 µg) without adjuvant
and one dose level (1 µg ) with the adjuvant CpG 1018. Randomization into each group will be age
stratified with half of subjects between 18-39 years of age and the other half 40-59 years of age.
In the second stage of this combined Phase 1/2 study, 300 adults aged 18-75 years will be randomized
(2:5:5) to placebo, or one of two selected formulations of COVIVAC being evaluated in first phase.
To ensure that adequate safety and immune data will be available from older and elderly adults to
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inform the selection of COVIVAC formulation to advance to Phase 3 studies, randomization will be
age stratified by group with approximately one third of subjects in 18-39, 40-59, and 60-75 years of
age.
10.2. Randomization Procedures
Randomization for Part 1 (Phase 1) will be conducted after accumulation of 120 eligible subjects.
Randomization will be stratified by gender and age (less than 40 years old and 40 to 59 years old,
with approximately 50% of subjects in each age stratum). This is to ensure the groups are as similar
(homogenous) as possible to ensure the down-selection of formulations is not biased by differences in
demographic characteristics of the groups (such as age and gender). Randomization details will be
outlined in a Randomization Plan prior to study initiation.
Each group will be divided into two subgroups, a sentinel subgroup (n=6) and a larger subgroup
(n=24) that includes the remaining subjects to be evaluated at that dose level (or for that formulation
in the case of the one adjuvanted treatment group). Initially, a sentinel subgroup of 6 subjects will be
randomized to receive COVIVAC 1 µg or placebo in a 5:1 ratio. Sentinel subjects will be monitored
for reactogenicity and safety through Day 8 (Visit 2), including for the initial 24 hours post-injection
in clinic. If the PSRT has no safety concerns based on blinded review of all safety data, including
clinical laboratory results, through Visit 2, the second subgroup of 24 subjects will be randomized to
receive COVIVAC 1 µg or placebo at the same ratio; on the same day, the sentinel subgroup (n=6)
for the second dose level to be evaluated (COVIVAC 3 µg) can be randomized to receive study
vaccine or placebo in a 5:1 ratio, and so on for the subsequent dose level and formulation (see Table
4). The same procedure will be used for the COVIVAC 10 µg and COVIVAC 1 µg + CpG arms for a
total of n=25 in each active group and n=20 in the placebo group. Randomization will be stratified by
age (less than 40 years old and 40 to 59 years old) with approximately 50% of subjects in each
stratum.
After the interim analysis of data from the first phase informs the down selection to two candidate
groups 300 adults aged 18-75 years will be randomized (2:5:5) to placebo, or one of two selected
formulations of COVIVAC being evaluated in Phase 1. Twelve (12) subjects in each of the three
Phase 2 groups (equally distributed between the three age strata) will be selected for CMI at the time
of randomization. Randomization will be age stratified by group with approximately one third of
subjects in 18-39, 40-59, and 60-75 years of age.
10.3. Sample Size and Power
This Phase 1/2 study has a two-part selection design with group elimination after the first part (i.e.
Phase 1). A total of 25 (n1) subjects per group will be randomized across 4 candidate and one placebo
group (n1=20) in the first phase. Assay titers will be analyzed on the log scale. The sample size and
power calculations assume an interim analysis will be conducted after D43 of the first phase to
eliminate two candidate groups by selecting the two groups with the largest means. Additionally, the
observed seroresponse rate (defined as the percentage of subjects in a treatment group with at least a
4-fold rise from baseline in 80% neutralizing antibody titers) will need to be at least 52% at the lower
limit of the 95% exact confidence interval. Based on this criterion, there is less than 10% chance of
incorrectly failing to consider advancing a vaccine candidate with a true seroresponse rate of 85% or
higher, which is estimated to be the minimum response rate that would be consistent with further
investment in an additional second-wave COVID-19 vaccine. The Sponsor may consider other factors
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in selecting the two most suitable candidates to advance to second phase. In the second phase, 125
and 50 (n2) additional subjects will be randomized to the two candidate groups and the placebo group,
respectively. The final analysis will be conducted on the full samples from the first and second phase
(n1 + n2).
Safety: Assuming 25 evaluable subjects per group in the first phase (and for elderly subjects enrolled
in the second phase) and 150 total subjects (n1 + n2) in the two candidate groups included in the
second phase, the probability of observing at least one serious or severe adverse event by the
underlying rate is shown in Table 7. If no events are observed the upper bound of the exact 95%
confidence interval would be 13.7% for the three eliminated groups and 2.4% in the two selected
groups.
Table 7. Probability to observe at least one serious or severe adverse event by sample size and
underlying event rate.
Sample size per
group
25
25
25
25
150
150
150
150
150
150
True Event Rate
10.0%
7.5%
5.0%
2.5%
10.0%
7.5%
5.0%
2.5%
1.0%
0.5%
Probability to
observe at least one
92.8%
85.8%
72.3%
46.9%
99.9%
99.9%
99.9%
97.8%
77.9%
52.9%
Immunogenicity: Groups with seroresponse below 52% at the lower limit of the 95% exact
confidence interval will not be considered for selection for the second phase. This provides 90%
power to correctly advance candidates with a true seroresponse rate ≥85%.
This is a two-stage selection design for selecting the group with the largest mean. Power for selecting
the candidate with the largest true mean is driven both by the variability and the smallest difference
between the highest mean and the means in the other three candidate groups.
Table 8 shows the power to correctly select the candidate with the largest true mean in the first phase
(to advance to the second phase) and the overall power for the Phase 1/2 by minimum fold-difference
(on the titer scale) between the highest mean and the other means, assuming log10 variability of 0.5.
These calculations assume in the first phase there are n1=22 evaluable subjects in the four candidate
groups, two groups are eliminated after the first phase, there are n2=112 additional evaluable subjects
in the remaining two candidate groups at D43 of second phase (n1 + n2=134), and µ4> µ1= µ2= µ3.
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Table 8. Power to select the candidate with the highest true mean to progress to second phase
and overall for the Phase 1/2 overall by minimum fold-difference between the highest candidate
mean and the other means, assuming log10 variability of 0.5.
Fold-difference Phase 1 down-
selection power
Power for overall
Phase 1/2
1.1
62% 
46% 
1.2
73% 
66% 
1.3
82% 
78% 
1.4
87% 
86% 
1.5
91% 
91% 
1.6
94% 
94% 
1.7
96% 
96% 
1.8
98% 
98% 
1.9
99% 
99% 
2.0
99% 
99% 
10.4. Definitions of Populations to be Analyzed
10.4.1. Enrolled Population
All subjects who provide written informed consent, regardless of the subject’s screening,
randomization, and treatment status in the study.
10.4.2. Exposed Population
All subjects in the enrolled population who were randomized and received at least one vaccination
dose (i.e., were accrued).
10.4.3. Safety Analysis Population
All subjects in the exposed population for whom any safety data is available. All safety analyses will
be performed using this population. The denominators for different safety endpoints may vary
according to the number of subjects with available data for the specific endpoint. For instance, the
solicited local and systemic adverse event endpoint will be based only on those who have the
corresponding CRF data regardless of other safety data. Treatment groups for safety analysis will be
assigned according to the actual treatment received.
10.4.4. Full Analysis Population
All subjects in the exposed population for whom any post-study product administration
immunogenicity results are available. An immunogenicity analysis will also be performed using this
population.
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10.4.5. Per Protocol Population
All subjects in the exposed population who have no major protocol deviations that are determined to
potentially interfere with the immunogenicity assessment of the study product.
This population will serve as the primary analysis population for the immunogenicity endpoints. The
population will be adapted by time point to include all eligible subjects’ data up to the time of
disqualifying protocol deviation. The criteria (e.g., intake of prohibited medication expected to
influence the immune response) for exclusion of subjects from the per protocol population, and
determination of any exclusions based on a blinded review of the data, will be established before
database freeze and lock for both interim and final analyses, respectively.
10.5. Analysis Sequence and Analytical Methodology
Interim analyses will be performed after the last subject in the first phase has completed Visit 6 (Day
57) assessments and all the results are available. At the time of the interim analysis safety results
(unblinded to the DSMB only) and immunogenicity results (unblinded at group level only) will aid in
the selection of formulations to evaluate in the second phase of the study. Appendix 6 is a template of
the interim study report that will be generated based on this analysis.
A second interim analysis will be performed after the last subject has completed Visit 6 (Day 57)
assessments and all the results are available. The second interim analysis of immunogenicity and
safety endpoints will aid in the selection of a formulation to be evaluated in a future Phase 3 trial.
A final analysis on all safety and immunogenicity data will be performed after the study ends, when
all additional safety and immunogenicity data have been collected following the last subject’s last
study visit (Visit 8, Day 365), and the database is cleaned and locked. Detailed statistical procedures,
listings, table shells, and figures will be provided in a separate statistical analysis plan (SAP) which
will be finalized prior to the interim analyses.
Unless otherwise specified, all statistical test will be two-sided with a significance level of 0.05. A
95% CI will be provided for estimates, as appropriate. All statistical analyses will be performed using
SAS® software version 9.4 or later.
10.5.1. Analysis of Demographic and Baseline Characteristics
Baseline demographics and characteristics, including age, height, weight, sex, race ethnicity, and
BMI will be summarized for both the exposed and per protocol populations by treatment group using
descriptive statistics (mean, standard deviation, median, 25th and 75th quartiles, minimum and
maximum for continuous and rates for categorical).
For the exposed population, medical history will be listed and summarized by category. Using the
WHO Drug Dictionary, concomitant medications will be tabulated by anatomical therapeutic
chemical (ATC) classification, preferred drug name and treatment group. Medical history will be
tabulated by MedDRA System Organ Class (SOC), Preferred Term (PT) and treatment group.
Summaries of subject disposition will be prepared for all subjects, including the number and percent
enrolled, screened, randomized, and administered study product, as well as a CONSORT diagram
describing study participation and discontinuation. The reasons for screen failures and
discontinuations will be summarized and listed.
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A summary and listing of visit attendance will be prepared, in addition to a summary and listing of
study product administration and sample collection/availability for each sample.
10.5.2. Analysis of Primary Objectives
All safety assessment will take place in the safety analysis population, according to the treatment
received. All subject-level percentages (solicited/unsolicited AEs, clinical safety laboratory
abnormalities, etc.) will be supplemented with two-sided 95% CIs computed via the Clopper-Pearson
method. Individual summaries (denominators for percentages) will be limited to the number of
subjects with the appropriate analysis population with the data available for analysis for the given
endpoint. Summaries will be provided overall by group and by stage and age strata.
Solicited local and systemic adverse events: All solicited AEs will be summarized according to
defined severity grading scales. Frequencies and percentages of subjects experiencing each solicited
AE will be presented for each symptom severity. Summary tables showing the occurrence of any
local or systemic solicited AE during the first 7 days after each administration of study product.
Data listings of all solicited AEs will be provided by subject. For common AEs group comparisons
may be explored.
Clinically significant hematological and biochemical measurements: For clinical safety laboratory
data collected at screening and 7 days post-first administration of study product (Visit 2, Day 8) and
post-second administration of study product (Visit 4, Day 36), individual Hgb, WBC count, Plt, AST,
ALT, total bilirubin, and creatinine values will be presented as number of subjects out of range
(above and below normal range as appropriate) and tabulated by toxicity grading, relatedness, and
study group. In addition, changes from baseline (median/interquartile range) will be presented.
Unsolicited AEs: All unsolicited AEs with onset occurring during the first 28 days following study
product administration will be assessed for severity and as either related or not related to study
product by the investigator.
MAAEs and SAEs: All MAAEs and SAEs through Visit 8 (Day 365) will be recorded and the
number, severity, and relatedness to study product will be summarized. Subject-wise data listing will
be provided.
When an AE occurs more than once for a subject, the subject will be only counted once for the
corresponding PT according to the maximum severity of the events. A summary table will be
prepared for unsolicited AEs comprised of the following categories:
·
Unsolicited AEs
·
Related unsolicited AEs
·
MAAEs
·
Related MAAEs
·
SAEs
·
Related SAEs
·
SAEs leading to death
·
Unsolicited AEs leading to subject discontinuation
Adverse events of special interest: The number, severity, and relatedness of adverse events of special
interest (AESI), including
·
PIMMC
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·
AEs specific to COVID-19
will be summarized and provided in subject-wise data listings.
10.5.3. Analysis of Secondary Objectives
The analysis of immunogenicity will be performed on the per protocol population as the primary
analysis and the full analysis population as a secondary analysis. Analyses described below will be
summarized in the interim analyses for all subjects included in the first phase of the study. In the
second interim and final analyses, the candidates that advanced to the second phase will be
summarized by phase, age group (18-59 years and 60-75 years), and overall. Relative endpoints
derived from GMFR will include all subjects from the per protocol population. Absolute endpoints
such as those derived from the GMT will exclude baseline seropositive subjects.
Immunogenicity data will be descriptively analyzed. For estimation of the GMT, GMT ratio, and
corresponding confidence limits, analyses will incorporate censoring where appropriate and age-
adjusted log-scale coefficients will be back-transformed in order to compute the estimate and
corresponding confidence limits for the relevant quantity. GMFRs will be computed using age-
adjusted estimates of the log difference of the paired samples, with corresponding CIs computed via
the t-distribution, utilizing the antilog transformation to present the ratio. Analyses of binary
variables will include 95% CIs computed via the Clopper-Pearson method. Additionally, the
distribution of the titers will be summarized using reverse cumulative distribution curves.
NAb titers against SARS-CoV-2 pseudovirus will be measured by pseudovirus-based neutralization
assay and summarized at baseline, 28 days after the first vaccination, and 14 days, 6 months and 12
months after the second study injection overall and by age group (18-59 years and 60-75 years) with:
·
GMT with 95% CIs (including baseline),
·
GMFR from baseline with 95% CI, and
·
Percentage of subjects with NT50 and NT80 seroresponses against SARS-CoV-2
pseudovirus at 28 days after the first vaccination, and 14 days, 6 months and 12
months after the second vaccination as defined by
o a ≥ 4-fold increase from baseline, and
o a ≥ 10-fold increase from baseline.
Anti-S IgG antibody titers will be measured by ELISA and summarized at baseline, 28 days after the
first vaccination, and 14 days, 6 months and 12 months after the second study injection overall and by
age group (18-59 years and 60-75 years) with:
·
GMTs with 95% CIs (including baseline),
·
GMFR from baseline with 95% CI, and
·
Percent of subjects with IgG seroresponses and 95% CI of
o ≥ 4-fold increase from baseline
o ≥ 10-fold increase from baseline
10.5.4. Analysis of Exploratory Objectives
The S protein-specific T cell response elicited by each of two selected COVIVAC formulations will
be measured via ELISpot assay at baseline, 14 days, and 6 months after the second vaccination in a
subset of subjects enrolled in the second phase of the study. The magnitude, phenotype, and cytokine-
expressions pattern of S protein-specific T cells will be descriptively analyzed by timepoint (absolute
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and relative to baseline) by study arm. The anti-NDV HN IgG immune response elicited by each
formulation of COVIVAC will be measured by ELISA, at baseline, 28 days after the first
vaccination, and 14 days and 12 months after the second vaccination, in subjects enrolled in the
second phase of the study, and be summarized with GMTs with 95% CIs.
Other exploratory assays to characterize the immune response to COVIVAC may also be performed.
Details of all exploratory analyses will be described in the SAP.
10.6. Multiplicity
As the two-stage selection design relies on ranking of GMTs, not testing of differences between
candidate groups, no adjustment for multiplicity will be performed.
10.7. Handling of Subject Discontinuations and Missing Data
Missing immunogenicity data will not be imputed and will be analyzed as if they were randomly
missing. Over the study period, the frequency and percentage of subjects who discontinue from the
study will be provided by treatment group. All subjects who discontinue post-randomization will be
further described regarding their time to and their reasons for discontinuation. For subjects who
discontinue from the study, their data collected before discontinuation will be analyzed under the
analysis populations as applicable.
11. LABORATORY EVALUATIONS
11.1. Blood Sample Collection, Distribution, and Storage
Venous blood samples obtained for clinical laboratory tests will be processed and labeled at the site,
and sent to the lab of HMU’s hospital. Blood samples obtained to evaluate secondary
immunogenicity objectives will be processed, and serum samples aliquoted, labeled, and stored
at -70°C in freezers, as per instructions provided in the Laboratory Manual, before being tested at
Nexelis (Quebec, Canada). All stored serum samples will be logged into a secure database.
The volume of blood required for the different categories of assays at different visits are
shown in Table 9.
Table 9.
Blood Volume Requirements
Lab Panels
Tests
Hematologya:
WBC, hgb, plts
Viral Serology:
HBsAg, HCV Ab
Chemistrya:
creatinine, AST,
ALT, t bili
Humoral
Immunity:
Screen
Visit 1
2.5 mL
-
2 mL
-
1.5 mL
-
-
10 mL
Visit 2
Visit 3
2.5 mL
-
-
-
1.5 mL
-
-
10 mL
Visit 4
Visit 5
Visit 6
2.5 mL
-
-
-
-
-
1.5 mL
-
-
-
10 mL
-
Visit 7
Visit 8
-
-
-
-
-
-
10 mL
10 mL
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Lab Panels
Tests
PNA, ELISAs
CMI:*
ELISpot
Total Volume
(+ CMI)
Screen
Visit 1
Visit 2
Visit 3
-
16 mL
-
-
6 mL
10 mL
4 mL
10 mL
(26 mL)
Visit 4
Visit 5
-
16 mL
4 mL
10 mL
(26 mL)
Visit 6
-
-
Visit 7
Visit 8
16 mL
-
10 mL
10 mL
(26 mL)
a Only in Phase 1
* Subset of subjects in Phase 2
11.2. Safety Clinical Laboratory Assays
Protocol-mandated screening and clinical safety laboratory tests will be performed at the clinical
laboratory of HMU’s hospital, which is certified with International Organization for Standardization
(ISO) 15189.
If clinically significant abnormalities are identified during screening, subjects will be referred for
further medical management. If identified during the study, subjects may be asked to return to the
study clinic for further evaluation, including clinical evaluation and repeat laboratory testing as
warranted.
11.3. Immunological Assays (Secondary Objectives)
Assays to evaluate secondary immunogenicity objectives will be performed at Nexelis, as follows:
SARS-CoV-2 pseudovirus neutralization assay (PNA)
The PNA will be used to quantify the functional humoral immune response against SARS-CoV-2 by
measuring the 50% and 80% neutralizing titer (NT50 and NT80) against a SARS-CoV-2 pseudovirus.
The pseudotyped virus particles are made using a genetically modified Vesicular Stomatitis Virus that
expresses the wild-type spike protein of SARS-CoV-2 (Wuhan strain) and contains a luciferase reporter
which can be quantified in relative luminescence units (RLU). NT50 and NT80 are determined based on
the dilution of serum required to achieve 50% and 80% reduction in RLU value compared to
pseudoparticle control. The assay has been qualified.
SARS-CoV-2 pre-fusion Spike IgG ELISA
The ELISA assay detects IgG antibodies to the full-length pre-fusion spike protein of SARS-CoV-2.
Serum antibody content is expressed in ELISA Units (ELU)/ml. The assay has been validated.
At the completion of all the testing, the samples will be either destroyed or stored at an appropriate
place in a designated freezer at Nexelis or at a Sponsor-designated facility. The Sponsor will be
responsible for the oversight of sample storage and destruction.
11.4. Microbiological Assays
Nasal/pharyngeal swabs will be collected from subjects who experience signs and/or symptoms of
COVID-19 that are of sufficient severity to warrant testing for SARS-CoV-2 infection. The testing
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will be performed at the Laboratory of virus transmitted from animal to human, Virus Lab
Department of NIHE, a CLIA-certified diagnostics laboratory, using a singleplex RT-PCR assay. In
addition to detecting presence of virus, the assay also provides the PCR cycle threshold (Ct) value,
which may be used as an estimate of viral load. When swabs are received at the laboratory, they will
be processed and then divided into two aliquots. The first aliquot will be used to test for presence of
SARS-CoV-2, with results available on the day the swab was received. The second aliquot will be
stored in a designated freezer for possible additional testing, including for other respiratory viral
pathogens if judged to be helpful in the clinical management of individual cases.
11.5. Assay Qualification, Standardization, and Validation
Assays employed to evaluate the primary safety laboratory endpoint have been properly validated and
will be run with adequate controls. Immunological assays have been validated, or qualified, and are
run with adequate controls.
11.6. Biohazard Containment
As transmission of blood-borne pathogens can occur through contact with contaminated needles,
blood, and blood products, appropriate blood and secretion precautions will be employed by all
personnel in the drawing of blood and handling and shipping of all specimens for this study, as
recommended by the US Centers for Disease Control and Prevention. All dangerous goods materials,
including diagnostic specimens and infectious substances, must be transported according to
instructions detailed in the International Air Transport Association (IATA) Dangerous Goods
Regulations. Biohazardous waste will be contained according to institutional, transportation/carrier,
and all other applicable regulations.
12. DATA MANAGEMENT
The Sponsor-designated CRO’s study monitors will visit the site at regular intervals, as per the
Monitoring Plan, and perform pre-agreed source data verification of the data recorded in the
electronic data capture (EDC) system against the source documents available at the site. In addition,
missing data forms and fields will be queried by daily electronic edit checks or through manual edit
checks of the data by the data management team. Study monitors will closely evaluate pre-screening
data, inclusion/exclusion criteria, informed consents, data entry timeliness, and visit dates and
windows to ensure integrity of the study is maintained.
Any data discrepancies generated by the system will be flagged in the EDC system for the site staff
to provide a satisfactory resolution within the EDC system. The data management team will review
all the data discrepancy responses by the site to ensure the correctness of data. The medical history
events and the AEs will be coded using MedDRA dictionary version 21.1 or later and the
concomitant medications will be coded using the WHO Drug Dictionary. After completion of data
coding and resolution of all the queries in the database, the database will be declared to be complete
and accurate and will be locked for final statistical analysis of primary and secondary endpoints.
12.1. Case Report Form Development and Completion
Based on the final protocol of the study, a comprehensive set of CRFs will be prepared to capture all
the relevant data required for analysis and reporting. This study will utilize an EDC system such that
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the entire study data can be maintained in a secure electronic system. No written or electronic data
recorded prior to the study will be included in the CRFs or EDC system respectively.
All study data will be collected by the clinical study staff using designated source documents and will
be entered in the EDC system in an anonymized form. The study database will identify study subjects
only by unique study identification numbers through screening (subject ID) and randomization
assignments (randomization ID) and will not contain any identifying information such as name,
address or personal contact information, or any other regional/state/national identification number.
CRFs will be reviewed by the clinical team who are responsible for ensuring that they are accurate
and complete.
The data management activities will be performed as per the CRO’s SOPs. The appropriately trained
site personnel will ensure that the study data recorded in the EDC system is verifiable with the source
documents available at the site. To ensure that data are entered in a timely fashion so as to monitor
safety of the study, it is expected that the site will maintain data entry with a minimal expectation of
three business days from subject clinic visit. The study monitor plan will include assessments of data
entry timeliness.
The study site will maintain the source documents for each study subject. The source documents and
other supporting documents will be kept in a secure location. Source documentation will be available
for review by the study monitor to ensure that the collected data are consistent with the CRFs.
12.2. Record Archival
12.2.1. Archiving Data at Study Site
The study site will maintain appropriate medical and research records for this trial, in compliance
with ICH GCP, regulatory, sponsoring organization and institutional requirements for the protection
of confidentiality of subjects. The site will permit authorized representatives of the Sponsor and
regulatory agencies to examine (and when required by applicable law, to copy) clinical records for the
purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. After
completion of data coding and resolution of all the queries in the database, the database will be
declared to be complete and accurate and will be locked for final statistical analysis and made
available to the Sponsor for long-term storage in a master file.
12.2.2. Data Storage and Archival
The study monitor will provide the PI with an Investigator Site File, which will be used to file the
investigator’s brochure (IB), protocol, drug accountability records, correspondence with the EC,
Sponsor, CRO, and other study-related documents. The PI/designee will maintain, and store
securely, complete, accurate and current study records throughout the study.
As required by ICH GCP guidelines, the PI will keep essential documents until at least two years
after the last approval of a marketing application in an ICH region, and until there are no pending or
contemplated marketing applications in an ICH region, or at least two years have elapsed since the
formal discontinuation of clinical development of the study product. These documents should be
retained for a longer period, however, if required by the applicable regulatory requirements or by an
agreement with the Sponsor. The documents will be archived either at Clinical Trial Center at NIHE
or at any other secure location as agreed upon with the Sponsor. It is the responsibility of the Sponsor
to inform the PI/institution as to when these documents no longer need to be retained. Subjects’
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medical records and other original data will be archived in accordance with the local regulations or
facilities of the investigational site.
12.3. Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on Clinicaltrials.gov.
12.4. Confidentiality
Documented evidence that the PI is aware and agrees to the confidential nature of the information
related to the study must be obtained by means of a confidentiality agreement.
All information provided by the Sponsor and all data and information generated by the site as part of
the study (other than a subject’s medical records) will be kept confidential by the PI and other site
staff. This information and data will not be used by the PI or other site personnel for any purpose
other than conducting the study.
12.5. Publication
IVAC will work with the PI and other relevant personnel at NIHE on the publication of the complete
Phase 1/2 study outlined in this protocol in a timely fashion. Primary publication of the trial results
will be shared between the NIHE and IVAC. Other individuals having input into the study justifying
authorship will similarly be included in publication(s). Additional publications resulting from the
analysis of the study data will be agreed between IVAC and the NIHE on a case-by-case basis but
will generally include authors from both organizations. IVAC will be acknowledged in all
publications as the Sponsor of the trial.
If a written contract for the conduct of the study, which includes publication provisions inconsistent
with this statement, is executed between IVAC and the study site, that contract’s publication
provisions shall apply rather than this statement.
13. QUALITY ASSURANCE AND QUALITY CONTROL
13.1. General Considerations
The study will be conducted in full compliance with the protocol and ICH GCP to provide public
assurance that the rights, safety, and well-being of study subjects are protected, and that the clinical
study data are credible. To ensure quality and standardization, the site will develop SOPs for key
protocol procedures and conduct the study guided by the study and applicable site SOPs and other
written guidelines. The site will also develop routine operational checks to verify that critical protocol
requirements and procedures are executed correctly and completely at the time the work is being
performed. Prior to study initiation, the Sponsor and the designated CRO will conduct training on the
protocol and applicable SOPs for the study staff.
The investigational site will provide direct access to all study-related documents, source
data/documents, and reports for monitoring and auditing by the Sponsor, and inspection by regulatory
authorities.
13.2. External Monitoring
Sponsor monitoring responsibilities will be provided by the CRO. A site initiation visit will be
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conducted prior to beginning the study, and monitoring will be conducted at initiation, during, and at
closeout of the study by the study monitor or designee.
During the course of the study, the monitor will assess site activities at intervals to verify compliance
to the protocol; completeness, accuracy, and consistency of the data and study product accountability;
adherence to protocol and regulatory obligations; and to ensure that conduct of the research follows
GCP. The extent and frequency of the monitoring visits will be described in a separate Clinical
Monitoring Plan developed prior to study initiation. The monitor should have access to subject
medical records, study product accountability and other study-related records needed to verify the
entries on the CRFs.
The PI and the monitor will cooperate to ensure that any problems detected in the course of these
monitoring visits, including EDC completion and query resolution, are resolved in a predefined time
frame described in the Clinical Monitoring Plan.
To ensure the quality of clinical data for all subjects, a clinical data management review will be
performed on subject data received by the CRO. 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 GCP. To resolve any questions arising from the clinical data
management review process, data queries and/or site notifications will be sent to the site for
resolution as soon as possible and within the time frame described in the Clinical Monitoring Plan; all
queries must be resolved prior to database lock.
13.3. Independent Auditing
Sponsor representatives may audit the study to ensure that study procedures and data collected
comply with the protocol and applicable SOPs of the site and the CRO, and that data are correct and
complete. The PI will permit auditors (employees of the Sponsor or an external company designated
by the Sponsor) to verify source data validation of the regularly monitored clinical study. The
auditors will compare the entries in the CRFs with the source data and evaluate the study site for its
adherence to the clinical study protocol and GCP guidelines and applicable regulatory requirements.
13.4. Regulatory Agency Auditing
The PI must be aware that representatives from regulatory authorities may wish to inspect the CRFs
and associated study records. The PI will notify the Sponsor within 24 hours following contact by a
regulatory agency. The PI will make the relevant records available for inspection and will be
available to respond to reasonable requests and audit queries made by authorized representatives of
regulatory agencies. The PI will provide the Sponsor with copies of all correspondence that may
affect the review of the current study or her/his qualification as PI in clinical studies conducted by the
Sponsor. The Sponsor will provide any needed assistance in responding to regulatory audits or
correspondence.
14. OBLIGATIONS AND ROLES OF THE SPONSOR, PI, AND STUDY PERSONNEL
This study will be conducted according to GCP as well in accordance with Ministry of Health
regulations. The Sponsor will assure the trial is conducted in compliance with the protocol, GCP, and
regulatory authority requirements. The Sponsor will provide the PI with the funding and information
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needed to conduct the trial properly, ensuring proper monitoring of trial activities, and that the trial is
conducted in accordance with the general investigational plan and protocol contained in the
submissions to the regulatory authorities. The Sponsor will ensure that the PI and regulatory
authorities are immediately informed (within 24 hours of the Sponsor becoming aware) of significant
new adverse effects or risks with respect to the study vaccine. The Sponsor will ensure that they will
be immediately informed (within 24 hours of awareness) of any other safety concerns which could
influence decisions regarding informed consent, enrollment and vaccination in this trial.
The PI agrees to perform the research in strict accordance with this protocol, the ICH GCP (E6), as
well as in conformity with local regulations regarding the conduct of clinical studies (see Statement of
Compliance).
In addition, the PI will follow local and institutional requirements including, but not limited to,
investigational vaccines, clinical research, informed consent and ethics regulations. The Sponsor will
provide notification to the PI of protocol and amendment approvals by regulatory authorities when
applicable. Any modifications to the research protocol, the ICF, and/or change in PI will be
submitted for review and approval to regulatory authorities per their guidelines. The PI may deviate
from the protocol without prior approval only when the deviation is necessary to eliminate an
apparent immediate hazard to the study subject.
While the PI may delegate study duties to appropriate study personnel, the PI is ultimately
responsible for the conduct of all aspects of the study.
15. ETHICAL CONSIDERATIONS AND INFORMED CONSENT
The study will be performed in accordance with SOPs generated and agreed between the Sponsor-
designated CRO and the PI. The CRO has the responsibility for ensuring the site has the appropriate
SOPs to perform the study and the authority to defer to the site SOP rather than the CRO SOP when
appropriate. These SOPs have been developed in accordance with ICH Guidelines for GCP E6 R2
(2018), Directive 2001/20/EC, which are consistent with the Ethical Guidelines outlined in the
Declaration of Helsinki (2013), thus ensuring protection of the subjects. The study will commence
only after receipt of a favorable opinion from the EC listed in this protocol and Ministry of Health.
15.1. Ethical Review
Ethical review of this study for the clinical site will be jointly conducted by the Ministry of Health
IRBand NIHE EC. The Sponsor will enter into a reliance agreement with ECs for ethical review. The
PI is responsible for obtaining approval from the Ministry of Health IRBand NIHE EC, which will
review and approve the protocol, the informed consent form, and any recruitment materials
(advertising or informational material). This includes any modifications to these documents prior to,
or during the study. Any change to the protocol or informed consent form must be reviewed and
approved prior to implementation, except when necessary to eliminate apparent immediate hazard to
study subjects. In such a case, the change must be later documented in an amendment and reported to
the ECs as soon as possible. When a change involves only logistical or administrative aspects of the
study (e.g., change of a telephone number), formal EC approval may not be required, but such
amendments shall still be submitted to the ECs for information purposes, and the PI must provide the
Sponsor with written confirmation that such logistical or administrative amendments have been
submitted to the ECs. The PI will provide the Sponsor with a statement from the ECs confirming that
the ECs are organized and operates according to GCP and applicable laws and regulations. The PI is
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also responsible for obtaining continuing review throughout the duration of the study in accordance
with existing regulations
15.2. Informed Consent Process
Informed consent is a process that is initiated prior to the individual agreeing to participate in the
study and continues throughout the subject’s participation in the study. Before any study-
relatedactivities, the PI must ensure that the potential subject is fully informed about the objectives,
procedures, potential risks, and potential benefits of study participation.
Potential subjects will be provided with the EC-approved ICF, allowed ample time to read the
consent form, encouraged to ask questions about the study, have their questions answered and thenbe
given time to decide if they would like to participate in the study. If the subject is illiterate, there will
be a witness or legally appropriate representative attending the consent process to assure the subject is
properly consented. It will be emphasized that their participation is voluntary, and that they have the
right to decline to participate or to discontinue from the study at any time without giving any reason
and without compromising their other rights in any way.
The PI must obtain the subject’s voluntary, signed and dated ICF before any study-related procedures
are performed. Study staff must document the informed consent process. The original, signed ICF
must be kept in the site study file. A copy of the informed consent document will be given to the
subject for their records.
15.3. Study-Related Injury
IVAC will maintain product liability insurance to cover treatment for study-related injuries. IVAC
will also maintain employer liability insurance or shall self-insure, as necessary, to meet its liability
obligations under this protocol, as well as sufficient levels of all legally mandated insurance,
including (at a minimum) professional liability coverage for the investigator, trial team, and all other
employees, contractors, and agents providing services to this trial. As applicable, IVAC will maintain
insurance to cover any general liability and product liability to meet its obligations under Vietnam
law.
15.4. Risk/Benefit
There are certain symptoms and signs, systemic or injection site, which have historically
been associated with immunization, and if they do occur, usually are of mild or moderate intensity
and transient in nature. Consequently, in early clinical trials of investigational vaccines, these
symptoms and signs are typically considered as risks and are solicited as potential AEs in the first
week following immunization. In this trial, the solicited injection site AEs include pain,
tenderness, swelling or induration, and erythema. The solicited systemic AEs are fever, headache,
fatigue or malaise, myalgia, arthalgia, and nausea or vomiting. Since there may be unknown risks
associated with the COVIVAC vaccine, all subjects will be monitored for any unsolicited AEs for 28
days following study product administration and for any MAAEs or SAEs for the entire study period.
All subjects will also be monitored for specific AESI; these include potential immune-mediated
medical conditions, which may be associated with vaccination. In addition subjects will be closely
monitored for adverse events associated with COVID-19 to identify, and treat if indicated, potential
cases of COVID-19 during the trial, and to assess for possible vaccine-induced immune enhancement
of disease.
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CpG 1018 is the adjuvant used in HEPLISAV-B vaccine, which was licensed by the US FDA in
2018. HEPLISAV-B was well-tolerated and shown to have an adequate safety profile in clinical trials
in adults.49 Common adverse reactions from HEPLISAV-B included injection site pain, erythema,
and swelling, headache, malaise, myalgia, and fatigue. SAEs, autoimmune adverse events, and deaths
were infrequent in the HEPLISAV-B clinical program and similar in frequency between HEPLISAV-
B and the active comparator (Engerix-B). No deaths have been considered by the investigator to be
related to HEPLISAV-B. Interim analyses of an ongoing post-marketing study of over 30,000
HEPLISAV-B recipients and more than 35,000 active comparator recipients have raised no safety
concerns.
Hypersensitivity reactions may occur following the administration of any vaccine, including licensed
vaccines, which in rare circumstances may be life-threatening. All subjects will be informed in the
ICF of this possibility following study vaccine administration and will be observed for a minimum of
30 minutes following study vaccine administration. Appropriate emergency medical treatment will be
available in case of severe immediate reactions, such as anaphylaxis. Subjects with a known
hypersensitivity to any component of the study vaccine, or a history of hypersensitivity to any
vaccine, will be excluded from the study.
Blood drawing- and venipuncture-associated risks may include minor bleeding or bruising at the
venous access site, mild discomfort, upset stomach, dizziness, light-headedness, syncope, or very
rarely infection. Blood samples will only be drawn by trained staff members using aseptic technique,
and medical assistance will be available in case of any complications. Subjects will be informed of
these risks in the ICF and will be in a seated or supine position during blood draws.
No benefits can be guaranteed to subjects for their participation in this research study. Subjects who
participate in this study may benefit from the clinical assessments (e.g., medical history, physical
examination, and routine clinical safety laboratory tests) conducted at screening and during the
study, including the screening for infections. If the subject is found to have any newly diagnosed
medical condition or infection, the investigator will ensure that the subject is provided with
appropriate and adequate referrals within the health care system. The information gained from this
study may be useful in the development of a safe and effective vaccine to prevent COVID-19 for
which there is currently no licensed vaccine. Subjects may gain from knowing that they have been
involved in this development process. The known risks of participation in this study are believed to
be outweighed by the value of the information to be gained.
15.5. Subject Confidentiality
Every effort will be made to protect subject privacy and confidentiality. Personal identifiers will not
be included in any study reports. Medical records containing identifying information will be made
available for review when the study is monitored by the Sponsor or an authorized regulatory agency.
Direct access may include examining, analyzing, verifying, and reproducing any records and reports
that are important in the evaluation of the study.
All study-related information will be stored securely at the study site. All subject information will be
stored in locked file cabinets in areas with access limited to study staff. Data collection, process, and
administrative forms, and other reports will be identified only by a unique trial-related subject
identification code (subject/randomization ID) to maintain subject confidentiality. Laboratory reports
may include the name and date of birth of the subject to minimize the risk of errors in the busy
clinical laboratories. All local databases will be secured with password-protected access systems.
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Forms, lists, logbooks, appointment books, and any other listings that link subject ID numbers to
other identifying information will be stored in a separate, locked file in an area with limited access.
Subjects’ study information will not be released without their written permission, except as necessary
for monitoring, or as required/permitted by law/regulatory authorities.
15.6. Reimbursement
Pending EC approval, subjects will be compensated for their time and effort in this study. The study
ICF will state the plan for reimbursement. Subjects will not be charged for study injections, research
clinic visits, research-related examinations, or research-related laboratory tests.
15.7. Storage of Specimens
Stored study research samples will be labeled by a code that only the study site can link to the study
subject. All stored research samples will be logged into a secure database and any use documented.
Samples may be stored at the clinical sites and laboratories included in the contact cover page of this
protocol, to complete the analyses required to meet study primary, secondary and exploratory
analyses. As a part of the informed consent process, subjects will be informed of and asked to agree
to long-term storage of specimens for use in future, related research.
When samples are no longer needed for the purposes of the study, they will be kept or destroyed,
depending on whether subjects consent to remaining samples being used in future research. Their use
will be governed by a repository plan that is mutually agreeable to the Sponsor and NIHE. No genetic
testing will be done on the samples.
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16. APPENDICES
16.1.
Appendix 1: Solicited Injection Site and Systemic Reactions Toxicity Grading Table
Reaction to
Injectable
Product
Pain/
Tenderness
Erythemaa
Swelling/
Indurationa
Temperature
(oral)
Headache
Fatigue/
Malaise
Myalgia
Arthralgia
Nausea/
Vomiting
Mild
(Grade 1)
Does not
interfere with
activity
2.5 – 5 cm
2.5 – 5 cm and
does not
interfere with
activity
38.0 – 38.4°C
100.4 –
101.1°F
No interference
with activity
No interference
with activity
No interference
with activity
No interference
with activity
No
interference
with activity
Moderate
(Grade 2)
Some interference
with activity OR
Repeated use of non-
narcotic pain reliever
> 24 hours
5.1 – 10 cm
5.1 – 10 cm OR
Interferes with
activity
38.5 – 38.9°C
101.2 – 102.0°F
Some interference
with activity OR
Repeated use of
nonnarcotic pain
reliever >24 hours
Some interference
with activity
Some interference
with activity
Some interference
with activity
Some interference
with activity
Severe
(Grade 3)
Significant; prevents
daily activity OR
Any use of narcotic
pain reliever
> 10 cm and/or
ulceration OR
secondary infection
OR phlebitis OR
sterile abscess OR
drainage
> 10 cm OR prevents
daily activity and/or
ulceration OR
secondary infection
OR phlebitis OR
sterile abscess OR
drainage
39.0 – 40°C
102.1 – 104°F
Significant; prevents
daily activity OR
Any use of
narcotic pain reliever
Significant; prevents
daily activity
Significant; prevents
daily activity
Significant; prevents
daily activity
Prevents daily activity
OR Requires
outpatient IV
hydration
Potentially Life
Threatening
(Grade 4)
Emergency room
(ER) visit or
hospitalization
Necrosis or
exfoliative dermatitis
Necrosis
> 40°C
> 104°F
ER visit or
hospitalization
ER visit or
hospitalization
ER visit or
hospitalization
ER visit or
hospitalization
ER visit or
hospitalization for
hypotensive shock
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a For erythema and swelling/induration, longest diameter should be noted in centimeters. Swelling/induration
should be evaluated and graded using the functional scale as well as the actual measurement.
The grading scales for local and systemic AEs have been derived from Guidance for Industry, Toxicity
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials,
U.S. Department of Health and Human Services, FDA, CBER, September 2007(
https://www.fda.gov/media/73679/download) and the Division of AIDS (DAIDS) Table for Grading the
Severity of Adult and Pediatric Adverse Events (Version 2.1, July 2017) from the US NIH
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf).
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16.2.
Appendix 2: Vital Signs Toxicity Grading Table
Vital Signsa
Tachycardia – beats per
minute
Bradycardia –beats per
minuteb
Hypertension (systolic)
– mm Hg
Hypertension (diastolic)
– mm Hg
Hypotension (systolic)
– mm Hg
Respiratory Rate –
breaths per minute
Mild
(Grade 1)
101 – 115
50 – 54
141 – 150
91 – 99
85 – 89
21 – 23
Moderate
(Grade 2)
116 – 130
45 – 49
151 – 165
100 – 105
80 – 84
24 – 27
Severe
(Grade 3)
> 130
< 45
> 165
> 105
< 80
> 27
Potentially Life Threatening
(Grade 4)
Hospitalization for arrhythmia
ER visit or hospitalization for
arrhythmia
ER visit or hospitalization for
malignant hypertension
ER visit or hospitalization for
malignant hypertension
ER visit or hospitalization for
hypotensive shock
Intubation
a Subject should be at rest for all vital sign measurements.
b Grade 1 bradycardia or grade 1 tachypnea will not be considered an abnormality for this study, unless judged
to be clinically significant by the PI in consultation with the Sponsor
The grading scales for abnormal vital signs have been derived from Guidance for Industry, Toxicity Grading
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S.
Department of Health and Human Services, FDA, CBER, September 2007.
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16.3. Appendix 3: Serum and Hematology Toxicity Grading Table
Serum
Creatinine
(mg/dL)
Liver function tests
– AST, ALT
increased
Total bilirubin
Hematology
Hemoglobin
[Female]
(g/dL)
Hemoglobin
[Male]
(g/dL)
OR
Hemoglobin,
change from
baseline value
(g/dL)
WBC, increased
(cell/mm3)
WBC, decreased
(cell/mm3)
Platelets, decreased
(cell/mm3)
Mild
(Grade 1)
1.1 – 1.3 x ULN
1.25 – < 2.5 x ULN
1.1 – < 1.6 x ULN
Mild
(Grade 1)
11.0 – 12.0
12.5 – 13.5
1.0 – 1.5
10,800 – 15,000
2,500 – 3,400
100,000 – <125,000
Moderate
(Grade 2)
> 1.3 – 1.8 x ULN
OR increase of
> 0.3 above
baseline
2.5 – <5.0 x ULN
1.6 – < 2.6 x ULN
Moderate
(Grade 2)
9.5 – 10.9
10.5 – 12.4
1.6 – 2.0
15,001 – 20,000
1,500 – 2,499
50,000 – <100,000
Severe
(Grade 3)
> 1.8 – < 3.5 x
ULN OR increase
of
1.5 – < 2.0 x above
baseline
5.0 – < 10.0 x
ULN
2.6 – < 5.0 x ULN
Severe
(Grade 3)
8.0 – 9.4
8.5 – 10.4
2.1 – 5.0
20,0001 – 25,000
1,000 – 1,499
25,000 – < 50,000
Potentially Life
Threatening
(Grade 4)
≥ 3 .5 x ULN
OR increase of
> 2.0 x above
baseline
≥ 10.0 x ULN
≥ 5.0 x ULN
Potentially Life
Threatening
(Grade 4)
< 8.0
< 8.5
> 5.0
> 25,0000
< 1,000
< 25,000
Abbreviation: ULN = upper limit of normal range
Note: the laboratory values provided in this table serve as guidelines and are dependent upon institutional
normal parameters.
The grading scales for laboratory abnormalities have been derived from Guidance for Industry, Toxicity
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials,
U.S. Department of Health and Human Services, FDA, CBER, September 2007, and the Division of AIDS
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 2.1, July 2017) from
the US NIH.
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16.4. Appendix 4: Potential Immune-Mediated Medical Conditions (PIMMC)
Categories
Neuroinflammatory Disorders:
Musculoskeletal and Connective Tissue Disorders:
Vasculidities:
Gastrointestinal Disorders:
Hepatic Disorders:
Diagnoses
Acute disseminated encephalomyelitis (including
site specific variants: e.g., non-infectious
encephalitis, encephalomyelitis, myelitis,
myeloradiculomyelitis), cranial nerve disorders
including paralyses/paresis (e.g., Bell’s palsy),
generalized convulsion, Guillain-Barre syndrome
(including Miller Fisher syndrome and other
variants), immune-mediated peripheral
neuropathies and plexopathies (including chronic
inflammatory demyelinating polyneuropathy,
multifocal motor neuropathy and polyneuropathies
associated with monoclonal gammopathy),
myasthenia gravis, multiple sclerosis, narcolepsy,
optic neuritis, transverse myelitis, uveitis
Antisynthetase syndrome, dermatomyositis,
juvenile chronic arthritis (including Still’s disease),
mixed connective tissue disorder, polymyalgia
rheumatic, polymyositis, psoriatic arthropathy,
relapsing polychondritis, rheumatoid arthritis,
scleroderma (including diffuse systemic form and
CREST syndrome), spondyloarthritis (including
ankylosing spondylitis, reactive arthritis [Reiter's
Syndrome] and undifferentiated spondyloarthritis),
systemic lupus erythematosus, systemic sclerosis,
Sjogren’s syndrome
Large vessels vasculitis (including giant cell
arteritis such as Takayasu's arteritis and temporal
arteritis), medium sized and/or small vessels
vasculitis (including polyarteritis nodosa,
Kawasaki's disease, microscopic polyangiitis,
Wegener's granulomatosis, Churg–Strauss
syndrome [allergic granulomatous angiitis],
Buerger’s disease [thromboangiitis obliterans],
necrotizing vasculitis and anti-neutrophil
cytoplasmic antibody [ANCA] positive vasculitis
[type unspecified], Henoch-Schonlein purpura,
Behcet's syndrome, leukocytoclastic vasculitis)
Crohn’s disease, celiac disease, ulcerative colitis,
ulcerative proctitis
Autoimmune hepatitis, autoimmune cholangitis,
primary sclerosing cholangitis, primary biliary
cirrhosis
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Version: 1.0 dated February 05, 2021_ IVAC
Diagnoses
Renal Disorders:
Cardiac Disorders:
Skin Disorders:
Hematologic Disorders:
Metabolic Disorders:
Other Disorders:
Autoimmune glomerulonephritis (including
Immunoglobulin A nephropathy,
glomerulonephritis rapidly progressive,
membranous glomerulonephritis,
membranoproliferative glomerulonephritis, and
mesangioproliferative glomerulonephritis
Autoimmune myocarditis/cardiomyopathy
Alopecia areata, psoriasis, vitiligo, Raynaud’s
phenomenon, erythema nodosum, autoimmune
bullous skin diseases (including pemphigus,
pemphigoid and dermatitis herpetiformis),
cutaneous lupus erythematosus, morphoea, lichen
planus, Stevens-Johnson syndrome, Sweet’s
syndrome
Autoimmune hemolytic anemia, autoimmune
thrombocytopenia, antiphospholipid syndrome,
thrombocytopenia
Autoimmune thyroiditis, Grave’s or Basedow’s
disease, Hashimoto thyroiditisA, diabetes mellitus
type 1, Addison’s disease
Goodpasture syndrome, idiopathic pulmonary
fibrosis, pernicious anemia, sarcoidosis
ANew onset only
This list was derived from Tavares Da Silva F, De Keyser F, Lambert PH, Robinson WH, Westhovens R,
Sindic C. Optimal approaches to data collection and analysis of potential immune mediated disorders in
clinical trials of new vaccines. Vaccine. 2013 Apr 3;31(14):1870-6.
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
16.5. Appendix 5: Adverse Events Specific to COVID-19 Disease
Body System
Immunologic
Respiratory
Cardiac
Hematologic
Renal
Gastrointestinal
Neurologic
Dermatologic
Diagnoses
Enhanced disease following immunization
Multisystem inflammatory syndrome in children
(MIS-C)
Acute respiratory distress syndrome (ARDS)
Acute cardiac injury including:
• Microangiopathy
• Heart failure and cardiogenic shock
• Stress cardiomyopathy
• Coronary artery disease
• Arrhythmia
• Myocarditis, pericarditis
Coagulation disorder
• Deep vein thrombosis
• Pulmonary embolus
• Cerebrovascular stroke
• Limb ischemia
• Hemorrhagic disease
• Thrombotic complications
Acute kidney injury
Liver injury
Guillain Barré Syndrome
Anosmia, ageusia
Meningoencephalitis
Chilblain-like lesions
Single organ cutaneous vasculitis
Erythema multiforme
This listing is based on Safety Platform for Emergency Vaccines (SPEAC) D2.3 Priority List of
Adverse Events of Special Interest: COVID-19, V2.0 Date May 25, 2020.
https://brightoncollaboration.us/wp-content/uploads/2020/06/SPEAC_D2.3_V2.0_COVID-
19_20200525_public.pdf
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
16.6. Appendix 6: Template of interim study report for transition to Phase 2
1. Cover pages (according to the CSR template by MOH VN)
-
Study title, protocol number
-
Key individuals and institution involving the study.
-
Timeline for study implementation for Phase 1
2. Protocol synopsis
3. Brief Investigational plan
4. Study Participant disposition until D43
-
Enrollment/screening counts: total participants screened/enrolled/screen failures/Early
termination
-
Screening failure summary: illegible, withdrawn consent, study no longer for enrollment,
others.
-
Study progress: number of subject attending ICF/screening, V1/D1, V2/D8, V3/D29, V4/D36,
V5/D43, V6/D57 visits
-
Protocol deviations
5. Demographic and key baseline characteristics
6. Immunogenicity analysis till cutoff date
-
Humoral (functional) immune response
7. DSMB safety recommendation (unblinded)
8. Safety analysis till cutoff date (blinded)
-
Local solicited AEs
-
Systemic solicited AEs
-
Unsolicited AEs
-
SAEs
-
MAAEs
-
AESI
9. Discussion and recommendation of two selected doses for Phase 2
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Study Protocol: Version: 1.0 dated February 05, 2021_ IVAC
16.7. Appendix 7: References
1 Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in
China, 2019. N Engl J Med 2020.
2 WHO. Middle East respiratory syndrome coronavirus (MERS-CoV) MERS Monthly Summary, November
2019. https://www.who.int/emergencies/mers-cov/en/. Accessed 22 May 2020.
3 Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., et
al. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: implications
for virus origins and receptor binding. Lancet. 2020 02 22; 395(10224):565-574.
4 Johns Hopkins University & Medicine Coronavirus Resource Center. https://coronavirus.jhu.edu/map.html
Accessed 6 January 2020.
5 Cowling BJ, Ali ST, Ng TWY, et al. Impact assessment of non-pharmaceutical interventions against
coronavirus disease 2019 and influenza in Hong Kong: an observational study. Lancet Public Health.
2020;5(5):e279‐e288.
6 Mehtar S, Preiser W, Lakhe N, Bousso A, et al. Limiting the spread of COVID-19 in Africa: one size
mitigation strategies do not fit all countries Lancet Glob Health 2020 Published Online April 28, 2020
https://doi.org/10.1016/ S2214-109X(20)30212-6
7 Roberton T, Carter ED, Chou VB, et al. Early estimates of the indirect effects of the COVID-19 pandemic on
maternal and child mortality in low-income and middle-income countries: a modelling study [published online
ahead of print, 2020 May 12]. Lancet Glob Health. 2020;10.1016/S2214-109X(20)30229-1.
8 Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of
the SARS-CoV-2 Spike Glycoprotein. Cell. 2020;181(2):281‐292.e6.
9 Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected
Pneumonia. N Engl J Med. 2020;382(13):1199‐1207.
10 Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus Disease 2019 Case Surveillance – United
States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep 2020; 69:759.
11 Cheung KS, Hung IF, Chan PP, et al. Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus
Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis [published
online ahead of print, 2020 Apr 3]. Gastroenterology. 2020;S0016-5085(20)30448-0.
12 Levinson R, Elbax M, Ben-Ami R, Shasha D, Levinson T, Choshen G, Petrov K, Gadoth A, Paran Y,
Anosmia and dysgeusia in patients with mild SARS-CoV-2 infection. medRxiv 2020.04.11.20055483
13 Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019
(COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease
Control and Prevention [published online ahead of print, 2020 Feb 24]. JAMA. 2020;10.1001/jama.2020.2648.
14 Sutton D, Fuchs K, D'Alton M, Goffman D. Universal Screening for SARS-CoV-2 in Women Admitted for
Delivery. N Engl J Med. 2020;382(22):2163‐2164.
15 Peiris JS, Yuen KY, Osterhaus AD, Stöhr K. The severe acute respiratory syndrome. N Engl J Med.
2003;349(25):2431‐2441.
16 Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes
Among 5700 Patients Hospitalized With COVID-19 in the New York City Area [published online ahead of
print, 2020 Apr 22] [published correction appears in doi: 10.1001/jama.2020.7681]. JAMA.
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